Toward Evidence-Based Genetic Research on Lifelong Premature Ejaculation: A Critical Evaluation of Methodology

PubMed Central

2011-01-01

Recently, four premature ejaculation (PE) subtypes have been distinguished on the basis of the duration of the intravaginal ejaculation latency time (IELT). These four PE subtypes have different etiologies and pathogeneses. Genetic research on PE should consider the existence of these PE subtypes and the accurate measurement of the IELT with a stopwatch. Currently, three methods of genetic research on PE have been used. They differ in the investigated population, tool of measurement, study design, and variables of PE. From animal and human research, it is derived that the central serotonergic system "modulates" ejaculation, whereas the ejaculation (reflex) itself is probably not under direct influence of the serotonergic system, but rather under the influence of other neurotransmitter systems in the spinal cord. For genetic research on PE, it is important to take into account that the (serotonergic) modulation of the IELT is variable among men and may even be absent. This means that serotonergic genetic polymorphisms may only be found in men with PE who respond with an ejaculation delay treatment with a selective serotonin reuptake inhibitor. PMID:21344023

Investigating the Link between Molecular Subtypes of Glioblastoma, Epithelial-Mesenchymal Transition, and CD133 Cell Surface Protein

PubMed Central

Zarkoob, Hadi; Taube, Joseph H.; Singh, Sheila K.; Mani, Sendurai A.; Kohandel, Mohammad

2013-01-01

In this manuscript, we use genetic data to provide a three-faceted analysis on the links between molecular subclasses of glioblastoma, epithelial-to-mesenchymal transition (EMT) and CD133 cell surface protein. The contribution of this paper is three-fold: First, we use a newly identified signature for epithelial-to-mesenchymal transition in human mammary epithelial cells, and demonstrate that genes in this signature have significant overlap with genes differentially expressed in all known GBM subtypes. However, the overlap between genes up regulated in the mesenchymal subtype of GBM and in the EMT signature was more significant than other GBM subtypes. Second, we provide evidence that there is a negative correlation between the genetic signature of EMT and that of CD133 cell surface protein, a putative marker for neural stem cells. Third, we study the correlation between GBM molecular subtypes and the genetic signature of CD133 cell surface protein. We demonstrate that the mesenchymal and neural subtypes of GBM have the strongest correlations with the CD133 genetic signature. While the mesenchymal subtype of GBM displays similarity with the signatures of both EMT and CD133, it also exhibits some differences with each of these signatures that are partly due to the fact that the signatures of EMT and CD133 are inversely related to each other. Taken together these data shed light on the role of the mesenchymal transition and neural stem cells, and their mutual interaction, in molecular subtypes of glioblastoma multiforme. PMID:23734191

Integrative Analysis of Prognosis Data on Multiple Cancer Subtypes

PubMed Central

Liu, Jin; Huang, Jian; Zhang, Yawei; Lan, Qing; Rothman, Nathaniel; Zheng, Tongzhang; Ma, Shuangge

2014-01-01

Summary In cancer research, profiling studies have been extensively conducted, searching for genes/SNPs associated with prognosis. Cancer is diverse. Examining the similarity and difference in the genetic basis of multiple subtypes of the same cancer can lead to a better understanding of their connections and distinctions. Classic meta-analysis methods analyze each subtype separately and then compare analysis results across subtypes. Integrative analysis methods, in contrast, analyze the raw data on multiple subtypes simultaneously and can outperform meta-analysis methods. In this study, prognosis data on multiple subtypes of the same cancer are analyzed. An AFT (accelerated failure time) model is adopted to describe survival. The genetic basis of multiple subtypes is described using the heterogeneity model, which allows a gene/SNP to be associated with prognosis of some subtypes but not others. A compound penalization method is developed to identify genes that contain important SNPs associated with prognosis. The proposed method has an intuitive formulation and is realized using an iterative algorithm. Asymptotic properties are rigorously established. Simulation shows that the proposed method has satisfactory performance and outperforms a penalization-based meta-analysis method and a regularized thresholding method. An NHL (non-Hodgkin lymphoma) prognosis study with SNP measurements is analyzed. Genes associated with the three major subtypes, namely DLBCL, FL, and CLL/SLL, are identified. The proposed method identifies genes that are different from alternatives and have important implications and satisfactory prediction performance. PMID:24766212

Behavior in Prader-Willi syndrome: relationship to genetic subtypes and age.

PubMed

Dykens, Elisabeth M; Roof, Elizabeth

2008-09-01

Some behavioral features of Prader-Willi syndrome (PWS) are associated with the major genetic subtypes of this disorder. While most agree that those with maternal uniparental disomy (UPD) have a distinctive cognitive and psychiatric profile, findings are more controversial regarding possible differences among persons who vary in paternal deletion size. Caregivers of 88 persons with PWS aged 5 to 51 years (M = 22 years) were administered measures of problem behavior, compulsivity, hyperphagia, and adaptive skills. The sample was well characterized as having relatively large, Type I (n = 26) or smaller, Type II (n = 29) deletions, or UPD (n = 33). No significant behavioral differences were found between the Type I versus Type II deletion groups. Within each genetic subtype, however, differences emerged in how advancing age related to behavior. Although age did not emerge as a significant correlate of behavior in the Type II or UPD groups, in the Type I group age was consistently associated with lower problem behaviors, adaptive skills, and externalizing symptoms. Although differences between deletion subtypes were not found, significant within-subtype differences emerged in relationships between age and behavior. Negative associations between age and behavior in the Type I group only may relate to non-imprinted genes that are deleted in Type I but not Type II cases, including CYFIP1. Altered expression of CYFIP1 is seen in other developmental disabilities, including 15q disorders, and haploinsufficiency of CYFIP1 in Type I PWS cases may be associated with age-related phenotypic effects. Findings underscore the importance of a life-span perspective in phenotypic research.

Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia

PubMed Central

O’Connor, David; Enshaei, Amir; Bartram, Jack; Hancock, Jeremy; Harrison, Christine J.; Hough, Rachael; Samarasinghe, Sujith; Schwab, Claire; Vora, Ajay; Wade, Rachel; Moppett, John; Moorman, Anthony V.; Goulden, Nick

2018-01-01

Purpose Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics. Patients and Methods We used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups. Results MRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different (P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype–specific MRD values allowed more refined risk group stratification. Conclusion A single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse. PMID:29131699

Genetic recombination and Cryptosporidium hominis virulent subtype IbA10G2.

PubMed

Li, Na; Xiao, Lihua; Cama, Vitaliano A; Ortega, Ynes; Gilman, Robert H; Guo, Meijin; Feng, Yaoyu

2013-10-01

Little is known about the emergence and spread of virulent subtypes of Cryptosporidium hominis, the predominant species responsible for human cryptosporidiosis. We conducted sequence analyses of 32 genetic loci of 53 C. hominis specimens isolated from a longitudinally followed cohort of children living in a small community. We identified by linkage disequilibrium and recombination analyses only limited genetic recombination, which occurred exclusively within the 60-kDa glycoprotein gene subtype IbA10G2, a predominant subtype for outbreaks in industrialized nations and a virulent subtype in the study community. Intensive transmission of virulent subtype IbA10G2 in the study area might have resulted in genetic recombination with other subtypes. Moreover, we identified selection for IbA10G2 at a 129-kb region around the 60-kDa glycoprotein gene in chromosome 6. These findings improve our understanding of the origin and evolution of C. hominis subtypes and the spread of virulent subtypes.

Geographic distribution of hepatitis C virus genotype 6 subtypes in Thailand.

PubMed

Akkarathamrongsin, Srunthron; Praianantathavorn, Kesmanee; Hacharoen, Nisachol; Theamboonlers, Apiradee; Tangkijvanich, Pisit; Tanaka, Yasuhito; Mizokami, Masashi; Poovorawan, Yong

2010-02-01

The nucleotide sequence of hepatitis C virus (HCV) genotype 6 found mostly in south China and south-east Asia, displays profound genetic diversity. The aim of this study to determine the genetic variability of HCV genotype 6 (HCV-6) in Thailand and locate the subtype distribution of genotype 6 in various geographic areas. Four hundred nineteen anti-HCV positive serum samples were collected from patients residing in - the central part of the country. HCV RNA positive samples based on reverse transcriptase- polymerase chain reaction (RT-PCR) of the 5'UTR were amplified with primers specific for the core and NS5B regions. Nucleotide sequences of both regions were analyzed for the genotype by phylogenetic analysis. To determine geographic distribution of HCV-6 subtypes, a search of the international database on subtype distribution in the respective countries was conducted. Among 375 HCV RNA positive samples, 71 had HCV-6 based on phylogenetic analysis of partial core and NS5B regions. The subtype distribution in order of predominance was 6f (56%), 6n (22%), 6i (11%), 6j (10%), and 6e (1%). Among the 13 countries with different subtypes of HCV-6, most sequences have been reported from Vietnam. Subtype 6f was found exclusively in Thailand where five distinct HCV-6 subtypes are circulating. HCV-6, which is endemic in south China and south-east Asia, displays profound genetic diversity and may have evolved over a considerable period of time. (c) 2009 Wiley-Liss, Inc.

Functional Incompatibility between the Generic NF-κB Motif and a Subtype-Specific Sp1III Element Drives the Formation of the HIV-1 Subtype C Viral Promoter

PubMed Central

Verma, Anjali; Rajagopalan, Pavithra; Lotke, Rishikesh; Varghese, Rebu; Selvam, Deepak; Kundu, Tapas K.

2016-01-01

ABSTRACT Of the various genetic subtypes of human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and simian immunodeficiency virus (SIV), only in subtype C of HIV-1 is a genetically variant NF-κB binding site found at the core of the viral promoter in association with a subtype-specific Sp1III motif. How the subtype-associated variations in the core transcription factor binding sites (TFBS) influence gene expression from the viral promoter has not been examined previously. Using panels of infectious viral molecular clones, we demonstrate that subtype-specific NF-κB and Sp1III motifs have evolved for optimal gene expression, and neither of the motifs can be replaced by a corresponding TFBS variant. The variant NF-κB motif binds NF-κB with an affinity 2-fold higher than that of the generic NF-κB site. Importantly, in the context of an infectious virus, the subtype-specific Sp1III motif demonstrates a profound loss of function in association with the generic NF-κB motif. An additional substitution of the Sp1III motif fully restores viral replication, suggesting that the subtype C-specific Sp1III has evolved to function with the variant, but not generic, NF-κB motif. A change of only two base pairs in the central NF-κB motif completely suppresses viral transcription from the provirus and converts the promoter into heterochromatin refractory to tumor necrosis factor alpha (TNF-α) induction. The present work represents the first demonstration of functional incompatibility between an otherwise functional NF-κB motif and a unique Sp1 site in the context of an HIV-1 promoter. Our work provides important leads as to the evolution of the HIV-1 subtype C viral promoter with relevance for gene expression regulation and viral latency. IMPORTANCE Subtype-specific genetic variations provide a powerful tool to examine how these variations offer a replication advantage to specific viral subtypes, if any. Only in subtype C of HIV-1 are two genetically distinct transcription factor binding sites positioned at the most critical location of the viral promoter. Since a single promoter regulates viral gene expression, the promoter variations can play a critical role in determining the replication fitness of the viral strains. Our work for the first time provides a scientific explanation for the presence of a unique NF-κB binding motif in subtype C, a major HIV-1 genetic family responsible for half of the global HIV-1 infections. The results offer compelling evidence that the subtype C viral promoter not only is stronger but also is endowed with a qualitative gain-of-function advantage. The genetically variant NF-κB and the Sp1III motifs may be respond differently to specific cell signal pathways, and these mechanisms must be examined. PMID:27194770

Memory in Intellectually Matched Groups of Young Participants with 22q11.2 Deletion Syndrome and Those with Schizophrenia

ERIC Educational Resources Information Center

Kravariti, Eugenia; Jacobson, Clare; Morris, Robin; Frangou, Sophia; Murray, Robin M.; Tsakanikos, Elias; Habel, Alex; Shearer, Jo

2010-01-01

The 22q11.2 deletion syndrome (22qDS) and schizophrenia have genetic and neuropsychological similarities, but are likely to differ in memory profile. Confirming differences in memory function between the two disorders, and identifying their genetic determinants, can help to define genetic subtypes in both syndromes, identify genetic risk factors…

Genetic overlap between diagnostic subtypes of ischemic stroke.

PubMed

Holliday, Elizabeth G; Traylor, Matthew; Malik, Rainer; Bevan, Steve; Falcone, Guido; Hopewell, Jemma C; Cheng, Yu-Ching; Cotlarciuc, Ioana; Bis, Joshua C; Boerwinkle, Eric; Boncoraglio, Giorgio B; Clarke, Robert; Cole, John W; Fornage, Myriam; Furie, Karen L; Ikram, M Arfan; Jannes, Jim; Kittner, Steven J; Lincz, Lisa F; Maguire, Jane M; Meschia, James F; Mosley, Thomas H; Nalls, Mike A; Oldmeadow, Christopher; Parati, Eugenio A; Psaty, Bruce M; Rothwell, Peter M; Seshadri, Sudha; Scott, Rodney J; Sharma, Pankaj; Sudlow, Cathie; Wiggins, Kerri L; Worrall, Bradford B; Rosand, Jonathan; Mitchell, Braxton D; Dichgans, Martin; Markus, Hugh S; Levi, Christopher; Attia, John; Wray, Naomi R

2015-03-01

Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene. Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes. © 2015 American Heart Association, Inc.

Differences in behavioural phenotype between parental deletion and maternal uniparental disomy in Prader-Willi syndrome: an ERP study.

PubMed

Stauder, Johannes E A; Boer, Harm; Gerits, Rolf H A; Tummers, Anke; Whittington, Joyce; Curfs, Leopold M G

2005-06-01

Paternal deletion and maternal uniparental disomy are the principal genetic subtypes associated with Prader-Willi syndrome (PWS). Recent clinical findings suggest differences in phenotype between these subtypes. The present experimental study addresses this issue using a cognitive psycho-physiological setup. Behaviour and event-related brain activity (ERP) was recorded by a continuous performance response inhibition task (CPT-AX) in adults with paternal deletion PWS (n=11), maternal uniparental disomy PWS (n=11) and normal controls (n=11). The dependent behavioural variables of the CPT-AX task were reaction time and correct scores. For the ERPs the N200 and P300 components were included which are related to early modality-specific inhibition and late general inhibition, respectively. The disomy group had fewer correct scores and increased reaction times as compared to the CPT-AX task than the control and deletion group. Both PWS subgroups differed significantly from the control group for the N200 amplitude. Only the control group showed the typical task modulation for the N200 amplitude. The amplitude of the P300 component was considerably smaller in the uniparental disomy group than in the deletion and control groups. The ERP results suggest that early modality specific inhibition is impaired in both PWS genetic subtypes. Late general inhibition is impaired in the uniparental disomy group only. Thus, although the ERP data suggests a common impairment in early visual inhibition processing, uniparental disomy and parental deletion genetic PWS subtypes clearly differ in their behavioural and brain activation phenotypes. The present study is the first experimental demonstration which explains the two principal genetic mechanisms that hinder the expression of the genes at 15q11-q13g in PWS result in different behavioural phenotype.

Bayesian Networks Predict Neuronal Transdifferentiation.

PubMed

Ainsworth, Richard I; Ai, Rizi; Ding, Bo; Li, Nan; Zhang, Kai; Wang, Wei

2018-05-30

We employ the language of Bayesian networks to systematically construct gene-regulation topologies from deep-sequencing single-nucleus RNA-Seq data for human neurons. From the perspective of the cell-state potential landscape, we identify attractors that correspond closely to different neuron subtypes. Attractors are also recovered for cell states from an independent data set confirming our models accurate description of global genetic regulations across differing cell types of the neocortex (not included in the training data). Our model recovers experimentally confirmed genetic regulations and community analysis reveals genetic associations in common pathways. Via a comprehensive scan of all theoretical three-gene perturbations of gene knockout and overexpression, we discover novel neuronal trans-differrentiation recipes (including perturbations of SATB2, GAD1, POU6F2 and ADARB2) for excitatory projection neuron and inhibitory interneuron subtypes. Copyright © 2018, G3: Genes, Genomes, Genetics.

Etiologic Ischemic Stroke Phenotypes in the NINDS Stroke Genetics Network

PubMed Central

Ay, Hakan; Arsava, Ethem Murat; Andsberg, Gunnar; Benner, Thomas; Brown, Robert D.; Chapman, Sherita N.; Cole, John W.; Delavaran, Hossein; Dichgans, Martin; Engström, Gunnar; Giralt-Steinhauer, Eva; Grewal, Raji P.; Gwinn, Katrina; Jern, Christina; Jimenez-Conde, Jordi; Jood, Katarina; Katsnelson, Michael; Kissela, Brett; Kittner, Steven J.; Kleindorfer, Dawn O.; Labovitz, Daniel L.; Lanfranconi, Silvia; Lee, Jin-Moo; Lehm, Manuel; Lemmens, Robin; Levi, Chris; Li, Linxin; Lindgren, Arne; Markus, Hugh S.; McArdle, Patrick F.; Melander, Olle; Norrving, Bo; Peddareddygari, Leema Reddy; Pedersén, Annie; Pera, Joanna; Rannikmäe, Kristiina; Rexrode, Kathryn M.; Rhodes, David; Rich, Stephen S.; Roquer, Jaume; Rosand, Jonathan; Rothwell, Peter M.; Rundek, Tatjana; Sacco, Ralph L.; Schmidt, Reinhold; Schürks, Markus; Seiler, Stephan; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie; Thijs, Vincent; Woodfield, Rebecca; Worrall, Bradford B.; Meschia, James F.

2014-01-01

Background and Purpose NINDS Stroke Genetics Network (SiGN) is an international consortium of ischemic stroke studies that aims to generate high quality phenotype data to identify the genetic basis of etiologic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Methods Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major etiologic groups without weighting towards the most likely cause) and causative ischemic stroke subtypes in 16,954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded re-adjudication of 1509 randomly selected cases. Results The distribution of etiologic categories varied by study, age, sex, and race (p<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke etiology (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (kappa 0.72, 95%CI:0.69-0.75) and phenotypic classifications (kappa 0.73, 95%CI:0.70-0.75). Conclusions This study demonstrates that etiologic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a stroke patient does not necessarily mean that it is the cause of stroke. PMID:25378430

Genetic Alterations in Glioma

PubMed Central

Bralten, Linda B. C.; French, Pim J.

2011-01-01

Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes. PMID:24212656

Genetic Factors Influencing Coagulation Factor XIII B-Subunit Contribute to Risk of Ischemic Stroke.

PubMed

Hanscombe, Ken B; Traylor, Matthew; Hysi, Pirro G; Bevan, Stephen; Dichgans, Martin; Rothwell, Peter M; Worrall, Bradford B; Seshadri, Sudha; Sudlow, Cathie; Williams, Frances M K; Markus, Hugh S; Lewis, Cathryn M

2015-08-01

Abnormal coagulation has been implicated in the pathogenesis of ischemic stroke, but how this association is mediated and whether it differs between ischemic stroke subtypes is unknown. We determined the shared genetic risk between 14 coagulation factors and ischemic stroke and its subtypes. Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls-the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke. One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest P=5.7×10(-04)); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest P=1.8×10(-04)) and the cardioembolic subtype (smallest P=1.7×10(-04)). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=-0.71, P=0.01) and the cardioembolic subtype (rG=-0.80, P=0.03). Genetic markers associated with low FXIIIB levels increase risk of ischemic stroke cardioembolic subtype. © 2015 The Authors.

Intestinal parasite infections in a rural community of Rio de Janeiro (Brazil): Prevalence and genetic diversity of Blastocystis subtypes.

PubMed

Barbosa, Carolina Valença; Barreto, Magali Muniz; Andrade, Rosemary de Jesus; Sodré, Fernando; d'Avila-Levy, Claudia Masini; Peralta, José Mauro; Igreja, Ricardo Pereira; de Macedo, Heloisa Werneck; Santos, Helena Lucia Carneiro

2018-01-01

Intestinal parasitic infections are considered a serious public health problem and widely distributed worldwide, mainly in urban and rural environments of tropical and subtropical countries. Globally, soil-transmitted helminths and protozoa are the most common intestinal parasites. Blastocystis sp. is a highly prevalent suspected pathogenic protozoan, and considered an unusual protist due to its significant genetic diversity and host plasticity. A total of 294 stool samples were collected from inhabitants of three rural valleys in Rio de Janeiro, Brazil. The stool samples were evaluated by parasitological methods, fecal culture, nested PCR and PCR/Sequencing. Overall prevalence by parasitological analyses was 64.3% (189 out of 294 cases). Blastocystis sp. (55.8%) was the most prevalent, followed by Endolimax nana (18.7%), Entamoeba histolytica complex (7.1%), hookworm infection (7.1%), Entomoeba coli (5.8%), Giardia intestinalis (4.1%), Iodamoeba butchilii (1.0%), Trichuris trichiura (1.0%), Pentatrichomonas hominis (0.7%), Enterobius vermicularis (0.7%), Ascaris lumbricoides (0.7%) and Strongyloides stercoralis (0.7%). Prevalence of IPIs was significantly different by gender. Phylogenetic analysis of Blastocystis sp. and BLAST search revealed five different subtypes: ST3 (34.0%), ST1 (27.0%), ST2 (27.0%), ST4 (3.5%), ST8 (7.0%) and a non-identified subtype. Our findings demonstrate that intestinal parasite infection rates in rural areas of the Sumidouro municipality of Rio de Janeiro, Brazil are still high and remain a challenge to public health. Moreover, our data reveals significant genetic heterogeneity of Blastocystis sp. subtypes and a possible novel subtype, whose confirmation will require additional data. Our study contributes to the understanding of potential routes of transmission, epidemiology, and genetic diversity of Blastocystis sp. in rural areas both at a regional and global scale.

Genetic changes that accompanied shifts of low pathogenic avian influenza viruses toward higher pathogenicity in poultry

PubMed Central

Abdelwhab, El-Sayed M; Veits, Jutta; Mettenleiter, Thomas C

2013-01-01

Avian influenza viruses (AIV) of H5 and H7 subtypes exhibit two different pathotypes in poultry: infection with low pathogenic (LP) strains results in minimal, if any, health disturbances, whereas highly pathogenic (HP) strains cause severe morbidity and mortality. LPAIV of H5 and H7 subtypes can spontaneously mutate into HPAIV. Ten outbreaks caused by HPAIV are known to have been preceded by circulation of a predecessor LPAIV in poultry. Three of them were caused by H5N2 subtype and seven involved H7 subtype in combination with N1, N3, or N7. Here, we review those outbreaks and summarize the genetic changes which resulted in the transformation of LPAIV to HPAIV under natural conditions. Mutations that were found directly in those outbreaks are more likely to be linked to virulence, pathogenesis, and early adaptation of AIV. PMID:23863606

Comparative genomic analysis reveals occurrence of genetic recombination in virulent Cryptosporidium hominis subtypes and telomeric gene duplications in Cryptosporidium parvum.

PubMed

Guo, Yaqiong; Tang, Kevin; Rowe, Lori A; Li, Na; Roellig, Dawn M; Knipe, Kristine; Frace, Michael; Yang, Chunfu; Feng, Yaoyu; Xiao, Lihua

2015-04-18

Cryptosporidium hominis is a dominant species for human cryptosporidiosis. Within the species, IbA10G2 is the most virulent subtype responsible for all C. hominis-associated outbreaks in Europe and Australia, and is a dominant outbreak subtype in the United States. In recent yearsIaA28R4 is becoming a major new subtype in the United States. In this study, we sequenced the genomes of two field specimens from each of the two subtypes and conducted a comparative genomic analysis of the obtained sequences with those from the only fully sequenced Cryptosporidium parvum genome. Altogether, 8.59-9.05 Mb of Cryptosporidium sequences in 45-767 assembled contigs were obtained from the four specimens, representing 94.36-99.47% coverage of the expected genome. These genomes had complete synteny in gene organization and 96.86-97.0% and 99.72-99.83% nucleotide sequence similarities to the published genomes of C. parvum and C. hominis, respectively. Several major insertions and deletions were seen between C. hominis and C. parvum genomes, involving mostly members of multicopy gene families near telomeres. The four C. hominis genomes were highly similar to each other and divergent from the reference IaA25R3 genome in some highly polymorphic regions. Major sequence differences among the four specimens sequenced in this study were in the 5' and 3' ends of chromosome 6 and the gp60 region, largely the result of genetic recombination. The sequence similarity among specimens of the two dominant outbreak subtypes and genetic recombination in chromosome 6, especially around the putative virulence determinant gp60 region, suggest that genetic recombination plays a potential role in the emergence of hyper-transmissible C. hominis subtypes. The high sequence conservation between C. parvum and C. hominis genomes and significant differences in copy numbers of MEDLE family secreted proteins and insulinase-like proteases indicate that telomeric gene duplications could potentially contribute to host expansion in C. parvum.

HIV-1 genetic diversity and its distribution characteristics among newly diagnosed HIV-1 individuals in Hebei province, China.

PubMed

Lu, Xinli; Zhao, Cuiying; Wang, Wei; Nie, Chenxi; Zhang, Yuqi; Zhao, Hongru; Chen, Suliang; Cui, Ze

2016-01-01

Since the first HIV-1 case in 1989, Hebei province has presented a clearly rising trend of HIV-1 prevalence, and HIV-1 genetic diversity has become the vital barrier to HIV prevention and control in this area. To obtain detailed information of HIV-1 spread in different populations and in different areas of Hebei, a cross-sectional HIV-1 molecular epidemiological investigation was performed across the province. Blood samples of 154 newly diagnosed HIV-1 individuals were collected from ten prefectures in Hebei using stratified sampling. Partial gag and env genes were amplified and sequenced. HIV-1 genotypes were identified by phylogenetic tree analyses. Among the 139 subjects genotyped, six HIV-1 subtypes were identified successfully, including subtype B (41.0 %), CRF01_AE (40.3 %), CRF07_BC (11.5 %), CRF08_BC (4.3 %), unique recombinant forms (URFs) (1.4 %) and subtype C (1.4 %). Subtype B was identified as the most frequent subtype. Two URF recombination patterns were the same as CRF01_AE/B. HIV-1 genotype distribution showed a significant statistical difference in different demographic characteristics, such as source (P < 0.05), occupation (P < 0.05) and ethnicity (P < 0.05). The distributions of subtype B (P < 0.05), CRF01_AE (P < 0.05), CRF07_BC (P < 0.05) and subtype C (P < 0.05) showed significant differences in all ten prefectures, and the distributions of all six subtypes were significantly different in Shijiazhuang (P < 0.05) and Xingtai (P < 0.05), but not in other prefectures (P > 0.05). The differences in HIV-1 genotype distribution were closely associated with transmission routes. Particularly, all six subtype strains were found in heterosexuals, showing that HIV-1 has spread from the high-risk populations to the general populations in Hebei, China. In addition, CRF01_AE instead of subtype B has become the major strain of HIV-1 infection among homosexuals. Our study revealed HIV-1 evolution and genotype distribution by investigating newly diagnosed HIV-1 individuals in Hebei, China. This study provides important information to enhance the strategic plan for HIV prevention and control in China.

Multilocus Sequence Typing of an Emerging Cryptosporidium hominis Subtype in the United States

PubMed Central

Tiao, Narry; Li, Na; Hlavsa, Michele

2014-01-01

The United States has experienced a substantial increase in the reported incidence of cryptosporidiosis since 2005. Accompanying this is the emergence of a new subtype of Cryptosporidium hominis based on variation at the 60-kDa glycoprotein (gp60) locus, IaA28R4, which has become a frequently identified subtype in both sporadic and outbreak-related cases. In this study, using multilocus sequence typing (MLST) at eight genetic loci, we characterized 62 specimens of IaA28R4 and 33 specimens of three other gp60 subtypes of C. hominis from four U.S. states with increased cryptosporidiosis incidences during the summer of 2008. Extensive genetic heterogeneity was seen within the gp60 subtype IaA28R4, but specimens from Ohio and southwestern states formed two distinct subpopulations, suggesting that there were at least two origins of IaA28R4 within the United States. Discordance in typing results was observed between gp60 and other genetic markers, especially DZ-HRGP, and this discordance was largely the result of genetic recombination within the gp60 subtype IaA28R4. The results of population genetic analyses supported the presence of two subpopulations of IaA28R4 and the occurrence of genetic recombination within this gp60 subtype. Thus, the IaA28R4 subtype at gp60 is likely a fitness marker for C. hominis, and genetic recombination is potentially a driving force in the emergence of the virulent IaA28R4 subtype in the United States. A rapid evolution of IaA28R4 was indicated by the observation of multiple MLST subtypes of IaA28R4 within two large outbreaks that lasted for extended periods and involved multiple swimming pools. PMID:24478483

High occurrence of Blastocystis sp. subtypes 1-3 and Giardia intestinalis assemblage B among patients in Zanzibar, Tanzania.

PubMed

Forsell, Joakim; Granlund, Margareta; Samuelsson, Linn; Koskiniemi, Satu; Edebro, Helén; Evengård, Birgitta

2016-06-29

Blastocystis is a common intestinal parasite with worldwide distribution but the distribution of Blastocystis and its subtypes in East Africa is largely unknown. In this study, we investigate the distribution of Blastocystis subtypes in Zanzibar, Tanzania and report the prevalence of intestinal parasites using both molecular methods and microscopy. Stool samples were collected from both diarrhoeic and non-diarrhoeic outpatients in Zanzibar. In addition to microscopy, real-time PCR for Blastocystis, Entamoeba histolytica and E. dispar, Giardia intestinalis, Cryptosporidium spp., and Dientamoeba fragilis was used. Blastocystis subtypes were determined by a conventional PCR followed by partial sequencing of the SSU-rRNA gene. Genetic assemblages of Giardia were determined by PCR with assemblage specific primers. Intestinal parasites were detected in 85 % of the 174 participants, with two or more parasites present in 56 %. Blastocystis sp. and Giardia intestinalis were the most common parasites, identified by PCR in 61 and 53 % of the stool samples respectively, but no correlation between carriage of Blastocystis and Giardia was found. The Blastocystis subtype distribution was ST1 34.0 %, ST2 26.4 %, ST3 25.5 %, ST7 0.9 %, and 13.2 % were positive only by qPCR (non-typable). The Giardia genetic assemblages identified were A 6.5 %, B 85 %, A + B 4.3 %, and non-typable 4.3 %. The detection rate with microscopy was substantially lower than with PCR, 20 % for Blastocystis and 13.8 % for Giardia. The prevalence of Blastocystis increased significantly with age while Giardia was most prevalent in children two to five years old. No correlation between diarrhoea and the identification of Giardia, Blastocystis, or their respective genetic subtypes could be shown and, as a possible indication of parasite load, the mean cycle threshold values in the qPCR for Giardia were equal in diarrhoeic and non-diarrhoeic patients. Carriage of intestinal parasites was very common in the studied population in Zanzibar. The most commonly detected parasites, Blastocystis and Giardia, had different age distributions, possibly indicating differences in transmission routes, immunity, and/or other host factors for these two species. In the Blastocystis subtype analysis ST1-3 were common, but ST4, a subtype quite common in Europe, was completely absent, corroborating the geographical differences in subtype distributions previously reported.

The Promise of Multi-Omics and Clinical Data Integration to Identify and Target Personalized Healthcare Approaches in Autism Spectrum Disorders

PubMed Central

Higdon, Roger; Earl, Rachel K.; Stanberry, Larissa; Hudac, Caitlin M.; Montague, Elizabeth; Stewart, Elizabeth; Janko, Imre; Choiniere, John; Broomall, William; Kolker, Natali

2015-01-01

Abstract Complex diseases are caused by a combination of genetic and environmental factors, creating a difficult challenge for diagnosis and defining subtypes. This review article describes how distinct disease subtypes can be identified through integration and analysis of clinical and multi-omics data. A broad shift toward molecular subtyping of disease using genetic and omics data has yielded successful results in cancer and other complex diseases. To determine molecular subtypes, patients are first classified by applying clustering methods to different types of omics data, then these results are integrated with clinical data to characterize distinct disease subtypes. An example of this molecular-data-first approach is in research on Autism Spectrum Disorder (ASD), a spectrum of social communication disorders marked by tremendous etiological and phenotypic heterogeneity. In the case of ASD, omics data such as exome sequences and gene and protein expression data are combined with clinical data such as psychometric testing and imaging to enable subtype identification. Novel ASD subtypes have been proposed, such as CHD8, using this molecular subtyping approach. Broader use of molecular subtyping in complex disease research is impeded by data heterogeneity, diversity of standards, and ineffective analysis tools. The future of molecular subtyping for ASD and other complex diseases calls for an integrated resource to identify disease mechanisms, classify new patients, and inform effective treatment options. This in turn will empower and accelerate precision medicine and personalized healthcare. PMID:25831060

Genetic diversity analysis of Blastocystis subtypes from both symptomatic and asymptomatic subjects using a barcoding region from the 18S rRNA gene.

PubMed

Rezaei Riabi, Tahereh; Mirjalali, Hamed; Haghighi, Ali; Rostami Nejad, Mohammad; Pourhoseingholi, Mohammad Amin; Poirier, Philippe; Delbac, Frederic; Wawrzyniak, Ivan; Zali, Mohammad Reza

2018-07-01

Blastocystis is the most prevalent protozoa found in human stool samples. This study aimed to evaluate genetic diversity among Blastocystis subtypes isolated from both symptomatic and asymptomatic subjects as well as the potential correlation between subtypes and symptoms. A total of 55 Blastocystis-positive isolates were included in this study. A barcoding region of the small subunit rDNA was amplified and genetically assessed using MEGA6 and DnaSP regarding the presence of symptoms. BLAST analyses revealed the presence of 5 different subtypes (ST1, ST2, ST3, ST6 and ST7) among the samples. ST3 was the most prevalent subtype (25/55, 45%) while only one ST7 isolate was detected. Moreover, alleles 4 and 86 for ST1; alleles 9, 11 and 12 for ST2; alleles 31, 34, 36, 37 and 52 for ST3; allele 122 for ST6 and allele 137 for ST7 were detected. No statistically significant association was found between gender and symptoms with certain subtypes. Analysis of the intra-subtype variability in both symptomatic and asymptomatic subjects revealed highest similarity among ST1 isolates while lowest similarity was seen among ST3 isolates. Neutrality indices, Tajima's D and Fu's Fs, were negative but only statistically significant for ST3. Furthermore, highest values of Hd, π and S were observed among ST1, ST2 and ST3 isolated from symptomatic patients indicating high level of diversity among isolates obtained from these subjects. In addition, inter-subtype analysis showed the highest similarity between ST1 and ST2 isolates and the lowest similarity between ST2 and ST7 isolates. This is the first study revealing the presence of both ST6 and ST7 isolates in human from Iran. Phylogenetic analysis did not suggest any significant correlation between clinical manifestations and certain subtypes although genetic analysis showed highest value of diversity and significant neutrality indices among ST3 isolates obtained from symptomatic patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Molecular detection and characterization of beak and feather disease virus in psittacine birds in Tehran, Iran

PubMed Central

Haddadmarandi, M. R.; Madani, S. A.; Nili, H.; Ghorbani, A.

2018-01-01

Beak and feather disease virus (BFDV), a member of genus circovirus, is a small, non-enveloped, single stranded DNA virus. Although BFDVs are among the most well studied circoviruses, there is little to no information about BFDVs in Iran. The aim of the present study was to detect and identify BFDV molecules from the birds referred to the avian clinic of The Faculty of Veterinary Medicine, Tehran University, Iran. A total of 55 DNA samples were extracted from birds from nine different species of the order psittaciformes. A robust conventional polymerase chain reaction (PCR) was applied to detect the rep gene of the virus. Ten out of 55 samples, from four different species, were tested positive for BFDVs in PCR (Melopsittacus undulates (4), Psittacula Krameri (3), Psittacus erithacus (2), Platycercus eximius (1)). Molecular identification of the detected BFDVs was performed based on their rep gene sequences. The phylogenetic analysis revealed that the Iranian BFDVs from this study were clustered into four genetically distinct clades belonging to different genetic subtypes of BFDVs (L1, N1, T1, and I4). Although the relation between the samples and their related subtypes in the tree are discussed, further studies are needed to elucidate the host specificity and incidence of the BFDVs from different genetic subtypes. PMID:29805458

Molecular detection and characterization of beak and feather disease virus in psittacine birds in Tehran, Iran.

PubMed

Haddadmarandi, M R; Madani, S A; Nili, H; Ghorbani, A

2018-01-01

Beak and feather disease virus (BFDV), a member of genus circovirus, is a small, non-enveloped, single stranded DNA virus. Although BFDVs are among the most well studied circoviruses, there is little to no information about BFDVs in Iran. The aim of the present study was to detect and identify BFDV molecules from the birds referred to the avian clinic of The Faculty of Veterinary Medicine, Tehran University, Iran. A total of 55 DNA samples were extracted from birds from nine different species of the order psittaciformes. A robust conventional polymerase chain reaction (PCR) was applied to detect the rep gene of the virus. Ten out of 55 samples, from four different species, were tested positive for BFDVs in PCR ( Melopsittacus undulates (4), Psittacula Krameri (3), Psittacus erithacus (2), Platycercus eximius (1)). Molecular identification of the detected BFDVs was performed based on their rep gene sequences. The phylogenetic analysis revealed that the Iranian BFDVs from this study were clustered into four genetically distinct clades belonging to different genetic subtypes of BFDVs (L1, N1, T1, and I4). Although the relation between the samples and their related subtypes in the tree are discussed, further studies are needed to elucidate the host specificity and incidence of the BFDVs from different genetic subtypes.

Clinicopathogenomic analysis of mismatch repair proficient colorectal adenocarcinoma uncovers novel prognostic subgroups with differing patterns of genetic evolution.

PubMed

Braxton, David R; Zhang, Ray; Morrissette, Jennifer D; Loaiza-Bonilla, Arturo; Furth, Emma E

2016-10-01

Cancer somatic genetic evolution is a direct contributor to heterogeneity at the clonal and molecular level in colorectal adenocarcinoma (COAD). We sought to determine the extent to which genetic evolution may be detected in COAD in routinely obtained single clinical specimens and establish clinical significance with regard to clinicopathologic and outcome data. One hundred and twenty three cases of routinely collected mismatch repair proficient COAD were sequenced on the Illumina Truseq Amplicon assay. Measures of intratumoral heterogeneity and the preferential timing of mutational events were assessed and compared to clinicopathologic data. Survival subanalysis was performed on 55 patients. Patient age (p = 0.013) and specimen percent tumor (p = 0.033) was associated with clonal diversity, and biopsy (p = 0.044) and metastasis (p = 0.044) returned fewer mutations per case. APC and TP53 mutations preferentially occurred early while alterations in FBXW7, FLT3, SMAD4, GNAS and PTEN preferentially occurred as late events. Temporal heterogeneity was evident in KRAS and PIK3CA mutations. Hierarchical clustering revealed a TP53 mutant subtype and a MAPK-PIK3CA subtype with differing patterns of late mutational events. Survival subanalysis showed a decreased median progression free survival for the MAPK-PIK3CA subtype (8 months vs. 13 months; univariate logrank p = 0.0380, cox model p= 0.018). Neoadjuvant therapy associated mutations were found for ERBB2 (p = 0.0481) and FBXW7 (p = 0.015). Our data indicate novel molecular subtypes of mismatch repair proficient COAD display differing patterns of genetic evolution which correlate with clinical outcomes. Furthermore, we report treatment acquired and/or selected mutations in ERBB2 and FBXW7. © 2016 UICC.

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.

PubMed

Cuellar-Partida, Gabriel; Lu, Yi; Dixon, Suzanne C; Fasching, Peter A; Hein, Alexander; Burghaus, Stefanie; Beckmann, Matthias W; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Vanderstichele, Adriaan; Doherty, Jennifer Anne; Rossing, Mary Anne; Chang-Claude, Jenny; Rudolph, Anja; Wang-Gohrke, Shan; Goodman, Marc T; Bogdanova, Natalia; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo B; Antonenkova, Natalia; Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M; Edwards, Robert P; Kelley, Joseph L; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Cannioto, Rikki; Høgdall, Estrid; Høgdall, Claus; Jensen, Allan; Giles, Graham G; Bruinsma, Fiona; Kjaer, Susanne K; Hildebrandt, Michelle A T; Liang, Dong; Lu, Karen H; Wu, Xifeng; Bisogna, Maria; Dao, Fanny; Levine, Douglas A; Cramer, Daniel W; Terry, Kathryn L; Tworoger, Shelley S; Stampfer, Meir; Missmer, Stacey; Bjorge, Line; Salvesen, Helga B; Kopperud, Reidun K; Bischof, Katharina; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Brooks-Wilson, Angela; Olson, Sara H; McGuire, Valerie; Rothstein, Joseph H; Sieh, Weiva; Whittemore, Alice S; Cook, Linda S; Le, Nhu D; Blake Gilks, C; Gronwald, Jacek; Jakubowska, Anna; Lubiński, Jan; Kluz, Tomasz; Song, Honglin; Tyrer, Jonathan P; Wentzensen, Nicolas; Brinton, Louise; Trabert, Britton; Lissowska, Jolanta; McLaughlin, John R; Narod, Steven A; Phelan, Catherine; Anton-Culver, Hoda; Ziogas, Argyrios; Eccles, Diana; Campbell, Ian; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Menon, Usha; Ramus, Susan J; Wu, Anna H; Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Timorek, Agnieszka; Szafron, Lukasz; Cunningham, Julie M; Fridley, Brooke L; Winham, Stacey J; Bandera, Elisa V; Poole, Elizabeth M; Morgan, Terry K; Goode, Ellen L; Schildkraut, Joellen M; Pearce, Celeste L; Berchuck, Andrew; Pharoah, Paul D P; Webb, Penelope M; Chenevix-Trench, Georgia; Risch, Harvey A; MacGregor, Stuart

2016-07-01

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling.

PubMed

Martín-Subero, José I; Kreuz, Markus; Bibikova, Marina; Bentink, Stefan; Ammerpohl, Ole; Wickham-Garcia, Eliza; Rosolowski, Maciej; Richter, Julia; Lopez-Serra, Lidia; Ballestar, Esteban; Berger, Hilmar; Agirre, Xabier; Bernd, Heinz-Wolfram; Calvanese, Vincenzo; Cogliatti, Sergio B; Drexler, Hans G; Fan, Jian-Bing; Fraga, Mario F; Hansmann, Martin L; Hummel, Michael; Klapper, Wolfram; Korn, Bernhard; Küppers, Ralf; Macleod, Roderick A F; Möller, Peter; Ott, German; Pott, Christiane; Prosper, Felipe; Rosenwald, Andreas; Schwaenen, Carsten; Schübeler, Dirk; Seifert, Marc; Stürzenhofecker, Benjamin; Weber, Michael; Wessendorf, Swen; Loeffler, Markus; Trümper, Lorenz; Stein, Harald; Spang, Rainer; Esteller, Manel; Barker, David; Hasenclever, Dirk; Siebert, Reiner

2009-03-12

Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic, and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) characterized for their morphologic, genetic, and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchic clustering indicated that methylation patterns in maB-NHLs were not strictly associated with morphologic, genetic, or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype-specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHLs studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in nonhematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHLs with different morphologic, genetic, and transcriptional background share a similar stem cell-like epigenetic pattern. This suggests that maB-NHLs originate from cells with stem cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling.

Shared genetic basis for migraine and ischemic stroke

PubMed Central

Malik, Rainer; Freilinger, Tobias; Winsvold, Bendik S.; Anttila, Verneri; Vander Heiden, Jason; Traylor, Matthew; de Vries, Boukje; Holliday, Elizabeth G.; Terwindt, Gisela M.; Sturm, Jonathan; Bis, Joshua C.; Hopewell, Jemma C.; Ferrari, Michel D.; Rannikmae, Kristiina; Wessman, Maija; Kallela, Mikko; Kubisch, Christian; Fornage, Myriam; Meschia, James F.; Lehtimäki, Terho; Sudlow, Cathie; Clarke, Robert; Chasman, Daniel I.; Mitchell, Braxton D.; Maguire, Jane; Kaprio, Jaakko; Farrall, Martin; Raitakari, Olli T.; Kurth, Tobias; Ikram, M. Arfan; Reiner, Alex P.; Longstreth, W.T.; Rothwell, Peter M.; Strachan, David P.; Sharma, Pankaj; Seshadri, Sudha; Quaye, Lydia; Cherkas, Lynn; Schürks, Markus; Rosand, Jonathan; Ligthart, Lannie; Boncoraglio, Giorgio B.; Davey Smith, George; van Duijn, Cornelia M.; Stefansson, Kari; Worrall, Bradford B.; Nyholt, Dale R.; Markus, Hugh S.; van den Maagdenberg, Arn M.J.M.; Cotsapas, Chris; Zwart, John A.; Palotie, Aarno

2015-01-01

Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. Methods: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. Results: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10−28 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10−20 for the CE score in MO). Conclusions: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype. PMID:25934857

Polymorphism study of Cryptosporidium hominis gp60 subtypes circulating in Tunisia.

PubMed

Essid, Rym; Chelbi, Hanen; Siala, Emna; Bensghair, Ines; Menotti, Jean; Bouratbine, Aïda

2017-09-01

Cryptosporidium spp. are a major cause of gastrointestinal diseases in humans worldwide. While a single subtype of Cryptosporidium hominis has been shown to be responsible for several large outbreaks related to water contamination in developed countries, little is known about the epidemiology of C. hominis in developing countries. This study reports the first genetic characterization of C. hominis at the subtype level in several human populations in Tunisia using the gp60 gene. Eighteen isolates were identified as C. hominis by a restriction fragment length polymorphism (RFLP) analysis. The prevalence of this species in different human populations ranges from 1.53% to 13.04% with a high prevalence being reported in immunocompromised children (13.04%) followed by patients with malignent myeloma (5.5%) and HIV-infected patients (4.59%). The gp60 analysis on C. hominis isolates, performed in 14 cases, showed the presence of a single subtype family: "Ia". Different subtypes were identified within this family (A11G1R1, A12R3, A23G1R1, A26G1R1, A27G1R1, A28G1R1). The IaA26G1R1 subtype was the most dominant subtype described in this area (50%). Despite the high genetic diversity of Cryptosporidium spp, a low heterogeneity at the subtype level was observed within C. hominis circulating in Tunisia. This distribution is an indicator for intensive and stable anthroponotic cryptosporidiosis in this region. Besides, the presence of a unique genotype in 5 HIV-infected patients attending the same hospital ward suggests the possible occurrence of hospital-acquired infection and underlines the need to implement preventive measures to avoid nosocomial transmission. Copyright © 2017 Elsevier Ltd. All rights reserved.

Origins based clinical and molecular complexities of epithelial ovarian cancer.

PubMed

Muinao, Thingreila; Pal, Mintu; Boruah, Hari Prasanna Deka

2018-06-08

Ovarian cancer is the most lethal of all common gynaecological malignancies in women worldwide. Ovarian cancer comprises of >15 distinct tumor types and subtypes characterized by histopathological features, environmental and genetic risk factors, precursor lesions and molecular events during oncogenesis. Recent studies on gene signatures profiling of different subtypes of ovarian cancer have revealed significant genetic heterogeneity between and within each ovarian cancer histological subtype. Thus, an immense interest have shown towards a more personalized medicine for understanding the clinical and molecular complexities of four major types of epithelial ovarian cancer (serous, endometrioid, clear cell, and mucinous). As such, further in depth studies are needed for identification of molecular signalling network complexities associated with effective prognostication and targeted therapies to prevent or treat metastasis. Therefore, understanding the metastatic potential of primary ovarian cancer and therapeutic interventions against lethal ovarian cancer for the development of personalized therapies is very much indispensable. Consequently, in this review we have updated the key dysregulated genes of four major subtypes of epithelial carcinomas. We have also highlighted the recent advances and current challenges in unravelling the complexities of the origin of tumor as well as genetic heterogeneity of ovarian cancer. Copyright © 2017. Published by Elsevier B.V.

Toward diagnostic and phenotype markers for genetically transmitted speech delay.

PubMed

Shriberg, Lawrence D; Lewis, Barbara A; Tomblin, J Bruce; McSweeny, Jane L; Karlsson, Heather B; Scheer, Alison R

2005-08-01

Converging evidence supports the hypothesis that the most common subtype of childhood speech sound disorder (SSD) of currently unknown origin is genetically transmitted. We report the first findings toward a set of diagnostic markers to differentiate this proposed etiological subtype (provisionally termed speech delay-genetic) from other proposed subtypes of SSD of unknown origin. Conversational speech samples from 72 preschool children with speech delay of unknown origin from 3 research centers were selected from an audio archive. Participants differed on the number of biological, nuclear family members (0 or 2+) classified as positive for current and/or prior speech-language disorder. Although participants in the 2 groups were found to have similar speech competence, as indexed by their Percentage of Consonants Correct scores, their speech error patterns differed significantly in 3 ways. Compared with children who may have reduced genetic load for speech delay (no affected nuclear family members), children with possibly higher genetic load (2+ affected members) had (a) a significantly higher proportion of relative omission errors on the Late-8 consonants; (b) a significantly lower proportion of relative distortion errors on these consonants, particularly on the sibilant fricatives /s/, /z/, and //; and (c) a significantly lower proportion of backed /s/ distortions, as assessed by both perceptual and acoustic methods. Machine learning routines identified a 3-part classification rule that included differential weightings of these variables. The classification rule had diagnostic accuracy value of 0.83 (95% confidence limits = 0.74-0.92), with positive and negative likelihood ratios of 9.6 (95% confidence limits = 3.1-29.9) and 0.40 (95% confidence limits = 0.24-0.68), respectively. The diagnostic accuracy findings are viewed as promising. The error pattern for this proposed subtype of SSD is viewed as consistent with the cognitive-linguistic processing deficits that have been reported for genetically transmitted verbal disorders.

A chimeric virus created by DNA shuffling of the capsid genes of different subtypes of porcine circovirus type 2 (PCV2) in the backbone of the non-pathogenic PCV1 induces protective immunity against the predominant PCV2b and the emerging PCV2d in pigs.

PubMed

Matzinger, Shannon R; Opriessnig, Tanja; Xiao, Chao-Ting; Catanzaro, Nicholas; Beach, Nathan M; Slade, David E; Nitzel, Gregory P; Meng, Xiang-Jin

2016-11-01

Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated disease (PCVAD). Available commercial vaccines all target PCV2a subtype, although the circulating predominant subtype worldwide is PCV2b, and the emerging PCV2d subtype is also increasingly associated with PCVAD. Here we molecularly bred genetically-divergent strains representing PCV2a, PCV2b, PCV2c, PCV2d, and "divergent PCV2a" subtypes by DNA-shuffling of the capsid genes to produce a chimeric virus representing PCV2 global genetic diversity. When placed in the PCV2a backbone, one chimeric virus (PCV2-3cl14) induced higher neutralizing antibody titers against different PCV2 subtypes. Subsequently, a candidate vaccine (PCV1-3cl14) was produced by cloning the shuffled 3cl14 capsid into the backbone of the non-pathogenic PCV1. A vaccine efficacy study revealed that chimeric virus PCV1-3cl14 induces protective immunity against challenge with PCV2b or PCV2d in pigs. The chimeric PCV1-3cl14 virus is a strong candidate for a novel vaccine in pigs infected with variable PCV2 strains. Copyright © 2016 Elsevier Inc. All rights reserved.

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

PubMed Central

Traylor, Matthew; Farrall, Martin; Holliday, Elizabeth G; Sudlow, Cathie; Hopewell, Jemma C; Cheng, Yu-Ching; Fornage, Myriam; Ikram, M Arfan; Malik, Rainer; Bevan, Steve; Thorsteinsdottir, Unnur; Nalls, Mike A; Longstreth, WT; Wiggins, Kerri L; Yadav, Sunaina; Parati, Eugenio A; DeStefano, Anita L; Worrall, Bradford B; Kittner, Steven J; Khan, Muhammad Saleem; Reiner, Alex P; Helgadottir, Anna; Achterberg, Sefanja; Fernandez-Cadenas, Israel; Abboud, Sherine; Schmidt, Reinhold; Walters, Matthew; Chen, Wei-Min; Ringelstein, E Bernd; O'Donnell, Martin; Ho, Weang Kee; Pera, Joanna; Lemmens, Robin; Norrving, Bo; Higgins, Peter; Benn, Marianne; Sale, Michele; Kuhlenbäumer, Gregor; Doney, Alexander S F; Vicente, Astrid M; Delavaran, Hossein; Algra, Ale; Davies, Gail; Oliveira, Sofia A; Palmer, Colin N A; Deary, Ian; Schmidt, Helena; Pandolfo, Massimo; Montaner, Joan; Carty, Cara; de Bakker, Paul I W; Kostulas, Konstantinos; Ferro, Jose M; van Zuydam, Natalie R; Valdimarsson, Einar; Nordestgaard, Børge G; Lindgren, Arne; Thijs, Vincent; Slowik, Agnieszka; Saleheen, Danish; Paré, Guillaume; Berger, Klaus; Thorleifsson, Gudmar; Hofman, Albert; Mosley, Thomas H; Mitchell, Braxton D; Furie, Karen; Clarke, Robert; Levi, Christopher; Seshadri, Sudha; Gschwendtner, Andreas; Boncoraglio, Giorgio B; Sharma, Pankaj; Bis, Joshua C; Gretarsdottir, Solveig; Psaty, Bruce M; Rothwell, Peter M; Rosand, Jonathan; Meschia, James F; Stefansson, Kari; Dichgans, Martin; Markus, Hugh S

2012-01-01

Summary Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10−6. However, we were unable to replicate any of these novel associations in the replication cohort. Interpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. Funding Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS). PMID:23041239

Population dynamics of HIV-1 inferred from gene sequences.

PubMed Central

Grassly, N C; Harvey, P H; Holmes, E C

1999-01-01

A method for the estimation of population dynamic history from sequence data is described and used to investigate the past population dynamics of HIV-1 subtypes A and B. Using both gag and env gene alignments the effective population size of each subtype is estimated and found to be surprisingly small. This may be a result of the selective sweep of mutations through the population, or may indicate an important role of genetic drift in the fixation of mutations. The implications of these results for the spread of drug-resistant mutations and transmission dynamics, and also the roles of selection and recombination in shaping HIV-1 genetic diversity, are discussed. A larger estimated effective population size for subtype A may be the result of differences in time of origin, transmission dynamics, and/or population structure. To investigate the importance of population structure a model of population subdivision was fitted to each subtype, although the improvement in likelihood was found to be nonsignificant. PMID:9927440

HIV type 1 subtypes among bar and hotel workers in Moshi, Tanzania.

PubMed

Kiwelu, Ireen E; Renjifo, Boris; Chaplin, Beth; Sam, Noel; Nkya, Watoky M M M; Shao, John; Kapiga, Saidi; Essex, Max

2003-01-01

The HIV-1 prevalence among bar and hotel workers in Tanzania suggests they are a high-risk group for HIV-1 infection. We determined the HIV-1 subtype of 3'-p24/5'-p7 gag and C2-C5 env sequences from 40 individuals representing this population in Moshi. Genetic patterns composed of A(gag)-A(env), C(gag)-C(env), and D(gag)-D(env) were found in 19 (48.0%), 8 (20.0%), and 3 (8.0%) samples, respectively. The remaining 10 samples (25%) had different subtypes in gag and env, indicative of intersubtype recombinants. Among these recombinants, two contained sequences from HIV-1 subsubtype A2, a new genetic variant in Tanzania. Five bar and hotel workers may have been infected with viruses from a common source, based on phylogenetic analysis. The information obtained by surveillance of HIV-1 subtypes in a high-risk population should be useful in the design and evaluation of behavioral, therapeutic, and vaccine trial interventions aimed at reducing HIV-1 transmission.

Genetic characterization of clade B measles viruses isolated in Tunisia and Libya 2002-2009 and a proposed new subtype within the B3 genotype.

PubMed

Haddad-Boubaker, Sondes; Rezq, Moftah; Smeo, Mohamed-Najeb; Ben Yahia, Ahlem; Abudher, Abdulhafid; Slim, Amin; Ben Ghorbel, Mohamed; Ahmed, Hinda; Rota, Paul; Triki, Hinda

2010-11-01

Genetic characterization was conducted on 18 wild-type measles viruses, detected in Tunisia and Libya from 2002 to 2009. Sequence analysis of the 456 nucleotides in the carboxy terminus of the nucleoprotein (N) gene and the entire hemagglutinin (H) gene indicated that all isolates were in genotype B3. All of the viruses from 2002 to 2007 and some of the isolates from 2009 belonged to subtype B3.1. In contrast, 7 of the viruses isolated during 2008 and 2009 were quite divergent from all B3 isolates. The nucleotide sequences of the N gene of these 7 isolates differed from the sequences of the Ibadan and New York reference strain by an average of 3.1 and 4.4%, respectively. The H gene sequences differed by 1.1 and 2.6% with the same reference strains. This is the first report describing the genetic characteristics of measles viruses from clade B isolated in North Africa; the results suggest that these viruses represent a new subtype of genotype B3. Copyright © 2010 Elsevier B.V. All rights reserved.

First report of an HIV-1 triple recombinant of subtypes B, C and F in Buenos Aires, Argentina.

PubMed

Pando, María A; Eyzaguirre, Lindsay M; Segura, Marcela; Bautista, Christian T; Marone, Rubén; Ceballos, Ana; Montano, Silvia M; Sánchez, José L; Weissenbacher, Mercedes; Avila, María M; Carr, Jean K

2006-09-07

We describe the genetic diversity of currently transmitted strains of HIV-1 in men who have sex with men (MSM) in Buenos Aires, Argentina between 2000 and 2004. Nearly full-length sequence analysis of 10 samples showed that 6 were subtype B, 3 were BF recombinant and 1 was a triple recombinant of subtypes B, C and F. The 3 BF recombinants were 3 different unique recombinant forms. Full genome analysis of one strain that was subtype F when sequenced in pol was found to be a triple recombinant. Gag and pol were predominantly subtype F, while gp120 was subtype B; there were regions of subtype C interspersed throughout. The young man infected with this strain reported multiple sexual partners and sero-converted between May and November of 2004. This study reported for the first time the full genome analysis of a triple recombinant between subtypes B, C and F, that combines in one virus the three most common subtypes in South America.

Intestinal parasite infections in a rural community of Rio de Janeiro (Brazil): Prevalence and genetic diversity of Blastocystis subtypes

PubMed Central

Barbosa, Carolina Valença; Barreto, Magali Muniz; Andrade, Rosemary de Jesus; Sodré, Fernando; d’Avila-Levy, Claudia Masini; Peralta, José Mauro; Igreja, Ricardo Pereira; de Macedo, Heloisa Werneck

2018-01-01

Background Intestinal parasitic infections are considered a serious public health problem and widely distributed worldwide, mainly in urban and rural environments of tropical and subtropical countries. Globally, soil-transmitted helminths and protozoa are the most common intestinal parasites. Blastocystis sp. is a highly prevalent suspected pathogenic protozoan, and considered an unusual protist due to its significant genetic diversity and host plasticity. Methodology/main findings A total of 294 stool samples were collected from inhabitants of three rural valleys in Rio de Janeiro, Brazil. The stool samples were evaluated by parasitological methods, fecal culture, nested PCR and PCR/Sequencing. Overall prevalence by parasitological analyses was 64.3% (189 out of 294 cases). Blastocystis sp. (55.8%) was the most prevalent, followed by Endolimax nana (18.7%), Entamoeba histolytica complex (7.1%), hookworm infection (7.1%), Entomoeba coli (5.8%), Giardia intestinalis (4.1%), Iodamoeba butchilii (1.0%), Trichuris trichiura (1.0%), Pentatrichomonas hominis (0.7%), Enterobius vermicularis (0.7%), Ascaris lumbricoides (0.7%) and Strongyloides stercoralis (0.7%). Prevalence of IPIs was significantly different by gender. Phylogenetic analysis of Blastocystis sp. and BLAST search revealed five different subtypes: ST3 (34.0%), ST1 (27.0%), ST2 (27.0%), ST4 (3.5%), ST8 (7.0%) and a non-identified subtype. Conclusions/significance Our findings demonstrate that intestinal parasite infection rates in rural areas of the Sumidouro municipality of Rio de Janeiro, Brazil are still high and remain a challenge to public health. Moreover, our data reveals significant genetic heterogeneity of Blastocystis sp. subtypes and a possible novel subtype, whose confirmation will require additional data. Our study contributes to the understanding of potential routes of transmission, epidemiology, and genetic diversity of Blastocystis sp. in rural areas both at a regional and global scale. PMID:29522552

Clinical subtypes and genetic heterogeneity: of lumping and splitting in Parkinson disease.

PubMed

von Coelln, Rainer; Shulman, Lisa M

2016-12-01

Recent studies on clinical, genetic and pathological heterogeneity of Parkinson disease have renewed the old debate whether we should think of Parkinson disease as one disease with variations, or as a group of independent diseases that happen to present with similar phenotypes. Here, we provide an overview of where the debate is coming from, and how recent findings in clinical subtyping, genetics and clinico-pathological correlation have shaped this controversy over the last few years. New and innovative clinical diagnostic criteria for Parkinson disease have been proposed and await validation. Studies using functional imaging or wearable biosensors, as well as biomarker studies, provide new support for the validity of the traditional clinical subtypes of Parkinson disease (tremor-dominant versus akinetic-rigid or postural instability/gait difficulty). A recent cluster analysis (as unbiased data-driven approach to subtyping) included a wide spectrum of nonmotor variables, and showed correlation of the proposed subtypes with disease progression in a longitudinal analysis. New genetic factors contributing to Parkinson disease susceptibility continue to be identified, including rare mutations causing monogenetic disease, common variants with small effect size and risk factors (like mutations in the gene for glucocerebrosidase) that fall in between the two other categories. Recent studies show some limited correlation between genetic factors and clinical heterogeneity. Despite some variations in patterns of pathology, Lewy bodies are still the hallmark of Parkinson disease, including the vast majority of genetic subgroups. Evidence of clinical, genetic and pathological heterogeneity of Parkinson disease continues to emerge, but clearly defined subtypes that hold up in more than one of these domains remain elusive. For research to identify such subtypes, splitting is likely the way forward; until then, for clinical practice, lumping remains the more pragmatic approach.

Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants.

PubMed

Malik, Rainer; Freilinger, Tobias; Winsvold, Bendik S; Anttila, Verneri; Vander Heiden, Jason; Traylor, Matthew; de Vries, Boukje; Holliday, Elizabeth G; Terwindt, Gisela M; Sturm, Jonathan; Bis, Joshua C; Hopewell, Jemma C; Ferrari, Michel D; Rannikmae, Kristiina; Wessman, Maija; Kallela, Mikko; Kubisch, Christian; Fornage, Myriam; Meschia, James F; Lehtimäki, Terho; Sudlow, Cathie; Clarke, Robert; Chasman, Daniel I; Mitchell, Braxton D; Maguire, Jane; Kaprio, Jaakko; Farrall, Martin; Raitakari, Olli T; Kurth, Tobias; Ikram, M Arfan; Reiner, Alex P; Longstreth, W T; Rothwell, Peter M; Strachan, David P; Sharma, Pankaj; Seshadri, Sudha; Quaye, Lydia; Cherkas, Lynn; Schürks, Markus; Rosand, Jonathan; Ligthart, Lannie; Boncoraglio, Giorgio B; Davey Smith, George; van Duijn, Cornelia M; Stefansson, Kari; Worrall, Bradford B; Nyholt, Dale R; Markus, Hugh S; van den Maagdenberg, Arn M J M; Cotsapas, Chris; Zwart, John A; Palotie, Aarno; Dichgans, Martin

2015-05-26

To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO). Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype. © 2015 American Academy of Neurology.

Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil.

PubMed

Lei, Zhengdeng; Tan, Iain Beehuat; Das, Kakoli; Deng, Niantao; Zouridis, Hermioni; Pattison, Sharon; Chua, Clarinda; Feng, Zhu; Guan, Yeoh Khay; Ooi, Chia Huey; Ivanova, Tatiana; Zhang, Shenli; Lee, Minghui; Wu, Jeanie; Ngo, Anna; Manesh, Sravanthy; Tan, Elisabeth; Teh, Bin Tean; So, Jimmy Bok Yan; Goh, Liang Kee; Boussioutas, Alex; Lim, Tony Kiat Hon; Flotow, Horst; Tan, Patrick; Rozen, Steven G

2013-09-01

Almost all gastric cancers are adenocarcinomas, which have considerable heterogeneity among patients. We sought to identify subtypes of gastric adenocarcinomas with particular biological properties and responses to chemotherapy and targeted agents. We compared gene expression patterns among 248 gastric tumors; using a robust method of unsupervised clustering, consensus hierarchical clustering with iterative feature selection, we identified 3 major subtypes. We developed a classifier for these subtypes and validated it in 70 tumors from a different population. We identified distinct genomic and epigenomic properties of the subtypes. We determined drug sensitivities of the subtypes in primary tumors using clinical survival data, and in cell lines through high-throughput drug screening. We identified 3 subtypes of gastric adenocarcinoma: proliferative, metabolic, and mesenchymal. Tumors of the proliferative subtype had high levels of genomic instability, TP53 mutations, and DNA hypomethylation. Cancer cells of the metabolic subtype were more sensitive to 5-fluorouracil than the other subtypes. Furthermore, in 2 independent groups of patients, those with tumors of the metabolic subtype appeared to have greater benefits with 5-fluorouracil treatment. Tumors of the mesenchymal subtype contain cells with features of cancer stem cells, and cell lines of this subtype are particularly sensitive to phosphatidylinositol 3-kinase-AKT-mTOR inhibitors in vitro. Based on gene expression patterns, we classified gastric cancers into 3 subtypes, and validated these in an independent set of tumors. The subgroups have differences in molecular and genetic features and response to therapy; this information might be used to select specific treatment approaches for patients with gastric cancer. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Ability of HIV-1 Nef to downregulate CD4 and HLA class I differs among viral subtypes

PubMed Central

2013-01-01

Background The highly genetically diverse HIV-1 group M subtypes may differ in their biological properties. Nef is an important mediator of viral pathogenicity; however, to date, a comprehensive inter-subtype comparison of Nef in vitro function has not been undertaken. Here, we investigate two of Nef’s most well-characterized activities, CD4 and HLA class I downregulation, for clones obtained from 360 chronic patients infected with HIV-1 subtypes A, B, C or D. Results Single HIV-1 plasma RNA Nef clones were obtained from N=360 antiretroviral-naïve, chronically infected patients from Africa and North America: 96 (subtype A), 93 (B), 85 (C), and 86 (D). Nef clones were expressed by transfection in an immortalized CD4+ T-cell line. CD4 and HLA class I surface levels were assessed by flow cytometry. Nef expression was verified by Western blot. Subset analyses and multivariable linear regression were used to adjust for differences in age, sex and clinical parameters between cohorts. Consensus HIV-1 subtype B and C Nef sequences were synthesized and functionally assessed. Exploratory sequence analyses were performed to identify potential genotypic correlates of Nef function. Subtype B Nef clones displayed marginally greater CD4 downregulation activity (p = 0.03) and markedly greater HLA class I downregulation activity (p < 0.0001) than clones from other subtypes. Subtype C Nefs displayed the lowest in vitro functionality. Inter-subtype differences in HLA class I downregulation remained statistically significant after controlling for differences in age, sex, and clinical parameters (p < 0.0001). The synthesized consensus subtype B Nef showed higher activities compared to consensus C Nef, which was most pronounced in cells expressing lower protein levels. Nef clones exhibited substantial inter-subtype diversity: cohort consensus residues differed at 25% of codons, while a similar proportion of codons exhibited substantial inter-subtype differences in major variant frequency. These amino acids, along with others identified in intra-subtype analyses, represent candidates for mediating inter-subtype differences in Nef function. Conclusions Results support a functional hierarchy of subtype B > A/D > C for Nef-mediated CD4 and HLA class I downregulation. The mechanisms underlying these differences and their relevance to HIV-1 pathogenicity merit further investigation. PMID:24041011

Dilated Cardiomyopathy: Genetic Determinants and Mechanisms.

PubMed

McNally, Elizabeth M; Mestroni, Luisa

2017-09-15

Nonischemic dilated cardiomyopathy (DCM) often has a genetic pathogenesis. Because of the large number of genes and alleles attributed to DCM, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of DCM, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to DCM and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of DCM, especially where arrhythmia risk is increased, and ultimately contribute to clinical management. © 2017 American Heart Association, Inc.

Distribution of Blastocystis subtypes isolated from humans from an urban community in Rio de Janeiro, Brazil.

PubMed

Valença Barbosa, Carolina; de Jesus Batista, Rosemary; Pereira Igreja, Ricardo; d'Avila Levy, Claudia Masini; Werneck de Macedo, Heloisa; Carneiro Santos, Helena Lúcia

2017-10-25

Blastocystis is a cosmopolitan protist parasite found in the human gastrointestinal tract and is highly prevalent in developing countries. Recent molecular studies have revealed extensive genetic diversity, which has been classified into different subtypes (STs) based on sequence analysis of small subunit ribosomal RNA gene. Blastocystis is one of the most common fecal parasites in Brazil, but the diversity of subtypes remains unknown in the country. This study aimed to determine the distribution of Blastocystis STs in an urban community in Duque de Caxias, Rio de Janeiro, Brazil. A total of 64 stool samples positive for Blastocystis in Pavlova's medium were subtyped by PCR and sequenced using primers targeting the small subunit rRNA gene, in addition to phylogenetic analysis and subtype-specific PCR using sequence-tagged-site (STS) primers. Endolimax nana (14%), Entamoeba complex (10.5%), Taenia sp. (0.6%), Trichuris trichiura (1.3%) and Enterobius vermicularis (1.3%) were detected in Blastocystis-positive samples. Of the 64 samples tested by PCR/DNA sequencing, 55 were identified as ST1 (42%), ST3 (49%), ST2 (7%) and ST4 (2%), and the presence of mixed ST (ST1 + ST3) infection was detected in nine samples (14%). DNA sequencing and phylogenetic analysis of Brazilian Blastocystis isolates identified four different subtypes. To our knowledge, this study provided the first genetic characterization of Blastocystis subtypes in an urban area of Rio de Janeiro, Brazil. We also identified ST4 for the first time in Brazil. Further studies are necessary to determine the distribution of STs across human populations in Rio de Janeiro.

[Genetic subtype and epidemiological feature of HIV-1 circulating strains among recently infected patients in Fujian province].

PubMed

Deng, Yongyue; Zhang, Chunyang; Yan, Yansheng; Yan, Pingping; Wu, Shouli

2014-06-01

In order to evaluate the distribution of genetic subtypes and epidemiological feature of HIV-1 circulating strains in Fujian province. Blood samples and epidemiological data were collected from 104 newly infected patients who were distinguished by BED-CEIA methodology, during 2011-2012. Viral sequences(n = 81) of HIV-1 gag, env, and pol segments were amplified by nested PCR. Subtypes B and four Circulating Recombinant Forms, (CRF01_AE, CRF07_BC, CRF08_BC and CRF55_01B) were found in the samples, CRF01_AE(45.68%)and CRF07_BC(35.80%) were the two main HIV-1 strains in Fujian province. Compared with previous data, the proportion of CRF07_BC rose significantly while it gradually decreased in CRF01_AE. Heterosexual contact was still the principal transmission route in Fujian province, but the number of infection among men-who-have-sex-with- men grew rapidly. Results from this study suggested that different subtypes of HIV-1 strain existed in Fujian province. The distribution of subtypes and the mode of transmission were changing with the progress of epidemic. Dynamic monitoring of the molecular epidemiology trends of HIV-1 infection should be enhanced.

Expressive and Receptive Language in Prader-Willi Syndrome: Report on Genetic Subtype Differences

ERIC Educational Resources Information Center

Dimitropoulos, Anastasia; Ferranti, Angela; Lemler, Maria

2013-01-01

Prader-Willi syndrome (PWS), most recognized for the hallmark hyperphagia and food preoccupations, is caused by the absence of expression of the paternally active genes in the q11-13 region of chromosome 15. Since the recognition of PWS as a genetic disorder, most research has focused primarily on the medical, genetic, and behavioral aspects of…

Relationship between the IQ of People with Prader-Willi Syndrome and that of Their Siblings: Evidence for Imprinted Gene Effects

ERIC Educational Resources Information Center

Whittington, J.; Holland, A.; Webb, T.

2009-01-01

Background: Genetic disorders occasionally provide the means to uncover potential mechanisms linking gene expression and physical or cognitive characteristics or behaviour. Prader-Willi syndrome (PWS) is one such genetic disorder in which differences between the two main genetic subtypes have been documented (e.g. higher verbal IQ in one vs.…

Genomic dysregulation in gastric tumors.

PubMed

Janjigian, Yelena Y; Kelsen, David P

2013-03-01

Gastric cancer is among the most common human malignancies and the second leading cause of cancer-related death. The different epidemiologic and histopathology of subtypes of gastric cancer are associated with different genomic patterns. Data suggests that gene expression patterns of proximal, distal gastric cancers-intestinal type, and diffuse/signet cell are well separated. This review summarizes the genetic and epigenetic changes thought to drive gastric cancer and the emerging paradigm of gastric cancer as three unique disease subtypes. Copyright © 2012 Wiley Periodicals, Inc.

Developmental trajectories of DSM-IV symptoms of attention-deficit/hyperactivity disorder: genetic effects, family risk and associated psychopathology.

PubMed

Larsson, Henrik; Dilshad, Rezin; Lichtenstein, Paul; Barker, Edward D

2011-09-01

DSM-IV specifies three ADHD subtypes; the combined, the hyperactive-impulsive and the inattentive. Little is known about the developmental relationships underlying these subtypes. The objective of this study was to describe the development of parent-reported hyperactivity-impulsivity and inattention symptoms from childhood to adolescence and to study their associations with genetic factors, family risk, and later adjustment problems in early adulthood. Data in this study comes from 1,450 twin pairs participating in a population-based, longitudinal twin study. Developmental trajectories were defined using parent-ratings of hyperactivity-impulsivity and inattention symptoms at age 8-9, 13-14, and 16-17. Twin methods were used to explore genetic influences on trajectories. Family risk measures included low socioeconomic status, large family size and divorce. Self-ratings of externalizing and internalizing problems in early adulthood were used to examine adjustment problems related to the different trajectory combinations. We found two hyperactivity-impulsivity trajectories (low, high/decreasing) and two inattention trajectories (low, high/increasing). Twin modeling revealed a substantial genetic component underlying both the hyperactivity-impulsivity and the inattention trajectory. Joint trajectory analyses identified four groups of adolescents with distinct developmental patterns of hyperactivity-impulsivity and inattention: a low/low group, a primarily hyperactive, a primarily inattentive and a combined (high/high) trajectory type. These trajectory combinations showed discriminant relations to adjustment problems in early adulthood. The hyperactive, inattentive and combined trajectory subtypes were associated with higher rates of family risk environments compared to the low/low group. Study results showed that for those on a high trajectory, hyperactivity decreased whereas inattention increased. The combinations of these trajectories lend developmental insight into how children shift from (i) a combined to inattentive subtype, and (ii) a hyperactive-impulsive to a combined subtype. This study suggests that ADHD subtypes cannot be viewed as discrete and stable categories. © 2011 The Authors. Journal of Child Psychology and Psychiatry © 2011 Association for Child and Adolescent Mental Health.

Toward Diagnostic and Phenotype Markers for Genetically Transmitted Speech Delay

ERIC Educational Resources Information Center

Shriberg, Lawrence D.; Lewis, Barbara A.; Tomblin, J. Bruce; McSweeny, Jane L.; Karlsson, Heather B.; Scheer, Alison R.

2005-01-01

Converging evidence supports the hypothesis that the most common subtype of childhood speech sound disorder (SSD) of currently unknown origin is genetically transmitted. We report the first findings toward a set of diagnostic markers to differentiate this proposed etiological subtype (provisionally termed "speech delay-genetic") from other…

The distribution of Blastocystis subtypes in isolates from Qatar.

PubMed

Abu-Madi, Marawan; Aly, Mahmoud; Behnke, Jerzy M; Clark, C Graham; Balkhy, Hanan

2015-09-17

Blastocystis is a common single-celled intestinal parasite of humans and other animals comprising at least 17 genetically distinct small subunit ribosomal RNA lineages (subtypes (STs)), nine of which have been found in humans. The geographic distribution of Blastocystis subtypes is variable, but the subtypes present in Qatar are at present unknown. Stool samples were collected from randomly selected, apparently healthy subjects arriving in Qatar for the first time. Blastocystis subtypes were determined by sequencing of the small subunit rRNA gene (SSU rDNA) PCR products. Phylogenetic analyses were done using Maximum Composite Likelihood method. 71.1 % of samples were positive for Blastocystis infection based on PCR-detection methodology compared to only 6.9 % by microscopy. Prevalence of Blastocystis did not differ between the sexes nor between age classes. However, there was a regional difference in prevalence with subjects arriving from Africa showing the highest (87.6 %), those from Western Asia intermediate (68.6 %) and from Eastern Asia the lowest prevalence (67.6 %). Genetic analysis detected only three STs. ST3 was the most common (69.3 %) and ST2 was the rarest (3.5 %), while ST1 had a prevalence of 27.2 %. ST2 showed a regional variation, being absent from the 64 Western Asian Blastocystis-positive subjects. Both ST1 and ST3 showed significant differences in prevalence between the sexes. This is the first report exploring the distribution of Blastocystis subtypes in our region. We recommend that stool screening via microscopy for the presence of Blastocystis should be abandoned since it is extremely insensitive. In future, the prevalence of Blastocystis infections should be based on PCR methodology and we predict that in the years ahead diagnostic PCR will become the tool of choice. More work is needed to identify the full range of Blastocystis subtypes that circulate in our region.

Intersubtype Differences in the Effect of a Rare p24 Gag Mutation on HIV-1 Replicative Fitness

PubMed Central

Chopera, Denis R.; Cotton, Laura A.; Zawaira, Alexander; Mann, Jaclyn K.; Ngandu, Nobubelo K.; Ntale, Roman; Carlson, Jonathan M.; Mlisana, Koleka; Woodman, Zenda; de Assis Rosa, Debra; Martin, Eric; Miura, Toshiyuki; Pereyra, Florencia; Walker, Bruce D.; Gray, Clive M.; Martin, Darren P.; Ndung'u, Thumbi; Brockman, Mark A.; Karim, Salim Abdool

2012-01-01

Certain immune-driven mutations in HIV-1, such as those arising in p24Gag, decrease viral replicative capacity. However, the intersubtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24Gag M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) (P = 0.0005) and appears to be a rare escape variant selected by HLA-B58 supertype alleles (P < 0.01). In contrast, in subtype C, it is a relatively common minor polymorphic variant (10 to 15%) whose appearance is not associated with a particular HLA allele. Using site-directed mutant viruses, we demonstrate that M250I reduces in vitro viral replicative capacity in both subtype B and subtype C sequences. However, whereas in subtype C downstream compensatory mutations at p24Gag codons 252 and 260 reduce the adverse effects of M250I, fitness costs in subtype B appear difficult to restore. Indeed, patient-derived subtype B sequences harboring M250I exhibited in vitro replicative defects, while those from subtype C did not. The structural implications of M250I were predicted by protein modeling to be greater in subtype B versus C, providing a potential explanation for its lower frequency and enhanced replicative defects in subtype B. In addition to accounting for genetic differences between HIV-1 subtypes, the design of cytotoxic-T-lymphocyte-based vaccines may need to account for differential effects of host-driven viral evolution on viral fitness. PMID:23015721

Detailed Molecular Epidemiologic Characterization of HIV-1 Infection in Bulgaria Reveals Broad Diversity and Evolving Phylodynamics

PubMed Central

Ivanov, Ivailo Alexiev; Beshkov, Danail; Shankar, Anupama; Hanson, Debra L.; Paraskevis, Dimitrios; Georgieva, Viara; Karamacheva, Lyudmila; Taskov, Hristo; Varleva, Tonka; Elenkov, Ivaylo; Stoicheva, Mariana; Nikolova, Daniela; Switzer, William M.

2013-01-01

Limited information is available to describe the molecular epidemiology of HIV-1 in Bulgaria. To better understand the genetic diversity and the epidemiologic dynamics of HIV-1 we analyzed 125 new polymerase (pol) sequences from Bulgarians diagnosed through 2009 and 77 pol sequences available from our previous study from persons infected prior to 2007. Epidemiologic and demographic information was obtained from each participant and phylogenetic analysis was used to infer HIV-1 evolutionary histories. 120 (59.5%) persons were infected with one of five different HIV-1 subtypes (A1, B, C, F1 and H) and 63 (31.2%) persons were infected with one of six different circulating recombinant forms (CRFs; 01_AE, 02_AG, 04_cpx, 05_DF, 14_BG, and 36_cpx). We also for the first time identified infection with two different clusters of unique A-like and F-like sub-subtype variants in 12 persons (5.9%) and seven unique recombinant forms (3.5%), including a novel J/C recombinant. While subtype B was the major genotype identified and was more prevalent in MSM and increased between 2000–2005, most non-B subtypes were present in persons ≥45 years old. CRF01_AE was the most common non-B subtype and was higher in women and IDUs relative to other risk groups combined. Our results show that HIV-1 infection in Bulgaria reflects the shifting distribution of genotypes coincident with the changing epidemiology of the HIV-1 epidemic among different risk groups. Our data support increased public health interventions targeting IDUs and MSM. Furthermore, the substantial and increasing HIV-1 genetic heterogeneity, combined with fluctuating infection dynamics, highlights the importance of sustained and expanded surveillance to prevent and control HIV-1 infection in Bulgaria. PMID:23527245

The effects of child maltreatment on early signs of antisocial behavior: Genetic moderation by Tryptophan Hydroxylase, Serotonin Transporter, and Monoamine Oxidase-A-Genes

PubMed Central

Cicchetti, Dante; Rogosch, Fred A.; Thibodeau, Eric

2013-01-01

Gene-environment interaction effects in predicting antisocial behavior in late childhood were investigated among maltreated and nonmaltreated low-income children (N = 627, M age = 11.27). Variants in three genes, TPH1, 5-HTTLPR, and MAOA uVNTR, were examined. In addition to child maltreatment status, we also considered the impact of maltreatment subtypes, developmental timing of maltreatment, and chronicity. Indicators of antisocial behavior were obtained from self-, peer-, and adult counselor-reports. In a series of ANCOVAs, child maltreatment and its parameters demonstrated strong main effects on early antisocial behavior as assessed by all forms of report. Genetic effects operated primarily in the context of gene-environment interactions, moderating the impact of child maltreatment on outcomes. Across the three genes, among nonmaltreated children no differences in antisocial behavior were found based on genetic variation. In contrast, among maltreated children specific polymorphisms of TPH1, 5-HTTLPR, and MAOA were each related to heightened self-report of antisocial behavior; the interaction of 5-HTTLPR and developmental timing of maltreatment also indicated more severe antisocial outcomes for children with early onset and recurrent maltreatment based on genotype. TPH1 and 5-HTTLPR interacted with maltreatment subtype to predict peer-report of antisocial behavior; genetic variation contributed to larger differences in antisocial behavior among abused children. TPH1 and 5-HTTLPR polymorphisms also moderated the effects of maltreatment subtype on adult report of antisocial behavior; again genetic effects were strongest for children who were abused. Additionally, TPH1 moderated the effect of developmental timing of maltreatment and chronicity on adult report of antisocial behavior. The findings elucidate how genetic variation contributes to identifying which maltreated children are most vulnerable to antisocial development. PMID:22781862

The European Prader-Willi Syndrome Clinical Research Database: An Aid in the Investigation of a Rare Genetically Determined Neurodevelopmental Disorder

ERIC Educational Resources Information Center

Holland, A.; Whittington, J.; Cohen, O.; Curfs, L.; Delahaye, F.; Dudley, O.; Horsthemke, B.; Lindgren, A. -C.; Nourissier, C.; Sharma, N.; Vogels, A.

2009-01-01

Background: Prader-Willi Syndrome (PWS) is a rare genetically determined neurodevelopmental disorder with a complex phenotype that changes with age. The rarity of the syndrome and the need to control for different variables such as genetic sub-type, age and gender limits clinical studies of sufficient size in any one country. A clinical research…

Adaptive Evolution and Environmental Durability Jointly Structure Phylodynamic Patterns in Avian Influenza Viruses

PubMed Central

Roche, Benjamin; Drake, John M.; Brown, Justin; Stallknecht, David E.; Bedford, Trevor; Rohani, Pejman

2014-01-01

Avian influenza viruses (AIVs) have been pivotal to the origination of human pandemic strains. Despite their scientific and public health significance, however, there remains much to be understood about the ecology and evolution of AIVs in wild birds, where major pools of genetic diversity are generated and maintained. Here, we present comparative phylodynamic analyses of human and AIVs in North America, demonstrating (i) significantly higher standing genetic diversity and (ii) phylogenetic trees with a weaker signature of immune escape in AIVs than in human viruses. To explain these differences, we performed statistical analyses to quantify the relative contribution of several potential explanations. We found that HA genetic diversity in avian viruses is determined by a combination of factors, predominantly subtype-specific differences in host immune selective pressure and the ecology of transmission (in particular, the durability of subtypes in aquatic environments). Extending this analysis using a computational model demonstrated that virus durability may lead to long-term, indirect chains of transmission that, when coupled with a short host lifespan, can generate and maintain the observed high levels of genetic diversity. Further evidence in support of this novel finding was found by demonstrating an association between subtype-specific environmental durability and predicted phylogenetic signatures: genetic diversity, variation in phylogenetic tree branch lengths, and tree height. The conclusion that environmental transmission plays an important role in the evolutionary biology of avian influenza viruses—a manifestation of the “storage effect”—highlights the potentially unpredictable impact of wildlife reservoirs for future human pandemics and the need for improved understanding of the natural ecology of these viruses. PMID:25116957

High genetic variability of HIV-1 in female sex workers from Argentina.

PubMed

Pando, María A; Eyzaguirre, Lindsay M; Carrion, Gladys; Montano, Silvia M; Sanchez, José L; Carr, Jean K; Avila, María M

2007-08-13

A cross-sectional study on 625 Female Sex Workers (FSWs) was conducted between 2000 and 2002 in 6 cities in Argentina. This study describes the genetic diversity and the resistance profile of the HIV-infected subjects. Seventeen samples from HIV positive FSWs were genotyped by env HMA, showing the presence of 9 subtype F, 6 subtype B and 2 subtype C. Sequence analysis of the protease/RT region on 16 of these showed that 10 were BF recombinants, three were subtype B, two were subtype C, and one sample presented a dual infection with subtype B and a BF recombinant. Full-length genomes of five of the protease/RT BF recombinants were also sequenced, showing that three of them were CRF12_BF. One FSW had a dual HIV-1 infection with subtype B and a BF recombinant. The B sections of the BF recombinant clustered closely with the pure B sequence isolated from the same patient. Major resistance mutations to antiretroviral drugs were found in 3 of 16 (18.8%) strains. The genetic diversity of HIV strains among FSWs in Argentina was extensive; about three-quarters of the samples were infected with diverse BF recombinants, near twenty percent had primary ART resistance and one sample presented a dual infection. Heterosexual transmission of genetically diverse, drug resistant strains among FSWs and their clients represents an important and underestimated threat, in Argentina.

Multi-Scale Molecular Deconstruction of the Serotonin Neuron System.

PubMed

Okaty, Benjamin W; Freret, Morgan E; Rood, Benjamin D; Brust, Rachael D; Hennessy, Morgan L; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N; Dymecki, Susan M

2015-11-18

Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity-from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. Copyright © 2015 Elsevier Inc. All rights reserved.

Multi-Scale Molecular Deconstruction of the Serotonin Neuron System

PubMed Central

Okaty, Benjamin W.; Freret, Morgan E.; Rood, Benjamin D.; Brust, Rachael D.; Hennessy, Morgan L.; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N.; Dymecki, Susan M.

2016-01-01

Summary Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-Seq to deconstruct the mouse 5HT system at multiple levels of granularity—from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal: principles underlying system organization, novel 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers new subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. PMID:26549332

The molecular epidemiology of HIV in Asia.

PubMed

Weniger, B G; Takebe, Y; Ou, C Y; Yamazaki, S

1994-01-01

The human immunodeficiency virus (HIV) was introduced readily into Asia and has quickly spread between Asian states through both parenteral and sexual modes of transmission. Only 1 year after Thailand's epidemic wave among intravenous drug users (IDUs) in 1988, the virus spread to the adjacent Myanmar and Malaysia, and another year later IDUs were infected in parts of India and China bordering Myanmar. Several methods can be used to quantify the genetic diversity, divergence, or variation within or between subtypes, genotypes, or isolates. Consensus sequences, representing the most common nucleotide in the genome, are often generated for comparison. 8 subtypes A through F, H, and O have been described for HIV-1 based on the genetic similarities and differences in the env gene or viral envelope. Subtype A and D have been found primarily in central and western Africa. Subtype B is predominant in Europe, the Western hemisphere, Japan, and Australia. Subtype C has been found mostly in southern Africa, the Central African Republic, and India. Subtype E was first identified in Thailand and recently in the Central African Republic. Subtype F has been found in Romania and is a rare variant in Brazil. Isolates from Gabon and the Russian Federation were designated subtype H. An "outlier" subtype O containing 2 human and 2 chimpanzee isolates has been identified in Cameroon and Gabon. Sequencing of the relatively conserved gag gene of geographically diverse HIV-1 isolates yielded a classification with 7 subtypes A-D and F-H. Other topics discussed include genome characterization, comparison with foreign isolates, segregation by mode of transmission, and biologic properties of HIV-1 variants in Thailand; regional diversity of HIV-1 subtypes and substantial spread of HIV-2 in India; as well as HIV transmission and infections in Japan, Australia, Cambodia, China, Taiwan, Philippines, Malaysia, Myanmar, and in states created out of the former Soviet Union.

Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration.

PubMed

Kantor, Rami; Katzenstein, David A; Efron, Brad; Carvalho, Ana Patricia; Wynhoven, Brian; Cane, Patricia; Clarke, John; Sirivichayakul, Sunee; Soares, Marcelo A; Snoeck, Joke; Pillay, Candice; Rudich, Hagit; Rodrigues, Rosangela; Holguin, Africa; Ariyoshi, Koya; Bouzas, Maria Belen; Cahn, Pedro; Sugiura, Wataru; Soriano, Vincent; Brigido, Luis F; Grossman, Zehava; Morris, Lynn; Vandamme, Anne-Mieke; Tanuri, Amilcar; Phanuphak, Praphan; Weber, Jonathan N; Pillay, Deenan; Harrigan, P Richard; Camacho, Ricardo; Schapiro, Jonathan M; Shafer, Robert W

2005-04-01

The genetic differences among HIV-1 subtypes may be critical to clinical management and drug resistance surveillance as antiretroviral treatment is expanded to regions of the world where diverse non-subtype-B viruses predominate. To assess the impact of HIV-1 subtype and antiretroviral treatment on the distribution of mutations in protease and reverse transcriptase, a binomial response model using subtype and treatment as explanatory variables was used to analyze a large compiled dataset of non-subtype-B HIV-1 sequences. Non-subtype-B sequences from 3,686 persons with well characterized antiretroviral treatment histories were analyzed in comparison to subtype B sequences from 4,769 persons. The non-subtype-B sequences included 461 with subtype A, 1,185 with C, 331 with D, 245 with F, 293 with G, 513 with CRF01_AE, and 618 with CRF02_AG. Each of the 55 known subtype B drug-resistance mutations occurred in at least one non-B isolate, and 44 (80%) of these mutations were significantly associated with antiretroviral treatment in at least one non-B subtype. Conversely, of 67 mutations found to be associated with antiretroviral therapy in at least one non-B subtype, 61 were also associated with antiretroviral therapy in subtype B isolates. Global surveillance and genotypic assessment of drug resistance should focus primarily on the known subtype B drug-resistance mutations.

Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression.

PubMed

Kiguoya, Marion W; Mann, Jaclyn K; Chopera, Denis; Gounder, Kamini; Lee, Guinevere Q; Hunt, Peter W; Martin, Jeffrey N; Ball, T Blake; Kimani, Joshua; Brumme, Zabrina L; Brockman, Mark A; Ndung'u, Thumbi

2017-07-01

There are marked differences in the spread and prevalence of HIV-1 subtypes worldwide, and differences in clinical progression have been reported. However, the biological reasons underlying these differences are unknown. Gag-protease is essential for HIV-1 replication, and Gag-protease-driven replication capacity has previously been correlated with disease progression. We show that Gag-protease replication capacity correlates significantly with that of whole isolates ( r = 0.51; P = 0.04), indicating that Gag-protease is a significant contributor to viral replication capacity. Furthermore, we investigated subtype-specific differences in Gag-protease-driven replication capacity using large well-characterized cohorts in Africa and the Americas. Patient-derived Gag-protease sequences were inserted into an HIV-1 NL4-3 backbone, and the replication capacities of the resulting recombinant viruses were measured in an HIV-1-inducible reporter T cell line by flow cytometry. Recombinant viruses expressing subtype C Gag-proteases exhibited substantially lower replication capacities than those expressing subtype B Gag-proteases ( P < 0.0001); this observation remained consistent when representative Gag-protease sequences were engineered into an HIV-1 subtype C backbone. We identified Gag residues 483 and 484, located within the Alix-binding motif involved in virus budding, as major contributors to subtype-specific replicative differences. In East African cohorts, we observed a hierarchy of Gag-protease-driven replication capacities, i.e., subtypes A/C < D < intersubtype recombinants ( P < 0.0029), which is consistent with reported intersubtype differences in disease progression. We thus hypothesize that the lower Gag-protease-driven replication capacity of subtypes A and C slows disease progression in individuals infected with these subtypes, which in turn leads to greater opportunity for transmission and thus increased prevalence of these subtypes. IMPORTANCE HIV-1 subtypes are unevenly distributed globally, and there are reported differences in their rates of disease progression and epidemic spread. The biological determinants underlying these differences have not been fully elucidated. Here, we show that HIV-1 Gag-protease-driven replication capacity correlates with the replication capacity of whole virus isolates. We further show that subtype B displays a significantly higher Gag-protease-mediated replication capacity than does subtype C, and we identify a major genetic determinant of these differences. Moreover, in two independent East African cohorts we demonstrate a reproducible hierarchy of Gag-protease-driven replicative capacity, whereby recombinants exhibit the greatest replication, followed by subtype D, followed by subtypes A and C. Our data identify Gag-protease as a major determinant of subtype differences in disease progression among HIV-1 subtypes; furthermore, we propose that the poorer viral replicative capacity of subtypes A and C may paradoxically contribute to their more efficient spread in sub-Saharan Africa. Copyright © 2017 American Society for Microbiology.

A strategy for molecular diagnostics of Fanconi anemia in Brazilian patients.

PubMed

Pilonetto, Daniela V; Pereira, Noemi F; Bonfim, Carmem M S; Ribeiro, Lisandro L; Bitencourt, Marco A; Kerkhoven, Lianne; Floor, Karijn; Ameziane, Najim; Joenje, Hans; Gille, Johan J P; Pasquini, Ricardo

2017-07-01

Fanconi anemia (FA) is a predominantly autosomal recessive disease with wide genetic heterogeneity resulting from mutations in several DNA repair pathway genes. To date, 21 genetic subtypes have been identified. We aimed to identify the FA genetic subtypes in the Brazilian population and to develop a strategy for molecular diagnosis applicable to routine clinical use. We screened 255 patients from Hospital de Clínicas, Universidade Federal do Paraná for 11 common FA gene mutations. Further analysis by multiplex ligation-dependent probe amplification (MLPA) for FANCA and Sanger sequencing of all coding exons of FANCA , -C , and - G was performed in cases who harbored a single gene mutation. We identified biallelic mutations in 128/255 patients (50.2%): 89, 11, and 28 carried FANCA , FANCC , and FANCG mutations, respectively. Of these, 71 harbored homozygous mutations, whereas 57 had compound heterozygous mutations. In 4/57 heterozygous patients, both mutations were identified by the initial screening, in 51/57 additional analyses was required for classification, and in 2/57 the second mutation remained unidentified. We found 52 different mutations of which 22 were novel. The proposed method allowed genetic subtyping of 126/255 (49.4%) patients at a significantly reduced time and cost, which makes molecular diagnosis of FA Brazilian patients feasible.

Atrial Fibrillation Genetic Risk and Ischemic Stroke Mechanisms.

PubMed

Lubitz, Steven A; Parsons, Owen E; Anderson, Christopher D; Benjamin, Emelia J; Malik, Rainer; Weng, Lu-Chen; Dichgans, Martin; Sudlow, Cathie L; Rothwell, Peter M; Rosand, Jonathan; Ellinor, Patrick T; Markus, Hugh S; Traylor, Matthew

2017-06-01

Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, but the relationship between AF and noncardioembolic stroke subtypes are unclear. Because AF may be unrecognized, and because AF has a substantial genetic basis, we assessed for predisposition to AF across ischemic stroke subtypes. We examined associations between AF genetic risk and Trial of Org 10172 in Acute Stroke Treatment stroke subtypes in 2374 ambulatory individuals with ischemic stroke and 5175 without from the Wellcome Trust Case-Control Consortium 2 using logistic regression. We calculated AF genetic risk scores using single-nucleotide polymorphisms associated with AF in a previous independent analysis across a range of preselected significance thresholds. There were 460 (19.4%) individuals with cardioembolic stroke, 498 (21.0%) with large vessel, 474 (20.0%) with small vessel, and 814 (32.3%) individuals with strokes of undetermined cause. Most AF genetic risk scores were associated with stroke, with the strongest association ( P =6×10 - 4 ) attributed to scores of 944 single-nucleotide polymorphisms (each associated with AF at P <1×10 - 3 in a previous analysis). Associations between AF genetic risk and stroke were enriched in the cardioembolic stroke subset (strongest P =1.2×10 - 9 , 944 single-nucleotide polymorphism score). In contrast, AF genetic risk was not significantly associated with noncardioembolic stroke subtypes. Comprehensive AF genetic risk scores were specific for cardioembolic stroke. Incomplete workups and subtype misclassification may have limited the power to detect associations with strokes of undetermined pathogenesis. Future studies are warranted to determine whether AF genetic risk is a useful biomarker to enhance clinical discrimination of stroke pathogeneses. © 2017 American Heart Association, Inc.

HIV Genetic Diversity and Drug Resistance.

PubMed

Santos, André F; Soares, Marcelo A

2010-02-01

Most of the current knowledge on antiretroviral (ARV) drug development and resistance is based on the study of subtype B of HIV-1, which only accounts for 10% of the worldwide HIV infections. Cumulative evidence has emerged that different HIV types, groups and subtypes harbor distinct biological properties, including the response and susceptibility to ARV. Recent laboratory and clinical data highlighting such disparities are summarized in this review. Variations in drug susceptibility, in the emergence and selection of specific drug resistance mutations, in viral replicative capacity and in the dynamics of resistance acquisition under ARV selective pressure are discussed. Clinical responses to ARV therapy and associated confounding factors are also analyzed in the context of infections by distinct HIV genetic variants.

[Molecular epidemiological analysis of HIV-1 variants circulating in Russia in 1987-2015].

PubMed

Lapovok, I A; Lopatukhin, A E; Kireev, D E; Kazennova, E V; Lebedev, A V; Bobkova, M R; Kolomeets, A N; Turbina, G I; Shipulin, G A; Ladnaya, N N; Pokrovsky, V V

To simultaneously analyze HIV-1 samples from all Russian regions to characterize the epidemiology of HIV infection in the country as a whole. The most extensive study was conducted to examine nucleotide sequences of the pol gene of HIV-1 samples isolated from HIV-positive persons in different regions of Russia, with the diagnosis date being fixed during 1987-2015. The nucleotide sequences of the HIV-1 genome were analyzed using computer programs and on-line applications to identify a virus subtype and new recombinant forms. The nucleotide sequences of the pol gene were analyzed in 1697 HIV-1 samples and the findings were that the genetic variant subtype A1 (IDU-A) was dominant throughout the entire territory of Russia (in more than 80% of all infection cases). Other virus variants circulating in Russia were analyzed; the phenomenon of the higher distribution of the recombinant form CRF63/02A in Siberia, which had been previously described in the literature, was also confirmed. Four new recombinant forms generated by the virus subtype A1 (IDU-A) and B and two AG recombinant forms were found. There was a larger genetic distance between the viruses of IDU-A variant circulating among the injecting drug users and those infected through heterosexual contact, as well as a change in the viruses of subtype G that caused the outbreak in the south of the country over time in 1988-1989. The findings demonstrate continuous HIV-1 genetic variability and recombination over time in Russia, as well as increased genetic diversity with higher HIV infection rates in the population.

Divergent genetic evolution of hemagglutinin in influenza A H1N1 and A H1N2 subtypes isolated in the south-France since the winter of 2001-2002.

PubMed

Al Faress, Shaker; Cartet, Gaëlle; Ferraris, Olivier; Norder, Helene; Valette, Martine; Lina, Bruno

2005-07-01

Influenza A viruses are divided into subtypes based on their hemagglutinin (H1 to H15) and neuraminidase (N1 to N9) glycoproteins. Of these, three A subtypes H1N1, H3N2 and H1N2 circulate in the human population. Influenza A viruses display a high antigenic variability called "antigenic drift" which allows the virus to escape antibody neutralization. Evaluate the mutations apparition that might predict a divergent antigenic evolution of hemagglutinin in influenza A H1N1 and A H1N2 viruses. During the three winters of 2001-2002 to 2003-2004, 58 A H1N1 and 23 A H1N2 subtypes have been isolated from patients with influenza-like illness in the south of France. The HA1 region was analyzed by RT-PCR and subsequently sequenced to compare the HA1 genetic evolution of influenza A H1N1 and A H1N2 subtypes. Our results showed that 28 amino acid substitutions have accumulated in the HA1 region since the circulation of A/New Caledonia/20/99-like viruses in France. Of these, fifteen were located in four antigenic sites (B, C, D and E). Six of them were observed only in the A H1N2 isolates, six only in the A H1N1 isolates and three in both subtypes. Furthermore, nine of twenty two A H1N2 isolates from the winter of 2002-2003 shared a T90A amino acid change which has not been observed in any A H1N1 isolate; resulting in the introduction of a new glycosylation site close to the antigenic site E. This might mask some antigenic E determinants and therefore, modify the A H1N2 antigenicity. The divergent genetic evolution of hemagglutinin may ultimately lead to a significant different antigenicity between A H1N1 and A H1N2 subtypes that would require the introduction of a new subtype in the vaccine batches.

Roles of specific Kv channel types in repolarization of the action potential in genetically identified subclasses of pyramidal neurons in mouse neocortex

PubMed Central

Pathak, Dhruba; Guan, Dongxu

2016-01-01

The action potential (AP) is a fundamental feature of excitable cells that serves as the basis for long-distance signaling in the nervous system. There is considerable diversity in the appearance of APs and the underlying repolarization mechanisms in different neuronal types (reviewed in Bean BP. Nat Rev Neurosci 8: 451–465, 2007), including among pyramidal cell subtypes. In the present work, we used specific pharmacological blockers to test for contributions of Kv1, Kv2, or Kv4 channels to repolarization of single APs in two genetically defined subpopulations of pyramidal cells in layer 5 of mouse somatosensory cortex (etv1 and glt) as well as pyramidal cells from layer 2/3. These three subtypes differ in AP properties (Groh A, Meyer HS, Schmidt EF, Heintz N, Sakmann B, Krieger P. Cereb Cortex 20: 826–836, 2010; Guan D, Armstrong WE, Foehring RC. J Neurophysiol 113: 2014–2032, 2015) as well as laminar position, morphology, and projection targets. We asked what the roles of Kv1, Kv2, and Kv4 channels are in AP repolarization and whether the underlying mechanisms are pyramidal cell subtype dependent. We found that Kv4 channels are critically involved in repolarizing neocortical pyramidal cells. There are also pyramidal cell subtype-specific differences in the role for Kv1 channels. Only Kv4 channels were involved in repolarizing the narrow APs of glt cells. In contrast, in etv1 cells and layer 2/3 cells, the broader APs are partially repolarized by Kv1 channels in addition to Kv4 channels. Consistent with their activation in the subthreshold range, Kv1 channels also regulate AP voltage threshold in all pyramidal cell subtypes. PMID:26864770

Genomic Epidemiology of Salmonella enterica Serotype Enteritidis based on Population Structure of Prevalent Lineages

PubMed Central

Desai, Prerak T.; den Bakker, Henk C.; Mikoleit, Matthew; Tolar, Beth; Trees, Eija; Hendriksen, Rene S.; Frye, Jonathan G.; Porwollik, Steffen; Weimer, Bart C.; Wiedmann, Martin; Weinstock, George M.; Fields, Patricia I.; McClelland, Michael

2014-01-01

Salmonella enterica serotype Enteritidis is one of the most commonly reported causes of human salmonellosis. Its low genetic diversity, measured by fingerprinting methods, has made subtyping a challenge. We used whole-genome sequencing to characterize 125 S. enterica Enteritidis and 3 S. enterica serotype Nitra strains. Single-nucleotide polymorphisms were filtered to identify 4,887 reliable loci that distinguished all isolates from each other. Our whole-genome single-nucleotide polymorphism typing approach was robust for S. enterica Enteritidis subtyping with combined data for different strains from 2 different sequencing platforms. Five major genetic lineages were recognized, which revealed possible patterns of geographic and epidemiologic distribution. Analyses on the population dynamics and evolutionary history estimated that major lineages emerged during the 17th–18th centuries and diversified during the 1920s and 1950s. PMID:25147968

Atypical β-Catenin Activated Child Hepatocellular Tumor

PubMed Central

Unlu, Havva Akmaz; Karakus, Esra; Yazal Erdem, Arzu; Yakut, Zeynep Ilerisoy

2015-01-01

Hepatocellular adenomas are a benign, focal, hepatic neoplasm that have been divided into four subtypes according to the genetic and pathological features. The β-catenin activated subtype accounts for 10-15% of all hepatocellular adenomas and specific magnetic resonance imaging features have been defined for different hepatocellular adenomas subtypes. The current study aimed to report the magnetic resonance imaging features of a well differentiated hepatocellular carcinoma that developed on the basis of β-catenin activated hepatocellular adenomas in a child. In this case, atypical diffuse steatosis was determined in the lesion. In the literature, diffuse steatosis, which is defined as a feature of the hepatocyte nuclear factor-1α-inactivated hepatocellular adenomas subtype, has not been previously reported in any β-catenin activated hepatocellular adenomas case. Interlacing magnetic resonance imaging findings between subtypes show that there are still many mysteries about this topic and larger studies are warranted. PMID:26157702

Comparison of the COBAS TAQMAN HIV-1 HPS with VERSANT HIV-1 RNA 3.0 assay (bDNA) for plasma RNA quantitation in different HIV-1 subtypes.

PubMed

Gomes, Perpétua; Palma, Ana Carolina; Cabanas, Joaquim; Abecasis, Ana; Carvalho, Ana Patrícia; Ziermann, Rainer; Diogo, Isabel; Gonçalves, Fátima; Lobo, Céu Sousa; Camacho, Ricardo

2006-08-01

Quantitation of HIV-1 RNA levels in plasma has an undisputed prognostic value and is extremely important for evaluating response to antiretroviral therapy. The purpose of this study was to evaluate the performance of the real-time PCR COBAS TaqMan 48 analyser, comparing it to the existing VERSANT 3.0 (bDNA) for HIV-1 RNA quantitation in plasma of individuals infected with different HIV-1 subtypes (104 blood samples). A positive linear correlation between the two tests (r2 = 0.88) was found. Quantitation by the COBAS TaqMan assay was approximately 0.32log10 higher than by bDNA. The relationship between the two assays was similar within all subtypes with a Deming regression of <1 and <0 for the Bland-Altman plots. Overall, no significant differences were found in plasma viral load quantitation in different HIV-1 subtypes between both assays; therefore these assays are suitable for viral load quantitation of highly genetically diverse HIV-1 plasma samples.

Combining Cell Type-Restricted Adenoviral Targeting with Immunostaining and Flow Cytometry to Identify Cells-of-Origin of Lung Cancer.

PubMed

Best, Sarah A; Kersbergen, Ariena; Asselin-Labat, Marie-Liesse; Sutherland, Kate D

2018-01-01

Lung cancers display considerable intertumoral heterogeneity, leading to the classification of distinct tumor subtypes. Our understanding of the genetic aberrations that underlie tumor subtypes has been greatly enhanced by recent genomic sequencing studies and state-of-the-art gene targeting technologies, highlighting evidence that distinct lung cancer subtypes may be derived from different "cells-of-origin". Here, we describe the intra-tracheal delivery of cell type-restricted Ad5-Cre viruses into the lungs of adult mice, combined with immunohistochemical and flow cytometry strategies for the detection of lung cancer-initiating cells in vivo.

HYDRA: Revealing heterogeneity of imaging and genetic patterns through a multiple max-margin discriminative analysis framework.

PubMed

Varol, Erdem; Sotiras, Aristeidis; Davatzikos, Christos

2017-01-15

Multivariate pattern analysis techniques have been increasingly used over the past decade to derive highly sensitive and specific biomarkers of diseases on an individual basis. The driving assumption behind the vast majority of the existing methodologies is that a single imaging pattern can distinguish between healthy and diseased populations, or between two subgroups of patients (e.g., progressors vs. non-progressors). This assumption effectively ignores the ample evidence for the heterogeneous nature of brain diseases. Neurodegenerative, neuropsychiatric and neurodevelopmental disorders are largely characterized by high clinical heterogeneity, which likely stems in part from underlying neuroanatomical heterogeneity of various pathologies. Detecting and characterizing heterogeneity may deepen our understanding of disease mechanisms and lead to patient-specific treatments. However, few approaches tackle disease subtype discovery in a principled machine learning framework. To address this challenge, we present a novel non-linear learning algorithm for simultaneous binary classification and subtype identification, termed HYDRA (Heterogeneity through Discriminative Analysis). Neuroanatomical subtypes are effectively captured by multiple linear hyperplanes, which form a convex polytope that separates two groups (e.g., healthy controls from pathologic samples); each face of this polytope effectively defines a disease subtype. We validated HYDRA on simulated and clinical data. In the latter case, we applied the proposed method independently to the imaging and genetic datasets of the Alzheimer's Disease Neuroimaging Initiative (ADNI 1) study. The imaging dataset consisted of T1-weighted volumetric magnetic resonance images of 123 AD patients and 177 controls. The genetic dataset consisted of single nucleotide polymorphism information of 103 AD patients and 139 controls. We identified 3 reproducible subtypes of atrophy in AD relative to controls: (1) diffuse and extensive atrophy, (2) precuneus and extensive temporal lobe atrophy, as well some prefrontal atrophy, (3) atrophy pattern very much confined to the hippocampus and the medial temporal lobe. The genetics dataset yielded two subtypes of AD characterized mainly by the presence/absence of the apolipoprotein E (APOE) ε4 genotype, but also involving differential presence of risk alleles of CD2AP, SPON1 and LOC39095 SNPs that were associated with differences in the respective patterns of brain atrophy, especially in the precuneus. The results demonstrate the potential of the proposed approach to map disease heterogeneity in neuroimaging and genetic studies. Copyright © 2016 Elsevier Inc. All rights reserved.

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma.

PubMed

Ricketts, Christopher J; De Cubas, Aguirre A; Fan, Huihui; Smith, Christof C; Lang, Martin; Reznik, Ed; Bowlby, Reanne; Gibb, Ewan A; Akbani, Rehan; Beroukhim, Rameen; Bottaro, Donald P; Choueiri, Toni K; Gibbs, Richard A; Godwin, Andrew K; Haake, Scott; Hakimi, A Ari; Henske, Elizabeth P; Hsieh, James J; Ho, Thai H; Kanchi, Rupa S; Krishnan, Bhavani; Kwiatkowski, David J; Lui, Wembin; Merino, Maria J; Mills, Gordon B; Myers, Jerome; Nickerson, Michael L; Reuter, Victor E; Schmidt, Laura S; Shelley, C Simon; Shen, Hui; Shuch, Brian; Signoretti, Sabina; Srinivasan, Ramaprasad; Tamboli, Pheroze; Thomas, George; Vincent, Benjamin G; Vocke, Cathy D; Wheeler, David A; Yang, Lixing; Kim, William Y; Robertson, A Gordon; Spellman, Paul T; Rathmell, W Kimryn; Linehan, W Marston

2018-04-03

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival. Published by Elsevier Inc.

Variation of types of alcoholism: review and subtypes identified in Han Chinese.

PubMed

Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Lu, Ru-Band

2014-01-03

Alcoholism, as it has been hypothesized, is caused by a highly heterogeneous genetic load. Since 1960, many reports have used the bio-psycho-social approach to subtype alcoholism; however, no subtypes have been genetically validated. We reviewed and compared the major single-gene, multiple-gene, and gene-to-gene interaction studies on alcoholism published during the past quarter-century, including many recent studies that have made contributions to the subtyping of alcoholism. Four subtypes of alcoholism have been reported: [1] pure alcoholism, [2] anxiety/depression alcoholism, [3] antisocial alcoholism, and [4] mixed alcoholism. Most of the important studies focused on three genes: DRD2, MAOA, and ALDH2. Therefore, our review focuses on these three genes. © 2013.

Discrimination of Avian Influenza Virus using Host-cell Infection Fingerprinting by Sulfinate-based Fluorescence Superoxide Probe.

PubMed

Hong, Seong Cheol; Murale, Dhiraj P; Jang, Se-Young; Haque, Md Mamunul; Seo, Minah; Lee, Seok; Woo, Deok Ha; Kwon, Junghoon; Song, Chang-Seon; Kim, Yun Kyung; Lee, Jun-Seok

2018-06-22

Avian Influenza (AI) caused an annual epidemic outbreak that led to destroying tens of millions of poultry worldwide. Current gold standard AI diagnosis method is an embryonic egg-based hemagglutination assay followed by immunoblotting or PCR sequencing to confirm subtypes. It requires, however, specialized facilities to handle egg inoculation and incubation, and the subtyping methods relied on costly reagents. Here, we demonstrated the first differential sensing approach to distinguish AI subtypes using series of cell lines and fluorescent sensor. Susceptibility of AI virus differs depending on genetic backgrounds of host cells. Thus, we examined cells from different organ origin, and the infection patterns against a panel of cells were utilized for AI virus subtyping. To quantify AI infection, we designed a highly cell-permeable fluorescent superoxide sensor to visualize infection. Though many AI monitoring strategies relied on sophisticated antibody have been extensively studied, our differential sensing strategy successfully proved discriminations of AI subtypes and demonstrated as a useful primary screening platform to monitor a large number of samples. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Emergence of new forms of human immunodeficiency virus type 1 intersubtype recombinants in central Myanmar.

PubMed

Motomura, K; Kusagawa, S; Kato, K; Nohtomi, K; Lwin, H H; Tun, K M; Thwe, M; Oo, K Y; Lwin, S; Kyaw, O; Zaw, M; Nagai, Y; Takebe, Y

2000-11-20

We have previously shown that HIV-1 env subtypes B' (a Thai-B cluster within subtype B) and E (CRF01_AE) are distributed in Yangon, the capital city of Myanmar. However, HIV strains from the rest of country have not yet been genetically characterized. In the present study, we determined env (C2/V3) and gag (p17) subtypes of 25 specimens from central Myanmar (Mandalay). Phylogenetic analyses identified 5 subtype C (20%), in addition to 10 CRF01_AE (40%) and 4 subtype B' (16%). Interestingly, the remaining six specimens (24%) showed discordance between gag and env subtypes; three gag subtype B'/env subtype C, one gag subtype B'/env subtype E, one gag subtype C/env subtype B', and one gag subtype C/env subtype E. These discordant specimens were found frequently among injecting drug users (4 of 12, 33%) and female commercial sex workers (2 of 8, 25%) engaging in high-risk behaviors. The recombinant nature of these HIV-1 strains was verified in three specimens, indicating the presence of new forms of HIV-1 intersubtype C/B' and C/B'/E recombinants with different recombination breakpoints. The data suggest that multiple subtypes of B', C, and CRF01_AE are cocirculating in central Myanmar, leading to the evolution of new forms of intersubtype recombinants among the risk populations exhibiting one of the highest HIV infection rates in the region.

Impact of HIV-1 Subtype and Antiretroviral Therapy on Protease and Reverse Transcriptase Genotype: Results of a Global Collaboration

PubMed Central

Kantor, Rami; Katzenstein, David A; Efron, Brad; Carvalho, Ana Patricia; Wynhoven, Brian; Cane, Patricia; Clarke, John; Sirivichayakul, Sunee; Soares, Marcelo A; Snoeck, Joke; Pillay, Candice; Rudich, Hagit; Rodrigues, Rosangela; Holguin, Africa; Ariyoshi, Koya; Bouzas, Maria Belen; Cahn, Pedro; Sugiura, Wataru; Soriano, Vincent; Brigido, Luis F; Grossman, Zehava; Morris, Lynn; Vandamme, Anne-Mieke; Tanuri, Amilcar; Phanuphak, Praphan; Weber, Jonathan N; Pillay, Deenan; Harrigan, P. Richard; Camacho, Ricardo; Schapiro, Jonathan M; Shafer, Robert W

2005-01-01

Background The genetic differences among HIV-1 subtypes may be critical to clinical management and drug resistance surveillance as antiretroviral treatment is expanded to regions of the world where diverse non-subtype-B viruses predominate. Methods and Findings To assess the impact of HIV-1 subtype and antiretroviral treatment on the distribution of mutations in protease and reverse transcriptase, a binomial response model using subtype and treatment as explanatory variables was used to analyze a large compiled dataset of non-subtype-B HIV-1 sequences. Non-subtype-B sequences from 3,686 persons with well characterized antiretroviral treatment histories were analyzed in comparison to subtype B sequences from 4,769 persons. The non-subtype-B sequences included 461 with subtype A, 1,185 with C, 331 with D, 245 with F, 293 with G, 513 with CRF01_AE, and 618 with CRF02_AG. Each of the 55 known subtype B drug-resistance mutations occurred in at least one non-B isolate, and 44 (80%) of these mutations were significantly associated with antiretroviral treatment in at least one non-B subtype. Conversely, of 67 mutations found to be associated with antiretroviral therapy in at least one non-B subtype, 61 were also associated with antiretroviral therapy in subtype B isolates. Conclusion Global surveillance and genotypic assessment of drug resistance should focus primarily on the known subtype B drug-resistance mutations. PMID:15839752

Genetic Diversity of HIV-1 in Tunisia.

PubMed

El Moussi, Awatef; Thomson, Michael M; Delgado, Elena; Cuevas, María Teresa; Nasr, Majda; Abid, Salma; Ben Hadj Kacem, Mohamed Ali; Benaissa Tiouiri, Hanene; Letaief, Amel; Chakroun, Mohamed; Ben Jemaa, Mounir; Hamdouni, Hayet; Tej Dellagi, Rafla; Kheireddine, Khaled; Boutiba, Ilhem; Pérez-Álvarez, Lucía; Slim, Amine

2017-01-01

In this study, the genetic diversity of HIV-1 in Tunisia was analyzed. For this, 193 samples were collected in different regions of Tunisia between 2012 and 2015. A protease and reverse transcriptase fragment were amplified and sequenced. Phylogenetic analyses were performed through maximum likelihood and recombination was analyzed by bootscanning. Six HIV-1 subtypes (B, A1, G, D, C, and F2), 5 circulating recombinant forms (CRF02_AG, CRF25_cpx, CRF43_02G, CRF06_cpx, and CRF19_cpx), and 11 unique recombinant forms were identified. Subtype B (46.4%) and CRF02_AG (39.4%) were the predominant genetic forms. A group of 44 CRF02_AG sequences formed a distinct Tunisian cluster, which also included four viruses from western Europe. Nine viruses were closely related to isolates collected in other African or in European countries. In conclusion, a high HIV-1 genetic diversity is observed in Tunisia and the local spread of CRF02_AG is first documented in this country.

Benefits and Limitations of Prenatal Screening for Prader-Willi Syndrome

PubMed Central

Butler, Merlin G.

2016-01-01

This review the status of genetic laboratory testing in Prader-Willi syndrome (PWS) due to different genetic subtypes, most often a paternally derived 15q11-q13 deletion, with benefits and limitations related to prenatal screening. Medical literature was searched for prenatal screening and genetic laboratory testing methods in use or under development and discussed in relationship to PWS. Genetic testing includes six established laboratory diagnostic approaches for PWS with direct application to prenatal screening. Ultrasonographic, obstetric and cytogenetic reports were summarized in relationship to the cause of Prader-Willi syndrome and identification of specific genetic subtypes including maternal disomy 15. Advances in genetic technology were described for diagnosing PWS specifically DNA methylation and high-resolution chromosomal SNP microarrays as current tools for genetic screening and incorporating next generation DNA sequencing for noninvasive prenatal testing (NIPT) using cell-free fetal DNA. Positive experiences are reported with NIPT for detection of numerical chromosomal problems (aneuploidies) but not for structural problems (microdeletions). These reports will be discussed along with future directions for genetic screening of PWS. In summary, this review describes and discusses the status of established and ongoing genetic testing options for PWS applicable in prenatal screening including NIPT and future directions for early diagnosis in Prader-Willi syndrome. PMID:27537837

Benefits and limitations of prenatal screening for Prader-Willi syndrome.

PubMed

Butler, Merlin G

2017-01-01

This review summarizes the status of genetic laboratory testing in Prader-Willi syndrome (PWS) with different genetic subtypes, most often a paternally derived 15q11-q13 deletion and discusses benefits and limitations related to prenatal screening. Medical literature was searched for prenatal screening and genetic laboratory testing methods in use or under development and discussed in relationship to PWS. Genetic testing includes six established laboratory diagnostic approaches for PWS with direct application to prenatal screening. Ultrasonographic, obstetric and cytogenetic reports were summarized in relationship to the cause of PWS and identification of specific genetic subtypes including maternal disomy 15. Advances in genetic technology were described for diagnosing PWS specifically DNA methylation and high-resolution chromosomal SNP microarrays as current tools for genetic screening and incorporating next generation DNA sequencing for noninvasive prenatal testing (NIPT) using cell-free fetal DNA. Positive experiences are reported with NIPT for detection of numerical chromosomal problems (aneuploidies) but not for structural problems (microdeletions). These reports will be discussed along with future directions for genetic screening of PWS. In summary, this review describes and discusses the status of established and ongoing genetic testing options for PWS applicable in prenatal screening including NIPT and future directions for early diagnosis in PWS. © 2016 John Wiley & Sons, Ltd. © 2016 John Wiley & Sons, Ltd.

Stroke Genetics Network (SiGN) Study: Design and rationale for a genome-wide association study of ischemic stroke subtypes

PubMed Central

Meschia, James F.; Arnett, Donna K.; Ay, Hakan; Brown, Robert D.; Benavente, Oscar; Cole, John W.; de Bakker, Paul I.W.; Dichgans, Martin; Doheny, Kimberly F.; Fornage, Myriam; Grewal, Raji; Gwinn, Katrina; Jern, Christina; Conde, Jordi Jimenez; Johnson, Julie A.; Jood, Katarina; Laurie, Cathy C.; Lee, Jin-Moo; Lindgren, Arne; Markus, Hugh S.; McArdle, Patrick F.; McClure, Leslie A.; Mitchell, Braxton D.; Schmidt, Reinhold; Rexrode, Kathryn M.; Rich, Stephen S.; Rosand, Jonathan; Rothwell, Peter M.; Rundek, Tatjana; Sacco, Ralph L.; Sharma, Pankaj; Shuldiner, Alan R.; Slowik, Agnieszka; Wassertheil-Smoller, Sylvia; Sudlow, Cathie; Thijs, Vincent; Woo, Daniel; Worrall, Bradford B.; Wu, Ona; Kittner, Steven J.

2014-01-01

Background and Purpose Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The NINDS Stroke Genetics Network (SiGN) contributes substantially to meta-analyses that focus on specific subtypes of stroke. Methods The NINDS Stroke Genetics Network (SiGN) includes ischemic stroke cases from 24 Genetic Research Centers (GRCs), 13 from the US and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the web-based Causative Classification of Stroke (CCS) system, with data entered by trained and certified adjudicators at participating GRCs. Through the Center for Inherited Diseases Research (CIDR), SiGN plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide SNP arrays, and add to these another 4,253 previously genotyped cases for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. CIDR-generated genotypes and corresponding phenotypic data will be shared with the scientific community through dbGaP, and brain MRI studies will be centrally archived. Conclusions The SiGN consortium, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke. PMID:24021684

Genetic variability among power athletes: The stronger vs. the faster.

PubMed

Ben-Zaken, Sigal; Eliakim, Alon; Nemet, Dan; Meckel, Yoav

2016-01-29

Athletic events can be divided into "aerobic-type event" or "anaerobic-type event" based on energetic usage. Power, speed, and strength, also used to specify sports subtypes. Weightlifters, sprinters, and jumpers feature high-intensity efforts lasting few seconds. However, their performance requires different proportions of power, speed, and strength. The aim of the current study was to examine genetic differences between subtypes of anaerobic athletes in 3 genetic variants: ACTN3 R577X, which is associated with muscle contractions, AGT Met235Thr which is associated with muscle growth, and PPARD T/C, which is associated with aerobic capacity. 71 sprinters and jumpers (S/J), 54 weightlifters (WL) and 86 controls participated in the study. Genomic DNA was extracted from peripheral blood using standard protocol. Genotypes were determined using Taqman allelic discrimination assay. ACTN3 RR-genotype frequency was significantly higher among S/J (39.4%) compared to WL (22.2%) and controls (18.6%). AGT ThrThr-genotype was significantly higher among WL (25.9%) compared to S/J (4.2%) and controls (12.8%). PPARD T294C genotype frequencies did not differ between groups. The results suggest that there may be a specific genetic makeup enabling an athlete to excel in speed-oriented events (sprints), rather than in strength-oriented events (weightlifting).

Primordial dwarfism: overview of clinical and genetic aspects.

PubMed

Khetarpal, Preeti; Das, Satrupa; Panigrahi, Inusha; Munshi, Anjana

2016-02-01

Primordial dwarfism is a group of genetic disorders which include Seckel Syndrome, Silver-Russell Syndrome, Microcephalic Osteodysplastic Primordial Dwarfism types I/III, II and Meier-Gorlin Syndrome. This genetic disorder group is characterized by intra-uterine growth retardation and post-natal growth abnormalities which occur as a result of disorganized molecular and genomic changes in embryonic stage and, thus, it represents a unique area to study growth and developmental abnormalities. Lot of research has been carried out on different aspects; however, a consolidated review that discusses an overall spectrum of this disorder is not accessible. Recent research in this area points toward important molecular and cellular mechanisms in human body that regulate the complexity of growth process. Studies have emerged that have clearly associated with a number of abnormal chromosomal, genetic and epigenetic alterations that can predispose an embryo to develop PD-associated developmental defects. Finding and associating such fundamental changes to its subtypes will help in re-examination of alleged functions at both cellular and developmental levels and thus reveal the intrinsic mechanism that leads to a balanced growth. Although such findings have unraveled a subtle understanding of growth process, we further require active research in terms of identification of reliable biomarkers for different subtypes as an immediate requirement for clinical utilization. It is hoped that further study will advance the understanding of basic mechanisms regulating growth relevant to human health. Therefore, this review has been written with an aim to present an overview of chromosomal, molecular and epigenetic modifications reported to be associated with different subtypes of this heterogenous disorder. Further, latest findings with respect to clinical and molecular genetics research have been summarized to aid the medical fraternity in their clinical utility, for diagnosing disorders where there are overlapping physical attributes and simultaneously inform about the latest developments in PD biology.

HIV Genetic Diversity and Drug Resistance

PubMed Central

Santos, André F.; Soares, Marcelo A.

2010-01-01

Most of the current knowledge on antiretroviral (ARV) drug development and resistance is based on the study of subtype B of HIV-1, which only accounts for 10% of the worldwide HIV infections. Cumulative evidence has emerged that different HIV types, groups and subtypes harbor distinct biological properties, including the response and susceptibility to ARV. Recent laboratory and clinical data highlighting such disparities are summarized in this review. Variations in drug susceptibility, in the emergence and selection of specific drug resistance mutations, in viral replicative capacity and in the dynamics of resistance acquisition under ARV selective pressure are discussed. Clinical responses to ARV therapy and associated confounding factors are also analyzed in the context of infections by distinct HIV genetic variants. PMID:21994646

Understanding the HIV-1 protease nelfinavir resistance mutation D30N in subtypes B and C through molecular dynamics simulations.

PubMed

Soares, Rosemberg O; Batista, Paulo R; Costa, Mauricio G S; Dardenne, Laurent E; Pascutti, Pedro G; Soares, Marcelo A

2010-09-01

A major concern in the antiretroviral (ARV) treatment of HIV infections with protease inhibitors (PI) is the emergence of resistance, which results from the selection of distinct mutations within the viral protease (PR) gene. Among patients who do not respond to treatment with the PI nelfinavir (NFV), the D30N mutation is often observed. However, several reports have shown that D30N emerges with different frequencies in distinct HIV-1 genetic forms or subtypes. In the present work, we analyzed the binding of NFV and the Gag substrate CA/p2 to PR from HIV-1 subtypes B and C through molecular dynamics (MD) simulations. The wild-type and drug-resistant D30N mutants were investigated in both subtypes. The compensatory mutations N83T and N88D, observed in vitro and in vivo when subtype C acquires D30N, were also studied. D30N appears to facilitate conformational changes in subtype B PR, but not in that from subtype C, and this could be associated with disestablishment of an alpha-helical region of the PR. Furthermore, the total contact areas of NFV or the CA/p2 substrate with the mutant PR correlated with changes in the resistance patterns and replicative capacity. Finally, we observed in our MD simulations that mutant PR proteins show different patterns for hydrophobic/van der Waals contact. These findings suggest that different molecular mechanisms contribute to resistance, and we propose that a single mutation has distinct impacts on different HIV-1 subtypes. (c) 2010 Elsevier Inc. All rights reserved.

[22q11.2DS Syndrome as a Genetic Subtype of Schizophrenia].

PubMed

Huertas-Rodríguez, Cindy Katherin; Payán-Gómez, César; Forero-Castro, Ruth Maribel

2015-01-01

The 22q11.2 deletion syndrome (22q11.2DS) is associated with the microdeletion of this chromosomal region, and represents the second most common genetic syndrome after Down's syndrome. In patients with schizophrenia, 22q11.2DS has a prevalence of 2%, and in selected groups can be increased to between 32-53%. To describe the generalities of 22q11.2DS syndrome as a genetic subtype of schizophrenia, its clinical characteristics, molecular genetic aspects, and frequency in different populations. A review was performed from 1967 to 2013 in scientific databases, compiling articles about 22q11.2DS syndrome and its association with schizophrenia. The 22q11.2 DS syndrome has a variable phenotype associated with other genetic syndromes, birth defects in many tissues and organs, and a high rate of psychiatric disorders, particularly schizophrenia. Likewise, it has been identified in clinical populations with schizophrenia selected by the presence of common syndromic characteristics. FISH, qPCR and MLPA techniques, and recently, aCGH and NGS technologies, are being used to diagnose this microdeletion. It is important in clinical practice to remember that people suffering the 22q11.2DS have a high genetic risk for developing schizophrenia, and it is considered that the simultaneous presence of this disease and 22q11.2DS represents a genetic subtype of schizophrenia. There are clear phenotypic criteria, molecular and cytogenetic methods to diagnose this group of patients, and to optimize a multidisciplinary approach in their monitoring. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Gene flow in environmental Legionella pneumophila leads to genetic and pathogenic heterogeneity within a Legionnaires' disease outbreak.

PubMed

McAdam, Paul R; Vander Broek, Charles W; Lindsay, Diane S J; Ward, Melissa J; Hanson, Mary F; Gillies, Michael; Watson, Mick; Stevens, Joanne M; Edwards, Giles F; Fitzgerald, J Ross

2014-01-01

Legionnaires' disease is a severe form of pneumonia caused by the environmental bacterium Legionella pneumophila. Outbreaks commonly affect people with known risk factors, but the genetic and pathogenic complexity of L. pneumophila within an outbreak is not well understood. Here, we investigate the etiology of the major Legionnaires' disease outbreak that occurred in Edinburgh, UK, in 2012, by examining the evolutionary history, genome content, and virulence of L. pneumophila clinical isolates. Our high resolution genomic approach reveals that the outbreak was caused by multiple genetic subtypes of L. pneumophila, the majority of which had diversified from a single progenitor through mutation, recombination, and horizontal gene transfer within an environmental reservoir prior to release. In addition, we discover that some patients were infected with multiple L. pneumophila subtypes, a finding which can affect the certainty of source attribution. Importantly, variation in the complement of type IV secretion systems encoded by different genetic subtypes correlates with virulence in a Galleria mellonella model of infection, revealing variation in pathogenic potential among the outbreak source population of L. pneumophila. Taken together, our study indicates previously cryptic levels of pathogen heterogeneity within a Legionnaires' disease outbreak, a discovery that impacts on source attribution for future outbreak investigations. Furthermore, our data suggest that in addition to host immune status, pathogen diversity may be an important influence on the clinical outcome of individual outbreak infections.

Human leukocyte antigen class I and II alleles in non-Hodgkin lymphoma etiology

PubMed Central

Abdou, Amr M.; Morton, Lindsay M.; Thomas, Rasmi; Cerhan, James R.; Gao, Xiaojiang; Cozen, Wendy; Rothman, Nathaniel; Davis, Scott; Severson, Richard K.; Bernstein, Leslie; Hartge, Patricia; Carrington, Mary

2010-01-01

Genome-wide association and candidate gene studies implicate different genetic variants within the 6p21 chromosomal region with different non-Hodgkin lymphoma (NHL) subtypes. Complementing these efforts, we conducted human leukocyte antigen (HLA) class I and class II genotyping among 610 NHL cases and 555 controls of non-Hispanic white descent from a US multicenter study. Allele-disease associations were assessed by logistic regression for NHL and its subtypes. Statistically significant associations between HLA and NHL subtypes include HLA-DRB1*0101 for follicular lymphoma (odds ratio [OR] = 2.14, P < .001), HLA-DRB1*0401 for diffuse large B-cell lymphoma (DLBCL; OR = 0.45, P = .006), and HLA-DRB1*13 and follicular lymphoma (OR = 0.48, P = .008). We further observed significant heterozygote advantage for HLA class I alleles and NHL, and particularly DLBCL (P trend = .01 for elevated risk with increasing number of homozygous alleles). Our results support a role for HLA in the etiology of NHL and its subtypes. PMID:20385791

Multiple introductions and onward transmission of HIV-1 subtype B strains in Shanghai, China.

PubMed

Li, Xiaoshan; Zhu, Kexin; Xue, Yile; Wei, Feiran; Gao, Rong; Duerr, Ralf; Fang, Kun; Li, Wei; Song, Yue; Du, Guoping; Yan, Wenjuan; Musa, Taha Hussein; Ge, You; Ji, Yu; Zhong, Ping; Wei, Pingmin

2017-08-01

To investigate the viral genetic evolution, spatial origins and patterns of transmission of HIV-1 subtype B in Shanghai, China. A total of 242 Shanghai subtype B and 1519 reference pol sequences were subjected to phylogenetic inference and genetic transmission network analyses. Phylogenetic analysis revealed that subtype B strains circulating in Shanghai were genetically diverse and closely associated with viral sequence lineages in Beijing (76 of 242 [31.4%]), Central China (Henan/Hebei/Hunan/Hubei) (43 of 242 [17.8%]), Chinese Taiwan (20 of 242 [8.3%]), Japan (6 of 242 [2.5%]), and Korea (7 of 242 [2.9%]), suggesting multiple introductions into Shanghai from mainland China and Taiwan, Japan, and Korea. Interestingly, a monophyletic Shanghai lineage (SH-L) (36 of 242 [14.9%]) of HIV-1 subtype B most likely originated from an Argentine strain, transferred through Liaoning infected individuals. In-depth analyses of 195 Shanghai subtype B sequences revealed that a total of 37.9% (n = 74) sequences contributed to 35 transmission networks, whereof 33.8% (n = 25) of the sequences associated with infected individuals from other provinces. Our new findings reflect the evolution complexity and transmission dynamics of HIV-1 subtype B in Shanghai, which would provide critical information for the design of effective prevention measures against HIV transmission. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

[Multilocus Sequence Typing analysis of human Campylobacter coli in Granada (Spain)].

PubMed

Carrillo-Ávila, J A; Sorlózano-Puerto, A; Pérez-Ruiz, M; Gutiérrez-Fernández, J

2016-12-01

Different subtypes of Campylobacter spp. have been associated with diarrhoea and a Multilocus Sequence Typing (MLST) method has been performed for subtyping. In the present work, MLST was used to analyse the genetic diversity of eight strains of Campylobacter coli. Nineteen genetic markers were amplified for MLST analysis: AnsB, DmsA, ggt, Cj1585c, CJJ81176-1367/1371, Tlp7, cj1321-cj1326, fucP, cj0178, cj0755/cfrA, ceuE, pldA, cstII, cstIII. After comparing the obtained sequences with the Campylobacter MLST database, the allele numbers, sequence types (STs) and clonal complexes (CCs) were assigned. The 8 C. coli isolates yielded 4 different STs belonging to 2 CCs. Seven isolates belong to ST-828 clonal complex and only one isolate belong to ST-21. Two samples came from the same patient, but were isolated in two different periods of time. MLST can be useful for taxonomic characterization of C. coli isolates.

Phylogenetic Diversity of Koala Retrovirus within a Wild Koala Population.

PubMed

Chappell, K J; Brealey, J C; Amarilla, A A; Watterson, D; Hulse, L; Palmieri, C; Johnston, S D; Holmes, E C; Meers, J; Young, P R

2017-02-01

Koala populations are in serious decline across many areas of mainland Australia, with infectious disease a contributing factor. Koala retrovirus (KoRV) is a gammaretrovirus present in most wild koala populations and captive colonies. Five subtypes of KoRV (A to E) have been identified based on amino acid sequence divergence in a hypervariable region of the receptor binding domain of the envelope protein. However, analysis of viral genetic diversity has been conducted primarily on KoRV in captive koalas housed in zoos in Japan, the United States, and Germany. Wild koalas within Australia have not been comparably assessed. Here we report a detailed analysis of KoRV genetic diversity in samples collected from 18 wild koalas from southeast Queensland. By employing deep sequencing we identified 108 novel KoRV envelope sequences and determined their phylogenetic diversity. Genetic diversity in KoRV was abundant and fell into three major groups; two comprised the previously identified subtypes A and B, while the third contained the remaining hypervariable region subtypes (C, D, and E) as well as four hypervariable region subtypes that we newly define here (F, G, H, and I). In addition to the ubiquitous presence of KoRV-A, which may represent an exclusively endogenous variant, subtypes B, D, and F were found to be at high prevalence, while subtypes G, H, and I were present in a smaller number of animals. Koala retrovirus (KoRV) is thought to be a significant contributor to koala disease and population decline across mainland Australia. This study is the first to determine KoRV subtype prevalence among a wild koala population, and it significantly expands the total number of KoRV sequences available, providing a more precise picture of genetic diversity. This understanding of KoRV subtype prevalence and genetic diversity will be important for conservation efforts attempting to limit the spread of KoRV. Furthermore, KoRV is one of the only retroviruses shown to exist in both endogenous (transmitted vertically to offspring in the germ line DNA) and exogenous (horizontally transmitted between infected individuals) forms, a division of fundamental evolutionary importance. Copyright © 2017 American Society for Microbiology.

An initial perspective of S-asteroid subtypes within asteroid families

NASA Technical Reports Server (NTRS)

Kelley, M. S.; Gaffey, M. J.

1993-01-01

Many main belt asteroids cluster around certain values of semi-major axis (a), inclination (i), and eccentricity (e). Hirayama was the first to notice these concentrations which he interpreted as evidence of disruptions of larger parent bodies. He called these clusters 'asteroid families'. The term 'families' is increasingly reserved for genetic associations to distinguish them from clusters of unknown or purely dynamical origin (e.g. the Phocaea cluster). Members of a genetic asteroid family represent fragments derived from various depths within the original parent planetesimal. Thus, family members offer the potential for direct examination of the interiors of parent bodies which have undergone metamorphism and differentiation similar to that occurring in the inaccessible interiors of terrestrial planets. The differentiation similar to that occurring in the inaccessible interiors of terrestrial planets. The condition that genetic family members represent the fragments of a parent object provides a critical test of whether an association (cluster in proper element space) is a genetic family. Compositions (types and relative abundances of materials) of family members must permit the reconstruction of a compositionally plausible parent body. The compositions of proposed family members can be utilized to test the genetic reality of the family and to determine the type and degree of internal differentiation within the parent planetesimal. The interpretation of the S-class mineralogy provides a preliminary evaluation of family memberships. Detailed mineralogical and petrological analysis was done based on the reflectance spectra of 39 S-type asteroids. The result is a division of the S-asteroid class into seven subtypes based on compositional differences. These subtypes, designated S(I) to S(VII), correspond to surface silicate assemblages ranging from monomineralic olivine (dunites) through olivine-pyroxene mixtures to pure pyroxene or pyroxene-feldspar mixtures (basalts). The most general conclusion is that the S-asteroids cannot be treated as a single group of objects without greatly oversimplifying their properties. Each S-subtype needs to be treated as an independent group with a distinct evolutionary history.

Genetic Architecture of Lacunar Stroke.

PubMed

Traylor, Matthew; Bevan, Steve; Baron, Jean-Claude; Hassan, Ahamad; Lewis, Cathryn M; Markus, Hugh S

2015-09-01

Lacunar strokes comprise ≈20% of all strokes. Despite this frequency, their pathogenesis is poorly understood. Previous genome-wide association studies in lacunar stroke have been disappointing, which may be because of phenotypic heterogeneity. Pathological and radiological studies suggest that there may be different pathologies underlying lacunar strokes. This has led to the suggestion of 2 subtypes: isolated lacunar infarcts and multiple lacunar infarcts and leukoaraiosis. We performed genome-wide analyses in a magnetic resonance imaging-verified cohort of 1012 younger onset lacunar stroke cases and 964 controls. Using these data, we first estimated the heritability of lacunar stroke and its 2 hypothesized subtypes, and secondly, we determined whether this is enriched for regulatory regions in the genome, as defined by data from Encyclopedia of DNA Elements (ENCODE) and other sources. Finally, we determine the evidence for a polygenic contribution from rare variation to lacunar stroke and its subtypes. Our results indicate a substantial heritable component to magnetic resonance imaging-verified lacunar stroke (20%-25%) and its 2 subtypes (isolated lacunar infarct, 15%-18%; multiple lacunar infarcts/leukoaraiosis, 23%-28%). This heritable component is significantly enriched for sites affecting expression of genes. In addition, we show that the risk of the 2 subtypes of lacunar stroke in isolation, but not in combination, is associated with rare variation in the genome. Lacunar stroke, when defined on magnetic resonance imaging, is a highly heritable complex disease. Much of this heritability arises from regions of the genome affecting gene regulation. Rare variation affects 2 subtypes of lacunar in isolation, suggesting that they may have distinct genetic susceptibility factors. © 2015 The Authors.

Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes.

PubMed

Flannick, Jason; Johansson, Stefan; Njølstad, Pål R

2016-07-01

Insights into the genetic basis of type 2 diabetes mellitus (T2DM) have been difficult to discern, despite substantial research. More is known about rare forms of diabetes mellitus, several of which share clinical and genetic features with the common form of T2DM. In this Review, we discuss the extent to which the study of rare and low-frequency mutations in large populations has begun to bridge the gap between rare and common forms of diabetes mellitus. We hypothesize that the perceived division between these diseases might be due, in part, to the historical ascertainment bias of genetic studies, rather than a clear distinction between disease pathophysiologies. We also discuss possible implications of a new model for the genetic basis of diabetes mellitus subtypes, where the boundary between subtypes becomes blurred.

Segregation of non-p.R132H mutations in IDH1 in distinct molecular subtypes of glioma.

PubMed

Gravendeel, Lonneke A M; Kloosterhof, Nanne K; Bralten, Linda B C; van Marion, Ronald; Dubbink, Hendrikus Jan; Dinjens, Winand; Bleeker, Fonnet E; Hoogenraad, Casper C; Michiels, Erna; Kros, Johan M; van den Bent, Martin; Smitt, Peter A E Sillevis; French, Pim J

2010-03-01

Mutations in the gene encoding the isocitrate dehydrogenase 1 gene (IDH1) occur at a high frequency (up to 80%) in many different subtypes of glioma. In this study, we have screened for IDH1 mutations in a cohort of 496 gliomas. IDH1 mutations were most frequently observed in low grade gliomas with c.395G>A (p.R132H) representing >90% of all IDH1 mutations. Interestingly, non-p.R132H mutations segregate in distinct histological and molecular subtypes of glioma. Histologically, they occur sporadically in classic oligodendrogliomas and at significantly higher frequency in other grade II and III gliomas. Genetically, non-p.R132H mutations occur in tumors with TP53 mutation, are virtually absent in tumors with loss of heterozygosity on 1p and 19q and accumulate in distinct (gene-expression profiling based) intrinsic molecular subtypes. The IDH1 mutation type does not affect patient survival. Our results were validated on an independent sample cohort, indicating that the IDH1 mutation spectrum may aid glioma subtype classification. Functional differences between p.R132H and non-p.R132H mutated IDH1 may explain the segregation in distinct glioma subtypes. (c) 2010 Wiley-Liss, Inc.

Complex Subtype Diversity of HIV-1 Among Drug Users in Major Kenyan Cities.

PubMed

Gounder, Kamini; Oyaro, Micah; Padayachi, Nagavelli; Zulu, Thando Mbali; de Oliveira, Tulio; Wylie, John; Ndung'u, Thumbi

2017-05-01

Drug users are increasingly recognized as a key population driving human immunodeficiency virus (HIV) spread in sub-Saharan Africa. To determine HIV-1 subtypes circulating in this population group and explore possible geographic differences, we analyzed HIV-1 sequences among drug users from Nairobi, Mombasa, and Kisumu in Kenya. We sequenced gag and env from 55 drug users. Subtype analysis from 220 gag clonal sequences from 54 of 55 participants (median = 4/participant) showed that 44.4% were A, 16.7% were C, 3.7% were D, and 35.2% were intersubtype recombinants. Of 156 env clonal sequences from 48 of 55 subjects (median = 3/participant), 45.8% were subtype A, 14.6% were C, 6.3% were D, and 33.3% were recombinants. Comparative analysis of both genes showed that 30 (63.8%) participants had concordant subtypes, while 17 (36.2%) were discordant. We identified one genetically linked transmission pair and two cases of dual infection. These data are indicative of extensive HIV-1 intersubtype recombination in Kenya and suggest decline in subtype D prevalence.

Complex Subtype Diversity of HIV-1 Among Drug Users in Major Kenyan Cities

PubMed Central

Gounder, Kamini; Oyaro, Micah; Padayachi, Nagavelli; Zulu, Thando Mbali; de Oliveira, Tulio; Wylie, John

2017-01-01

Abstract Drug users are increasingly recognized as a key population driving human immunodeficiency virus (HIV) spread in sub-Saharan Africa. To determine HIV-1 subtypes circulating in this population group and explore possible geographic differences, we analyzed HIV-1 sequences among drug users from Nairobi, Mombasa, and Kisumu in Kenya. We sequenced gag and env from 55 drug users. Subtype analysis from 220 gag clonal sequences from 54 of 55 participants (median = 4/participant) showed that 44.4% were A, 16.7% were C, 3.7% were D, and 35.2% were intersubtype recombinants. Of 156 env clonal sequences from 48 of 55 subjects (median = 3/participant), 45.8% were subtype A, 14.6% were C, 6.3% were D, and 33.3% were recombinants. Comparative analysis of both genes showed that 30 (63.8%) participants had concordant subtypes, while 17 (36.2%) were discordant. We identified one genetically linked transmission pair and two cases of dual infection. These data are indicative of extensive HIV-1 intersubtype recombination in Kenya and suggest decline in subtype D prevalence. PMID:28068781

ADHD latent class clusters: DSM-IV subtypes and comorbidity

PubMed Central

Elia, Josephine; Arcos-Burgos, Mauricio; Bolton, Kelly L.; Ambrosini, Paul J.; Berrettini, Wade; Muenke, Maximilian

2014-01-01

ADHD (Attention Deficit Hyperactivity Disorder) has a complex, heterogeneous phenotype only partially captured by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. In this report, latent class analyses (LCA) are used to identify ADHD phenotypes using K-SADS-IVR (Schedule for Affective Disorders & Schizophrenia for School Age Children-IV-Revised) symptoms and symptom severity data from a clinical sample of 500 ADHD subjects, ages 6–18, participating in an ADHD genetic study. Results show that LCA identified six separate ADHD clusters, some corresponding to specific DSM-IV subtypes while others included several subtypes. DSM-IV comorbid anxiety and mood disorders were generally similar across all clusters, and subjects without comorbidity did not aggregate within any one cluster. Age and gender composition also varied. These results support findings from population-based LCA studies. The six clusters provide additional homogenous groups that can be used to define ADHD phenotypes in genetic association studies. The limited age ranges aggregating in the different clusters may prove to be a particular advantage in genetic studies where candidate gene expression may vary during developmental phases. DSM-IV comorbid mood and anxiety disorders also do not appear to increase cluster heterogeneity; however, longitudinal studies that cover period of risk are needed to support this finding. PMID:19900717

Multicentre study of maternal and neonatal outcomes in individuals with Prader-Willi syndrome.

PubMed

Singh, Preeti; Mahmoud, Ranim; Gold, June-Anne; Miller, Jennifer L; Roof, Elizabeth; Tamura, Roy; Dykens, Elisabeth; Butler, Merlin G; Driscoll, Dan J; Kimonis, Virginia

2018-05-18

Prader-Willi syndrome (PWS) is a complex genetic disorder associated with three different genetic subtypes: deletion of the paternal copy of 15q11-q13, maternal UPD for chromosome 15 and imprinting defect. Patients are typically diagnosed because of neonatal hypotonia, dysmorphism and feeding difficulties; however, data on the prenatal features of PWS are limited. The aim of the study was to identify and compare frequencies of prenatal and neonatal clinical features of PWS among the three genetic subtypes. Data from 355 patients with PWS from the Rare Diseases Clinical Research Network PWS registry were used to analyse multiple maternal and neonatal factors collected during an 8-year multisite study. Among our cohort of 355 patients with PWS (61% deletion, 36% UPD and 3% imprinting defect) 54% were born by caesarean section, 26% were born prematurely and 34% with a low birth weight (frequencies 32%, 9.6% and 8.1%, respectively, in the general population). Fetal movements were reported as decreased in 72%. All babies were hypotonic, and 99% had feeding difficulties. Low Apgar scores (<7) were noted in 17.7% and 5.6% of patients, respectively, compared with 1% and 1.4%, respectively, in the general population. Maternal age and pre-pregnancy weight were significantly higher in the UPD group (p=0.01 and <0.001, respectively). We found a higher rate of perinatal complications in PWS syndrome compared with the general population. No significant differences in the genetic subtypes were noted except for a higher maternal age and pre-pregnancy weight in the UPD subgroup. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

PubMed Central

Wild, Peter J; Ikenberg, Kristian; Fuchs, Thomas J; Rechsteiner, Markus; Georgiev, Strahil; Fankhauser, Niklaus; Noske, Aurelia; Roessle, Matthias; Caduff, Rosmarie; Dellas, Athanassios; Fink, Daniel; Moch, Holger; Krek, Wilhelm; Frew, Ian J

2012-01-01

Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours. PMID:22678923

Childhood Brain Tumor Epidemiology: A Brain Tumor Epidemiology Consortium Review

PubMed Central

Johnson, Kimberly J.; Cullen, Jennifer; Barnholtz-Sloan, Jill S.; Ostrom, Quinn T.; Langer, Chelsea E.; Turner, Michelle C.; McKean-Cowdin, Roberta; Fisher, James L.; Lupo, Philip J.; Partap, Sonia; Schwartzbaum, Judith A.; Scheurer, Michael E.

2014-01-01

Childhood brain tumors are the most common pediatric solid tumor and include several histological subtypes. Although progress has been made in improving survival rates for some subtypes, understanding of risk factors for childhood brain tumors remains limited to a few genetic syndromes and ionizing radiation to the head and neck. In this report, we review descriptive and analytical epidemiology childhood brain tumor studies from the past decade and highlight priority areas for future epidemiology investigations and methodological work that is needed to advance our understanding of childhood brain tumor causes. Specifically, we summarize the results of a review of studies published since 2004 that have analyzed incidence and survival in different international regions and that have examined potential genetic, immune system, developmental and birth characteristics, and environmental risk factors. PMID:25192704

Different EGFR gene mutations in two patients with synchronous multiple lung cancers: A case report

PubMed Central

Sakai, Hiroki; Kimura, Hiroyuki; Tsuda, Masataka; Wakiyama, Yoichi; Miyazawa, Tomoyuki; Marushima, Hideki; Kojima, Koji; Hoshikawa, Masahiro; Takagi, Masayuki; Nakamura, Haruhiko

2017-01-01

Routine clinical and pathological evaluations to determine the relationship between different lesions are often not completely conclusive. Interestingly, detailed genetic analysis of tumor samples may provide important additional information and identify second primary lung cancers. In the present study, we report cases of two synchronous lung adenocarcinomas composed of two distinct pathological subtypes with different EGFR gene mutations: a homozygous deletion in exon 19 of the papillary adenocarcinoma subtype and a point mutation of L858R in exon 21 of the tubular adenocarcinoma. The present report highlights the clinical importance of molecular cancer biomarkers to guide management decisions in cases involving multiple lung tumors. PMID:29090842

Cancel all Hollidays for SLX4 mutations: identification of a new Fanconi anemia subtype, FANCP.

PubMed

Kang, M H

2011-07-01

SLX4, a coordinator of structure-specific endo-nucleases, is mutated in a new Fanconi anemia subtype Stoepker et al. (2011) Nature Genetics 43:138-141. Mutations of the SLX4 gene in Fanconi anemia Kim et al. (2011) Nature Genetics 43:142-146. © 2011 John Wiley & Sons A/S.

Gene-set and multivariate genome-wide association analysis of oppositional defiant behavior subtypes in attention-deficit/hyperactivity disorder.

PubMed

Aebi, Marcel; van Donkelaar, Marjolein M J; Poelmans, Geert; Buitelaar, Jan K; Sonuga-Barke, Edmund J S; Stringaris, Argyris; Consortium, Image; Faraone, Stephen V; Franke, Barbara; Steinhausen, Hans-Christoph; van Hulzen, Kimm J E

2016-07-01

Oppositional defiant disorder (ODD) is a frequent psychiatric disorder seen in children and adolescents with attention-deficit-hyperactivity disorder (ADHD). ODD is also a common antecedent to both affective disorders and aggressive behaviors. Although the heritability of ODD has been estimated to be around 0.60, there has been little research into the molecular genetics of ODD. The present study examined the association of irritable and defiant/vindictive dimensions and categorical subtypes of ODD (based on latent class analyses) with previously described specific polymorphisms (DRD4 exon3 VNTR, 5-HTTLPR, and seven OXTR SNPs) as well as with dopamine, serotonin, and oxytocin genes and pathways in a clinical sample of children and adolescents with ADHD. In addition, we performed a multivariate genome-wide association study (GWAS) of the aforementioned ODD dimensions and subtypes. Apart from adjusting the analyses for age and sex, we controlled for "parental ability to cope with disruptive behavior." None of the hypothesis-driven analyses revealed a significant association with ODD dimensions and subtypes. Inadequate parenting behavior was significantly associated with all ODD dimensions and subtypes, most strongly with defiant/vindictive behaviors. In addition, the GWAS did not result in genome-wide significant findings but bioinformatics and literature analyses revealed that the proteins encoded by 28 of the 53 top-ranked genes functionally interact in a molecular landscape centered around Beta-catenin signaling and involved in the regulation of neurite outgrowth. Our findings provide new insights into the molecular basis of ODD and inform future genetic studies of oppositional behavior. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Emerging molecular therapeutic targets for cholangiocarcinoma.

PubMed

Rizvi, Sumera; Gores, Gregory J

2017-09-01

Cholangiocarcinomas (CCAs) are diverse epithelial tumors arising from the liver or large bile ducts with features of cholangiocyte differentiation. CCAs are classified anatomically into intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA). Each subtype has distinct risk factors, molecular pathogenesis, therapeutic options, and prognosis. CCA is an aggressive malignancy with a poor overall prognosis and median survival of less than 2years in patients with advanced disease. Potentially curative surgical treatment options are limited to the subset of patients with early-stage disease. Presently, the available systemic medical therapies for advanced or metastatic CCA have limited therapeutic efficacy. Molecular alterations define the differences in biological behavior of each CCA subtype. Recent comprehensive genetic analysis has better characterized the genomic and transcriptomic landscape of each CCA subtype. Promising candidates for targeted, personalized therapy have emerged, including potential driver fibroblast growth factor receptor (FGFR) gene fusions and somatic mutations in isocitrate dehydrogenase (IDH)1/2 in iCCA, protein kinase cAMP-activated catalytic subunit alpha (PRKACA) or beta (PRKACB) gene fusions in pCCA, and ELF3 mutations in dCCA/ampullary carcinoma. A precision genomic medicine approach is dependent on an enhanced understanding of driver mutations in each subtype and stratification of patients according to their genetic drivers. We review the current genomic landscape of CCA, the potentially actionable molecular aberrations in each CCA subtype, and the role of immunotherapy in CCA. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

GABAA receptor subtype involvement in addictive behaviour.

PubMed

Stephens, D N; King, S L; Lambert, J J; Belelli, D; Duka, T

2017-01-01

GABA A receptors form the major class of inhibitory neurotransmitter receptors in the mammalian brain. This review sets out to summarize the evidence that variations in genes encoding GABA A receptor isoforms are associated with aspects of addictive behaviour in humans, while animal models of addictive behaviour also implicate certain subtypes of GABA A receptor. In addition to outlining the evidence for the involvement of specific subtypes in addiction, we summarize the particular contributions of these isoforms in control over the functioning of brain circuits, especially the mesolimbic system, and make a first attempt to bring together evidence from several fields to understanding potential involvement of GABA A receptor subtypes in addictive behaviour. While the weight of the published literature is on alcohol dependency, the underlying principles outlined are relevant across a number of different aspects of addictive behaviour. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Short communication: identification of a novel HIV type 1 subtype H/J recombinant in Canada with discordant HIV viral load (RNA) values in three different commercial assays.

PubMed

Kim, John E; Beckthold, Brenda; Chen, Zhaoxia; Mihowich, Jennifer; Malloch, Laurie; Gill, Michael John

2007-11-01

The presence of HIV-1 non-B subtypes is increasing worldwide. This poses challenges to commercial diagnostic and viral load (RNA) monitoring tests that are predominantly based on HIV-1 subtype B strains. Based on phylogenetic analysis of the gag, pol, and env gene regions, we describe the first HIV-1 H/J recombinant in Canada that presented divergent viral load values. DNA sequence analysis of the gag gene region further revealed that genetic diversity between this H/J recombinant and the primers and probes used in the bio-Merieux Nuclisens HIV-1 QT (Nuclisens) and Roche Amplicor Monitor HIV-1, v1.5 (Monitor) viral RNA assays can erroneously lead to undetectable viral load values. This observation appears to be more problematic in the Nuclisens assay. In light of increasing genetic diversity in HIV worldwide we recommend that DNA sequencing of HIV, especially in the gag gene region targeted by primers and probes used in molecular diagnostic and viral load tests, be incorporated into clinical monitoring practices.

Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene.

PubMed

Wan, Emily S; Castaldi, Peter J; Cho, Michael H; Hokanson, John E; Regan, Elizabeth A; Make, Barry J; Beaty, Terri H; Han, MeiLan K; Curtis, Jeffrey L; Curran-Everett, Douglas; Lynch, David A; DeMeo, Dawn L; Crapo, James D; Silverman, Edwin K

2014-08-06

Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported. Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45-80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering. The prevalence of PRISm in COPDGene is 12.3%. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter's syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative "COPD-subtype", "Restrictive-subtype", and a highly symptomatic "Metabolic-subtype". PRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted. Clinicaltrials.gov Identifier: NCT000608764.

The structure of genetic and environmental risk factors for fears and phobias

PubMed Central

Loken, E. K.; Hettema, J.M.; Aggen, S.H.; Kendler, K. S.

2014-01-01

Background Although prior genetic studies of interview-assessed fears and phobias have shown that genetic factors predispose individuals to fears and phobias, they have been restricted to the DSM-III to DSM-IV aggregated subtypes of phobias rather than to individual fearful and phobic stimuli. Method We examined the lifetime history of fears and/or phobias in response to 21 individual phobic stimuli in 4067 personally interviewed twins from same-sex pairs from the Virginia Adult Twin Study of Psychiatric and Substance Abuse Disorders (VATSPSUD). We performed multivariate statistical analyses using Mx and Mplus. Results The best-fitting model for the 21 phobic stimuli included four genetic factors (agora-social-acrophobia, animal phobia, blood-injection-illness phobia and claustrophobia) and three environmental factors (agora-social-hospital phobia, animal phobia, and situational phobia). Conclusions This study provides the first view of the architecture of genetic and environmental risk factors for phobic disorders and their subtypes. The genetic factors of the phobias support the DSM-IV and DSM-5 constructs of animal and blood-injection-injury phobias but do not support the separation of agoraphobia from social phobia. The results also do not show a coherent genetic factor for the DSM-IV and DSM-5 situational phobia. Finally, the patterns of co-morbidity across individual fears and phobias produced by genetic and environmental influences differ appreciably. PMID:24384457

The structure of genetic and environmental risk factors for fears and phobias.

PubMed

Loken, E K; Hettema, J M; Aggen, S H; Kendler, K S

2014-08-01

Although prior genetic studies of interview-assessed fears and phobias have shown that genetic factors predispose individuals to fears and phobias, they have been restricted to the DSM-III to DSM-IV aggregated subtypes of phobias rather than to individual fearful and phobic stimuli. We examined the lifetime history of fears and/or phobias in response to 21 individual phobic stimuli in 4067 personally interviewed twins from same-sex pairs from the Virginia Adult Twin Study of Psychiatric and Substance Abuse Disorders (VATSPSUD). We performed multivariate statistical analyses using Mx and Mplus. The best-fitting model for the 21 phobic stimuli included four genetic factors (agora-social-acrophobia, animal phobia, blood-injection-illness phobia and claustrophobia) and three environmental factors (agora-social-hospital phobia, animal phobia, and situational phobia). This study provides the first view of the architecture of genetic and environmental risk factors for phobic disorders and their subtypes. The genetic factors of the phobias support the DSM-IV and DSM-5 constructs of animal and blood-injection-injury phobias but do not support the separation of agoraphobia from social phobia. The results also do not show a coherent genetic factor for the DSM-IV and DSM-5 situational phobia. Finally, the patterns of co-morbidity across individual fears and phobias produced by genetic and environmental influences differ appreciably.

Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study.

PubMed

Whitwell, Jennifer L; Przybelski, Scott A; Weigand, Stephen D; Ivnik, Robert J; Vemuri, Prashanthi; Gunter, Jeffrey L; Senjem, Matthew L; Shiung, Maria M; Boeve, Bradley F; Knopman, David S; Parisi, Joseph E; Dickson, Dennis W; Petersen, Ronald C; Jack, Clifford R; Josephs, Keith A

2009-11-01

The behavioural variant of frontotemporal dementia is a progressive neurodegenerative syndrome characterized by changes in personality and behaviour. It is typically associated with frontal lobe atrophy, although patterns of atrophy are heterogeneous. The objective of this study was to examine case-by-case variability in patterns of grey matter atrophy in subjects with the behavioural variant of frontotemporal dementia and to investigate whether behavioural variant of frontotemporal dementia can be divided into distinct anatomical subtypes. Sixty-six subjects that fulfilled clinical criteria for a diagnosis of the behavioural variant of frontotemporal dementia with a volumetric magnetic resonance imaging scan were identified. Grey matter volumes were obtained for 26 regions of interest, covering frontal, temporal and parietal lobes, striatum, insula and supplemental motor area, using the automated anatomical labelling atlas. Regional volumes were divided by total grey matter volume. A hierarchical agglomerative cluster analysis using Ward's clustering linkage method was performed to cluster the behavioural variant of frontotemporal dementia subjects into different anatomical clusters. Voxel-based morphometry was used to assess patterns of grey matter loss in each identified cluster of subjects compared to an age and gender-matched control group at P < 0.05 (family-wise error corrected). We identified four potentially useful clusters with distinct patterns of grey matter loss, which we posit represent anatomical subtypes of the behavioural variant of frontotemporal dementia. Two of these subtypes were associated with temporal lobe volume loss, with one subtype showing loss restricted to temporal lobe regions (temporal-dominant subtype) and the other showing grey matter loss in the temporal lobes as well as frontal and parietal lobes (temporofrontoparietal subtype). Another two subtypes were characterized by a large amount of frontal lobe volume loss, with one subtype showing grey matter loss in the frontal lobes as well as loss of the temporal lobes (frontotemporal subtype) and the other subtype showing loss relatively restricted to the frontal lobes (frontal-dominant subtype). These four subtypes differed on clinical measures of executive function, episodic memory and confrontation naming. There were also associations between the four subtypes and genetic or pathological diagnoses which were obtained in 48% of the cohort. The clusters did not differ in behavioural severity as measured by the Neuropsychiatric Inventory; supporting the original classification of the behavioural variant of frontotemporal dementia in these subjects. Our findings suggest behavioural variant of frontotemporal dementia can therefore be subdivided into four different anatomical subtypes.

Genetic and caregiving-based contributions to infant attachment: unique associations with distress reactivity and attachment security.

PubMed

Raby, K Lee; Cicchetti, Dante; Carlson, Elizabeth A; Cutuli, J J; Englund, Michelle M; Egeland, Byron

2012-09-01

In the longitudinal study reported here, we examined genetic and caregiving-based contributions to individual differences in infant attachment classifications. For 154 mother-infant pairs, we rated mothers' responsiveness to their 6-month-old infants during naturalistic interactions and classified infants' attachment organization at 12 and 18 months using the Strange Situation procedure. These infants were later genotyped with respect to the serotonin-transporter-linked polymorphic region (5-HTTLPR). Maternal responsiveness uniquely predicted infants' attachment security. Infants' 5-HTTLPR variation uniquely predicted their subtype of attachment security at 12 months and their subtype of attachment insecurity at 12 and 18 months. The short allele for 5-HTTLPR was associated with attachment classifications characterized by higher emotional distress. These findings suggest that 5-HTTLPR variation contributes to infants' emotional reactivity and that the degree to which caregivers are responsive influences how effectively infants use their caregivers for emotion regulation. Theoretical implications for the study of genetic and caregiving influences are discussed.

Molecular and epidemiological characterization of HIV-1 subtypes among Libyan patients.

PubMed

Daw, Mohamed A; El-Bouzedi, Abdallah; Ahmed, Mohamed O; Dau, Aghnyia A

2017-04-28

The epidemiological and clinical aspects of human immunodeficiency virus subtypes are of great interest worldwide. These subtypes are rarely studied in North African countries. Libya is a large country with the longest coast on the Mediterranean Sea, facing the Southern European countries. Studies on the characterization of HIV-1 subtypes are limited in Libya. This study aimed to determine the magnitude of the HIV problem among the Libyan population and to better understand the genetic diversity and the epidemiologic dynamics of HIV 1, as well as to correlate that with the risk factors involved. A total of 159 HIV-1 strains were collected from 814 HIV positive patients from the four Libyan regions during a 16-year period (1995-2010). To determine the HIV-1 subtypes, genetic analysis and molecular sequencing were carried out using provirus polygene. Epidemiologic and demographic information was obtained from each participant and correlated with HIV-1 subtypes using logistic regression. The overall prevalence of HIV among Libyans ranged from 5 to 10 per 100,000 during the study period. It was higher among intravenous drug users (IVDUs) (53.9%), blood recipients (25.9%) and heterosexuals (17.6%) than by vertical transmission (2.6%). Prevalence was higher among males aged 20-40 years (M:F 1:6, P > 0.001). Among the 159 strains of HIV-1 available for typing, 117 strains (73.6%) were subtype B, 29 (18.2%) were CRF02_AG, and 13 (8.2%) were subtype A. HIV-1 subtype B was the most prevalent all over the country, and it was more prevalent in the Northern region, particularly among IVDUs (P < 0.001). GRF02_AG was common in the Eastern region, particularly among blood recipients while subtype A emerged in the Western region, particularly among IVDUs. HIV-1 infection is emerging in Libya with a shifting prevalence of subtypes associated with the changing epidemiology of HIV-1 among risk groups. A genetic analysis of HIV-1 strains demonstrated low subtype heterogeneity with the evolution of subtype B, and CRF_20 AG, as well as HIV-1 subtype A. Our study highlights the importance of expanded surveillance programs to control HIV infection and the necessity of introducing public health strategies to target the risk groups, particularly IVDUs.

Genetic Characterization of Clostridium botulinum Associated with Type B Infant Botulism in Japan▿

PubMed Central

Umeda, Kaoru; Seto, Yoshiyuki; Kohda, Tomoko; Mukamoto, Masafumi; Kozaki, Shunji

2009-01-01

The 15 proteolytic Clostridium botulinum type B strains, including 3 isolates associated with infant botulism in Japan, were genetically characterized by phylogenetic analysis of boNT/B gene sequences, genotyping, and determination of the boNT/B gene location by using pulsed-field gel electrophoresis (PFGE) for molecular epidemiological analysis of infant botulism in Japan. Strain Osaka05, isolated from a case in 2005, showed a unique boNT/B gene sequence and was considered to be a new BoNT/B subtype by phylogenetic analysis. Strain Osaka06, isolated from a case in 2006, was classified as the B2 subtype, the same as strain 111, isolated from a case in 1995. The five isolates associated with infant botulism in the United States were classified into the B1 subtype. Isolates from food samples in Japan were divided into the B1 and the B2 subtypes, although no relation with infant botulism was shown by PFGE genotyping. The results of PFGE and Southern blot hybridization with undigested DNA suggested that the boNT/B gene is located on large plasmids (approximately 150 kbp, 260 kbp, 275 kbp, or 280 kbp) in five strains belonging to three BoNT/B subtypes from various sources. The botulinum neurotoxin (BoNT) of Osaka05 was suggested to have an antigenicity different from the antigenicities of BoNT/B1 and BoNT/B2 by a sandwich enzyme-linked immunosorbent assay with the recombinant BoNT/B-C-terminal domain. We established a multiplex PCR assay for BoNT/B subtyping which will be useful for epidemiological studies of type B strains and the infectious diseases that they cause. PMID:19571018

The biological characteristics of predominant strains of HIV-1 genotype: modeling of HIV-1 infection among men who have sex with men.

PubMed

Dai, Di; Shang, Hong; Han, Xiao-Xu; Zhao, Bin; Liu, Jing; Ding, Hai-Bo; Xu, Jun-Jie; Chu, Zhen-Xing

2015-04-01

To investigate the molecular subtypes of prevalent HIV-1 strains and characterize the genetics of dominant strains among men who have sex with men. Molecular epidemiology surveys in this study concentrated on the prevalent HIV-1 strains in Liaoning province by year. 229 adult patients infected with HIV-1 and part of a high-risk group of men who have sex with men were recruited. Reverse transcription and nested PCR amplification were performed. Sequencing reactions were conducted and edited, followed by codon-based alignment. NJ phylogenetic tree analyses detected two distinct CRF01_AE phylogenetic clusters, designated clusters 1 and 2. Clusters 1 and 2 accounted for 12.8% and 84.2% of sequences in the pol gene and 17.6% and 73.1% of sequences in the env gene, respectively. Another six samples were distributed on other phylogenetic clusters. Cluster 1 increased significantly from 5.6% to 20.0%, but cluster 2 decreased from 87.5% to 80.0%. Genetic distance analysis indicated that CRF01_AE cluster 1 in Liaoning was homologous to epidemic CRF01_AE strains, but CRF01_AE cluster 2 was different from other scattered strains. Additionally, significant differences were found in tetra-peptide motifs at the tip of V3 loop between cluster 1 and 2; however, differences in coreceptor usage were not detected. This study shows that subtype CRF01_AE strain may be the most prevalent epidemic strain in the men who have sex with men. Genetic characteristics of the subtype CRF01_AE cluster strain in Liaoning showed homology to the prevalent strains of men who have sex with men in other parts of China. © 2015 Wiley Periodicals, Inc.

Subtyping Listeria monocytogenes isolates genetically related to the Swiss epidemic clone.

PubMed Central

Boerlin, P; Bannerman, E; Jemmi, T; Bille, J

1996-01-01

Macrorestriction analysis by pulsed-field gel electrophoresis was used to assess the diversity of strains within the epidemic-associated electrophoretic type 1 (ET1) clone of Listeria monocytogenes. For this purpose, a total of 144 isolates from Switzerland shown by multilocus enzyme electrophoresis to belong to the ET1 were examined. These isolates were subtyped by macrorestriction analysis using the enzymes ApaI and SmaI and field inversion gel electrophoresis. Among these 144 isolates, 45 were isolated in human listeriosis cases of the postepidemic period of 1988 to 1993 and 44 were isolated in animal listeriosis cases of the same period. Forty-seven isolates were from the epidemic period of 1983 to 1987, and eight additional isolates were from cattle from two different farms. Twenty-nine different subtypes could be identified among the 144 isolates tested. Five major subtypes were found more frequently than the others during the postepidemic period, both in humans and in animals. Two of these subtypes had been previously implicated in outbreaks of listeriosis, thus suggesting that particular pulsed-field gel electrophoresis subtypes may be frequently associated with disease in humans and animals. Two of these frequent subtypes were also suspected to be related to small clusters of listeriosis cases during the postepidemic period. The results obtained by typing epidemiologically related isolates from different animals within the same farms and from different body sites of a given patient confirmed the potential of macrorestriction analysis for epidemiological studies restricted to short periods of time and to small number of isolates. The analysis of 47 isolates related to the Swiss listeriosis epidemic period of 1983 to 1987 and the use of Southern blotting and hybridization experiments show that the interpretation of relatedness between isolates presenting slightly different macrorestriction patterns may be more complex than commonly accepted. In such cases, careful interpretation of the potential molecular mechanisms leading to the differences observed between patterns is necessary. PMID:8862575

Diversity of Group I and II Clostridium botulinum Strains from France Including Recently Identified Subtypes

PubMed Central

Mazuet, Christelle; Legeay, Christine; Sautereau, Jean; Ma, Laurence; Bouchier, Christiane; Bouvet, Philippe; Popoff, Michel R.

2016-01-01

In France, human botulism is mainly food-borne intoxication, whereas infant botulism is rare. A total of 99 group I and II Clostridium botulinum strains including 59 type A (12 historical isolates [1947–1961], 43 from France [1986–2013], 3 from other countries, and 1 collection strain), 31 type B (3 historical, 23 recent isolates, 4 from other countries, and 1 collection strain), and 9 type E (5 historical, 3 isolates, and 1 collection strain) were investigated by botulinum locus gene sequencing and multilocus sequence typing analysis. Historical C. botulinum A strains mainly belonged to subtype A1 and sequence type (ST) 1, whereas recent strains exhibited a wide genetic diversity: subtype A1 in orfX or ha locus, A1(B), A1(F), A2, A2b2, A5(B2′) A5(B3′), as well as the recently identified A7 and A8 subtypes, and were distributed into 25 STs. Clostridium botulinum A1(B) was the most frequent subtype from food-borne botulism and food. Group I C. botulinum type B in France were mainly subtype B2 (14 out of 20 historical and recent strains) and were divided into 19 STs. Food-borne botulism resulting from ham consumption during the recent period was due to group II C. botulinum B4. Type E botulism is rare in France, 5 historical and 1 recent strains were subtype E3. A subtype E12 was recently identified from an unusual ham contamination. Clostridium botulinum strains from human botulism in France showed a wide genetic diversity and seems to result not from a single evolutionary lineage but from multiple and independent genetic rearrangements. PMID:27189984

A Swedish national twin study of criminal behavior and its violent, white-collar and property subtypes.

PubMed

Kendler, K S; Maes, H H; Lönn, S L; Morris, N A; Lichtenstein, P; Sundquist, J; Sundquist, K

2015-08-01

We sought to clarify the etiological contribution of genetic and environmental factors to total criminal behavior (CB) measured as criminal convictions in men and women, and to violent (VCB), white-collar (WCCB) and property criminal behavior (PCB) in men only. In 21 603 twin pairs from the Swedish Twin Registry, we obtained information on all criminal convictions from 1973 to 2011 from the Swedish Crime Register. Twin modeling was performed using the OpenMx package. For all criminal convictions, heritability was estimated at around 45% in both sexes, with the shared environment accounting for 18% of the variance in liability in females and 27% in males. The correlation of these risk factors across sexes was estimated at +0.63. In men, the magnitudes of genetic and environmental influence were similar in the three criminal conviction subtypes. However, for violent and white-collar convictions, nearly half and one-third of the genetic effects were respectively unique to that criminal subtype. About half of the familial environmental effects were unique to property convictions. The familial aggregation of officially recorded CB is substantial and results from both genetic and familial environmental factors. These factors are moderately correlated across the sexes suggesting that some genetic and environmental influences on criminal convictions are unique to men and to women. Violent criminal behavior and property crime are substantially influenced respectively by genetic and shared environmental risk factors unique to that criminal subtype.

Prevalence and genetic characterization of Vibrio vulnificus in raw seafood and seawater in Malaysia.

PubMed

Paydar, Mohammadjavad; Thong, Kwai Lin

2013-10-01

Vibrio vulnificus is a highly invasive human pathogen that exists naturally in estuarine environment and coastal waters. In this study, we used different PCR assays to detect V. vulnificus in 260 seafood and 80 seawater samples. V. vulnificus was present in about 34 (13%) of the 260 seafood samples and 18 (23%) of the 80 seawater samples. Repetitive extragenic palindromic PCR (REP-PCR) and enterobacterial repetitive intergenic consensus PCR (ERIC-PCR) were applied to subtype the V. vulnificus isolates. Twenty-five REP profiles and 45 ERIC profiles were observed, and the isolates were categorized into 9 and 10 distinct clusters at the similarity of 80%, by REP-PCR and ERIC-PCR, respectively. ERIC-PCR is more discriminative than REP-PCR in subtyping V. vulnificus, demonstrating high genetic diversity among the isolates.

Recent Developments in Dystonia

PubMed Central

Jinnah, H. A.; Teller, Jan K.; Galpern, Wendy R.

2015-01-01

Purpose of review The dystonias are a family of related disorders with many different clinical manifestations and causes. This review summarizes recent developments regarding these disorders, focusing mainly on advances with direct clinical relevance from the past two years. Recent findings The dystonias are generally defined by their clinical characteristics, rather than by their underlying genetic or neuropathological defects. The many varied clinical manifestations and causes contribute to the fact that they are one of the most poorly recognized of all movement disorders. A series of recent publications has addressed these issues offering a revised definition and more logical means for classifying the many subtypes. Our understanding of the genetic and neurobiological mechanisms responsible for different types of dystonias also has grown rapidly, creating new opportunities and challenges for diagnosis and identifying increasing numbers of rare subtypes for which specific treatments are available. Summary Recent advances in describing the clinical phenotypes and determining associated genotypes have pointed to the need for new strategies for diagnosis, classification and treatment of the dystonias. PMID:26110799

Lobar Emphysema Distribution Is Associated With 5-Year Radiological Disease Progression.

PubMed

Boueiz, Adel; Chang, Yale; Cho, Michael H; Washko, George R; San José Estépar, Raul; Bowler, Russell P; Crapo, James D; DeMeo, Dawn L; Dy, Jennifer G; Silverman, Edwin K; Castaldi, Peter J

2018-01-01

Emphysema has considerable variability in its regional distribution. Craniocaudal emphysema distribution is an important predictor of the response to lung volume reduction. However, there is little consensus regarding how to define upper lobe-predominant and lower lobe-predominant emphysema subtypes. Consequently, the clinical and genetic associations with these subtypes are poorly characterized. We sought to identify subgroups characterized by upper-lobe or lower-lobe emphysema predominance and comparable amounts of total emphysema by analyzing data from 9,210 smokers without alpha-1-antitrypsin deficiency in the Genetic Epidemiology of COPD (COPDGene) cohort. CT densitometric emphysema was measured in each lung lobe. Random forest clustering was applied to lobar emphysema variables after regressing out the effects of total emphysema. Clusters were tested for association with clinical and imaging outcomes at baseline and at 5-year follow-up. Their associations with genetic variants were also compared. Three clusters were identified: minimal emphysema (n = 1,312), upper lobe-predominant emphysema (n = 905), and lower lobe-predominant emphysema (n = 796). Despite a similar amount of total emphysema, the lower-lobe group had more severe airflow obstruction at baseline and higher rates of metabolic syndrome compared with subjects with upper-lobe predominance. The group with upper-lobe predominance had greater 5-year progression of emphysema, gas trapping, and dyspnea. Differential associations with known COPD genetic risk variants were noted. Subgroups of smokers defined by upper-lobe or lower-lobe emphysema predominance exhibit different functional and radiological disease progression rates, and the upper-lobe predominant subtype shows evidence of association with known COPD genetic risk variants. These subgroups may be useful in the development of personalized treatments for COPD. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Spreading of HIV-1 subtype G and envB/gagG recombinant strains among injecting drug users in Lisbon, Portugal.

PubMed

Esteves, Aida; Parreira, Ricardo; Piedade, João; Venenno, Teresa; Franco, Margarida; Germano de Sousa, José; Patrício, Luis; Brum, Paula; Costa, António; Canas-Ferreira, Wanda F

2003-06-01

We have evaluated the genetic diversity of HIV-1 strains infecting injecting drug users (IDUs) in Lisbon, Portugal. Heteroduplex mobility assay and/or phylogenetic analysis revealed that env (C2V3C3 or gp41) subtype B is present in 63.7% of the 135 viral samples studied, followed by subtypes G (23.7%), A (6.7%), F (5.2%), and D (0.7%). Similar analysis of gag (p24/p7) performed on 91 of the specimens demonstrated that 49.5% of the infections were caused by subtype G viruses; other gag subtypes identified were B (39.5%), F (3.3%), A and D (1.1.% each), and the recombinant circulating form CRF02_AG (5.5%). Discordant env/gag sub-types were detected in 34.1% of the strains and may reflect the presence of dual infections and/or recombinant viruses. The presumptive B/G recombinant form was highly predominant (21 of 31). The genetic pattern of HIV-1 subtype B and G strains is suggestive of multiple introductions and recombination episodes and of a longstanding presence of both subtypes in the country. C2V3C3 amino acid sequences from IDU-derived subtype G viruses presented highly significant signatures, which distinguish the variants from this transmission group. The unusually high prevalence of subtype G sequences (34.1%), independent of the geographic origin of the infected individuals, makes this IDU HIV-1 epidemic unique.

Incidence of lymphoid neoplasms by subtype among six Asian ethnic groups in the United States, 1996-2004.

PubMed

Carreon, J Daniel; Morton, Lindsay M; Devesa, Susan S; Clarke, Christina A; Gomez, Scarlett L; Glaser, Sally L; Sakoda, Lori C; Linet, Martha S; Wang, Sophia S

2008-12-01

To establish baseline data for lymphoid neoplasm incidence by subtype for six Asian-American ethnic groups. Incident rates were estimated by age and sex for six Asian ethnic groups--Asian Indian/Pakistani, Chinese, Filipino, Japanese, Korean, Vietnamese--in five United States cancer registry areas during 1996-2004. For comparison, rates for non-Hispanic Whites were also estimated. During 1996-2004, Filipinos had the highest (24.0) and Koreans had the lowest incidence (12.7) of total lymphoid neoplasms. By subtype, Vietnamese and Filipinos had the highest incidence for diffuse large B-cell lymphoma (DLBCL) (8.0 and 7.2); Japanese had the highest incidence of follicular lymphoma (2.3). Although a general male predominance of lymphoid neoplasms was observed, this pattern varied by lymphoid neoplasm subtype. Whites generally had higher rates than all Asian ethnic groups for all lymphoid neoplasms and most lymphoma subtypes, although the magnitude of the difference varied by both ethnicity and lymphoma subtype. The observed variations in incidence patterns among Asian ethnic groups in the United States suggest that it may be fruitful to pursue studies that compare Asian populations for postulated environmental and genetic risk factors.

Distinct subtype distribution and somatic mutation spectrum of lymphomas in East Asia.

PubMed

Ren, Weicheng; Li, Wei; Ye, Xiaofei; Liu, Hui; Pan-Hammarström, Qiang

2017-07-01

Here, we give an updated overview of the subtype distribution of lymphomas in East Asia and also present the genome sequencing data on two major subtypes of these tumors. The distribution of lymphoma types/subtypes among East Asian countries is very similar, with a lower proportion of B-cell malignancies and a higher proportion of T/natural killer (NK)-cell lymphomas as compared to Western populations. Extranodal NK/T-cell lymphoma is more frequently observed in East Asia, whereas follicular lymphoma and chronic lymphocytic leukemia, are proportionally lower. The incidence rate of lymphoma subtypes in Asians living in the US was generally intermediate to the general rate in US and Asia, suggesting that both genetic and environmental factors may underlie the geographical variations observed.Key cancer driver mutations have been identified in Asian patients with diffuse large B-cell lymphoma or extranodal NK/T-cell lymphoma through genome sequencing. A distinct somatic mutation profile has also been observed in Chinese diffuse large B-cell lymphoma patients. The incidence and distribution of lymphoma subtypes differed significantly between patients from East Asia and Western countries, suggesting subtype-specific etiologic mechanisms. Further studies on the mechanism underlying these geographical variations may give new insights into our understanding of lymphomagenesis.

Do HIV-1 non-B subtypes differentially impact resistance mutations and clinical disease progression in treated populations? Evidence from a systematic review

PubMed Central

Bhargava, Madhavi; Cajas, Jorge Martinez; Wainberg, Mark A; Klein, Marina B; Pai, Nitika Pant

2014-01-01

There are 31 million adults living with HIV-1 non-B subtypes globally, and about 10 million are on antiretroviral therapy (ART). Global evidence to guide clinical practice on ART response in HIV-1 non-B subtypes remains limited. We systematically searched 11 databases for the period 1996 to 2013 for evidence. Outcomes documented included time to development of AIDS and/or death, resistance mutations, opportunistic infections, and changes in CD4 cell counts and viral load. A lack of consistent reporting of all clinical end points precluded a meta-analysis. In sum, genetic diversity that precipitated differences in disease progression in ART-naïve populations was minimized in ART-experienced populations, although variability in resistance mutations persisted across non-B subtypes. To improve the quality of patient care in global settings, recording HIV genotypes at baseline and at virologic failure with targeted non-B subtype-based point-of-care resistance assays and timely phasing out of resistance-inducing ART regimens is recommended. PMID:24998532

Diversity and evolution of avian influenza viruses in live poultry markets, free-range poultry and wild wetland birds in China.

PubMed

Chen, Liang-Jun; Lin, Xian-Dan; Guo, Wen-Ping; Tian, Jun-Hua; Wang, Wen; Ying, Xu-Hua; Wang, Miao-Ruo; Yu, Bin; Yang, Zhan-Qiu; Shi, Mang; Holmes, Edward C; Zhang, Yong-Zhen

2016-04-01

The wide circulation of novel avian influenza viruses (AIVs) highlights the risk of pandemic influenza emergence in China. To investigate the prevalence and genetic diversity of AIVs in different ecological contexts, we surveyed AIVs in live poultry markets (LPMs), free-range poultry and the wetland habitats of wild birds in Zhejiang and Hubei provinces. Notably, LPMs contained the highest frequency of AIV infection, and the greatest number of subtypes (n = 9) and subtype co-infections (n = 14), as well as frequent reassortment, suggesting that they play an active role in fuelling AIV transmission. AIV-positive samples were also identified in wild birds in both provinces and free-range poultry in one sampling site close to a wetland region in Hubei. H9N2, H7N9 and H5N1 were the most commonly sampled subtypes in the LPMs from Zhejiang, whilst H5N6 and H9N2 were the dominant subtypes in the LPMs from Hubei. Phylogenetic analyses of the whole-genome sequences of 43 AIVs revealed that three reassortant H5 subtypes were circulating in LMPs in both geographical regions. Notably, the viruses sampled from the wetland regions and free-range poultry contained complex reassortants, for which the origins of some segments were unclear. Overall, our study highlights the extent of AIV genetic diversity in two highly populated parts of central and south-eastern China, particularly in LPMs, and emphasizes the need for continual surveillance.

Birthdating of myenteric neuron subtypes in the small intestine of the mouse.

PubMed

Bergner, Annette J; Stamp, Lincon A; Gonsalvez, David G; Allison, Margaret B; Olson, David P; Myers, Martin G; Anderson, Colin R; Young, Heather M

2014-02-15

There are many different types of enteric neurons. Previous studies have identified the time at which some enteric neuron subtypes are born (exit the cell cycle) in the mouse, but the birthdates of some major enteric neuron subtypes are still incompletely characterized or unknown. We combined 5-ethynynl-2'-deoxyuridine (EdU) labeling with antibody markers that identify myenteric neuron subtypes to determine when neuron subtypes are born in the mouse small intestine. We found that different neurochemical classes of enteric neuron differed in their birthdates; serotonin neurons were born first with peak cell cycle exit at E11.5, followed by neurofilament-M neurons, calcitonin gene-related peptide neurons (peak cell cycle exit for both at embryonic day [E]12.5-E13.5), tyrosine hydroxylase neurons (E15.5), nitric oxide synthase 1 (NOS1) neurons (E15.5), and calretinin neurons (postnatal day [P]0). The vast majority of myenteric neurons had exited the cell cycle by P10. We did not observe any EdU+/NOS1+ myenteric neurons in the small intestine of adult mice following EdU injection at E10.5 or E11.5, which was unexpected, as previous studies have shown that NOS1 neurons are present in E11.5 mice. Studies using the proliferation marker Ki67 revealed that very few NOS1 neurons in the E11.5 and E12.5 gut were proliferating. However, Cre-lox-based genetic fate-mapping revealed a small subpopulation of myenteric neurons that appears to express NOS1 only transiently. Together, our results confirm a relationship between enteric neuron subtype and birthdate, and suggest that some enteric neurons exhibit neurochemical phenotypes during development that are different from their mature phenotype. Copyright © 2013 Wiley Periodicals, Inc.

Genomic profiles of low-grade murine gliomas evolve during progression to glioblastoma. | Office of Cancer Genomics

Cancer.gov

Background: Gliomas are diverse neoplasms with multiple molecular subtypes. How tumor-initiating mutations relate to molecular subtypes as these tumors evolve during malignant progression remains unclear.Methods: We used genetically engineered mouse models, histopathology, genetic lineage tracing, expression profiling, and copy number analyses to examine how genomic tumor diversity evolves during the course of malignant progression from low- to high-grade disease.

Genetic and biological characterisation of an avian-like H1N2 swine influenza virus generated by reassortment of circulating avian-like H1N1 and H3N2 subtypes in Denmark.

PubMed

Trebbien, Ramona; Bragstad, Karoline; Larsen, Lars Erik; Nielsen, Jens; Bøtner, Anette; Heegaard, Peter M H; Fomsgaard, Anders; Viuff, Birgitte; Hjulsager, Charlotte Kristiane

2013-09-18

The influenza A virus subtypes H1N1, H1N2 and H3N2 are the most prevalent subtypes in swine. In 2003, a reassorted H1N2 swine influenza virus (SIV) subtype appeared and became prevalent in Denmark. In the present study, the reassortant H1N2 subtype was characterised genetically and the infection dynamics compared to an "avian-like" H1N1 virus by an experimental infection study. Sequence analyses were performed of the H1N2 virus. Two groups of pigs were inoculated with the reassortant H1N2 virus and an "avian-like" H1N1 virus, respectively, followed by inoculation with the opposite subtype four weeks later. Measurements of HI antibodies and acute phase proteins were performed. Nasal virus excretion and virus load in lungs were determined by real-time RT-PCR. The phylogenetic analysis revealed that the reassorted H1N2 virus contained a European "avian-like" H1-gene and a European "swine-like" N2-gene, thus being genetically distinct from most H1N2 viruses circulating in Europe, but similar to viruses reported in 2009/2010 in Sweden and Italy. Sequence analyses of the internal genes revealed that the reassortment probably arose between circulating Danish "avian-like" H1N1 and H3N2 SIVs. Infected pigs developed cross-reactive antibodies, and increased levels of acute phase proteins after inoculations. Pigs inoculated with H1N2 exhibited nasal virus excretion for seven days, peaking day 1 after inoculation two days earlier than H1N1 infected pigs and at a six times higher level. The difference, however, was not statistically significant. Pigs euthanized on day 4 after inoculation, had a high virus load in all lung lobes. After the second inoculation, the nasal virus excretion was minimal. There were no clinical sign except elevated body temperature under the experimental conditions. The "avian-like" H1N2 subtype, which has been established in the Danish pig population at least since 2003, is a reassortant between circulating swine "avian-like" H1N1 and H3N2. The Danish H1N2 has an "avian-like" H1 and differs from most other reported H1N2 viruses in Europe and North America/Asia, which have H1-genes of human or "classical-swine" origin, respectively. The variant seems, however, also to be circulating in countries like Sweden and Italy. The infection dynamics of the reassorted "avian-like" H1N2 is similar to the older "avian-like" H1N1 subtype.

Genetic and biological characterisation of an avian-like H1N2 swine influenza virus generated by reassortment of circulating avian-like H1N1 and H3N2 subtypes in Denmark

PubMed Central

2013-01-01

Background The influenza A virus subtypes H1N1, H1N2 and H3N2 are the most prevalent subtypes in swine. In 2003, a reassorted H1N2 swine influenza virus (SIV) subtype appeared and became prevalent in Denmark. In the present study, the reassortant H1N2 subtype was characterised genetically and the infection dynamics compared to an “avian-like” H1N1 virus by an experimental infection study. Methods Sequence analyses were performed of the H1N2 virus. Two groups of pigs were inoculated with the reassortant H1N2 virus and an “avian-like” H1N1 virus, respectively, followed by inoculation with the opposite subtype four weeks later. Measurements of HI antibodies and acute phase proteins were performed. Nasal virus excretion and virus load in lungs were determined by real-time RT-PCR. Results The phylogenetic analysis revealed that the reassorted H1N2 virus contained a European “avian-like” H1-gene and a European “swine-like” N2-gene, thus being genetically distinct from most H1N2 viruses circulating in Europe, but similar to viruses reported in 2009/2010 in Sweden and Italy. Sequence analyses of the internal genes revealed that the reassortment probably arose between circulating Danish “avian-like” H1N1 and H3N2 SIVs. Infected pigs developed cross-reactive antibodies, and increased levels of acute phase proteins after inoculations. Pigs inoculated with H1N2 exhibited nasal virus excretion for seven days, peaking day 1 after inoculation two days earlier than H1N1 infected pigs and at a six times higher level. The difference, however, was not statistically significant. Pigs euthanized on day 4 after inoculation, had a high virus load in all lung lobes. After the second inoculation, the nasal virus excretion was minimal. There were no clinical sign except elevated body temperature under the experimental conditions. Conclusions The “avian-like” H1N2 subtype, which has been established in the Danish pig population at least since 2003, is a reassortant between circulating swine “avian-like” H1N1 and H3N2. The Danish H1N2 has an “avian-like” H1 and differs from most other reported H1N2 viruses in Europe and North America/Asia, which have H1-genes of human or “classical-swine” origin, respectively. The variant seems, however, also to be circulating in countries like Sweden and Italy. The infection dynamics of the reassorted “avian-like” H1N2 is similar to the older “avian-like” H1N1 subtype. PMID:24047399

Response to clozapine in a clinically identifiable subtype of schizophrenia

PubMed Central

Butcher, Nancy J.; Fung, Wai Lun Alan; Fitzpatrick, Laura; Guna, Alina; Andrade, Danielle M.; Lang, Anthony E.; Chow, Eva W. C.; Bassett, Anne S.

2015-01-01

Background Genetic testing in psychiatry promises to improve patient care through advances in personalised medicine. However, there are few clinically relevant examples. Aims To determine whether patients with a well-established genetic subtype of schizophrenia show a different response profile to the antipsychotic clozapine than those with idiopathic schizophrenia. Method We retrospectively studied the long-term safety and efficacy of clozapine in 40 adults with schizophrenia, half with a 22q11.2 deletion (22q11.2DS group) and half matched for age and clinical severity but molecularly confirmed to have no pathogenic copy number variant (idiopathic group). Results Both groups showed similar clinical improvement and significant reductions in hospitalisations, achieved at a lower median dose for those in the 22q11.2DS group. Most common side-effects were similarly prevalent between the two groups, however, half of the 22q11.2DS group experienced at least one rare serious adverse event compared with none of the idiopathic group. Many were successfully retried on clozapine. Conclusions Individuals with 22q11.2DS-schizophrenia respond as well to clozapine treatment as those with other forms of schizophrenia, but may represent a disproportionate number of those with serious adverse events, primarily seizures. Lower doses and prophylactic (for example anticonvulsant) management strategies can help ameliorate side-effect risks. This first systematic evaluation of antipsychotic response in a genetic subtype of schizophrenia provides a proof-of-principle for personalised medicine and supports the utility of clinical genetic testing in schizophrenia. PMID:25745132

Age and the means of bypassing stasis influence the intrinsic subtype of immortalized human mammary epithelial cells.

PubMed

Lee, Jonathan K; Garbe, James C; Vrba, Lukas; Miyano, Masaru; Futscher, Bernard W; Stampfer, Martha R; LaBarge, Mark A

2015-01-01

Based on molecular features, breast cancers are grouped into intrinsic subtypes that have different prognoses and therapeutic response profiles. With increasing age, breast cancer incidence increases, with hormone receptor-positive and other luminal-like subtype tumors comprising a majority of cases. It is not known at what stage of tumor progression subtype specification occurs, nor how the process of aging affects the intrinsic subtype. We examined subtype markers in immortalized human mammary epithelial cell lines established following exposure of primary cultured cell strains to a two-step immortalization protocol that targets the two main barriers to immortality: stasis (stress-associated senescence) and replicative senescence. Cell lines derived from epithelial cells obtained from non-tumorous pre- and post-menopausal breast surgery tissues were compared. Additionally, comparisons were made between lines generated using two different genetic interventions to bypass stasis: transduction of either an shRNA that down-regulated p16(INK4A), or overexpressed constitutive active cyclin D1/CDK2. In all cases, the replicative senescence barrier was bypassed by transduction of c-Myc. Cells from all resulting immortal lines exhibited normal karyotypes. Immunofluorescence, flow cytometry, and gene expression analyses of lineage-specific markers were used to categorize the intrinsic subtypes of the immortalized lines. Bypassing stasis with p16 shRNA in young strains generated cell lines that were invariably basal-like, but the lines examined from older strains exhibited some luminal features such as keratin 19 and estrogen receptor expression. Overexpression of cyclin D1/CDK2 resulted in keratin 19 positive, luminal-like cell lines from both young and old strains, and the lines examined from older strains exhibited estrogen receptor expression. Thus age and the method of bypassing stasis independently influence the subtype of immortalized human mammary epithelial cells.

De novo point mutations in patients diagnosed with ataxic cerebral palsy

PubMed Central

Parolin Schnekenberg, Ricardo; Perkins, Emma M.; Miller, Jack W.; Davies, Wayne I. L.; D’Adamo, Maria Cristina; Pessia, Mauro; Fawcett, Katherine A.; Sims, David; Gillard, Elodie; Hudspith, Karl; Skehel, Paul; Williams, Jonathan; O’Regan, Mary; Jayawant, Sandeep; Jefferson, Rosalind; Hughes, Sarah; Lustenberger, Andrea; Ragoussis, Jiannis

2015-01-01

Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies. PMID:25981959

The HIV-1 epidemic in Bolivia is dominated by subtype B and CRF12_BF "family" strains.

PubMed

Guimarães, Monick L; Velarde-Dunois, Ketty G; Segurondo, David; Morgado, Mariza G

2012-01-16

Molecular epidemiological studies of HIV-1 in South America have revealed the occurrence of subtypes B, F1 and BF1 recombinants. Even so, little information concerning the HIV-1 molecular epidemiology in Bolivia is available. In this study we performed phylogenetic analyses from samples collected in Bolivia at two different points in time over a 10 year span. We analyzed these samples to estimate the trends in the HIV subtype and recombinant forms over time. Fifty one HIV-1 positive samples were collected in Bolivia over two distinct periods (1996 and 2005). These samples were genetically characterized based on partial pol protease/reverse transcriptase (pr/rt) and env regions. Alignment and neighbor-joining (NJ) phylogenetic analyses were established from partial env (n = 37) and all pol sequences using Mega 4. The remaining 14 env sequences from 1996 were previously characterized based on HMA-env (Heteroduplex mobility assay). The Simplot v.3.5.1 program was used to verify intragenic recombination, and SplitsTree 4.0 was employed to confirm the phylogenetic relationship of the BF1 recombinant samples. Phylogenetic analysis of both env and pol regions confirmed the predominance of "pure" subtype B (72.5%) samples circulating in Bolivia and revealed a high prevalence of BF1 genotypes (27.5%). Eleven out of 14 BF1 recombinants displayed a mosaic structure identical or similar to that described for the CRF12_BF variant, one sample was classified as CRF17_BF, and two others were F1pol/Benv. No "pure" HIV-1 subtype F1 or B" variant of subtype B was detected in the present study. Of note, samples characterized as CRF12_BF-related were depicted only in 2005. HIV-1 genetic diversity in Bolivia is mostly driven by subtype B followed by BF1 recombinant strains from the CRF12_BF "family". No significant temporal changes were detected between the mid-1990s and the mid-2000s for subtype B (76.2% vs 70.0%) or BF1 recombinant (23.8% vs 30.0%) samples from Bolivia.

The HIV-1 epidemic in Bolivia is dominated by subtype B and CRF12_BF "family" strains

PubMed Central

2012-01-01

Background Molecular epidemiological studies of HIV-1 in South America have revealed the occurrence of subtypes B, F1 and BF1 recombinants. Even so, little information concerning the HIV-1 molecular epidemiology in Bolivia is available. In this study we performed phylogenetic analyses from samples collected in Bolivia at two different points in time over a 10 year span. We analyzed these samples to estimate the trends in the HIV subtype and recombinant forms over time. Materials and methods Fifty one HIV-1 positive samples were collected in Bolivia over two distinct periods (1996 and 2005). These samples were genetically characterized based on partial pol protease/reverse transcriptase (pr/rt) and env regions. Alignment and neighbor-joining (NJ) phylogenetic analyses were established from partial env (n = 37) and all pol sequences using Mega 4. The remaining 14 env sequences from 1996 were previously characterized based on HMA-env (Heteroduplex mobility assay). The Simplot v.3.5.1 program was used to verify intragenic recombination, and SplitsTree 4.0 was employed to confirm the phylogenetic relationship of the BF1 recombinant samples. Results Phylogenetic analysis of both env and pol regions confirmed the predominance of "pure" subtype B (72.5%) samples circulating in Bolivia and revealed a high prevalence of BF1 genotypes (27.5%). Eleven out of 14 BF1 recombinants displayed a mosaic structure identical or similar to that described for the CRF12_BF variant, one sample was classified as CRF17_BF, and two others were F1pol/Benv. No "pure" HIV-1 subtype F1 or B" variant of subtype B was detected in the present study. Of note, samples characterized as CRF12_BF-related were depicted only in 2005. Conclusion HIV-1 genetic diversity in Bolivia is mostly driven by subtype B followed by BF1 recombinant strains from the CRF12_BF "family". No significant temporal changes were detected between the mid-1990s and the mid-2000s for subtype B (76.2% vs 70.0%) or BF1 recombinant (23.8% vs 30.0%) samples from Bolivia. PMID:22248191

Molecular mechanism of the susceptibility difference between HLA-B*27:02/04/05 and HLA-B*27:06/09 to ankylosing spondylitis: substitution analysis, MD simulation, QSAR modelling, and in vitro assay.

PubMed

Cheng, X; Mei, Y; Ji, X; Xue, Q; Chen, D

2016-05-01

The human leukocyte antigen HLA-B27 is directly involved in the disease pathogenesis of ankylosing spondylitis (AS). HLA-B27 has a high degree of genetic polymorphism, with 105 currently known subtypes; the presence of aspartic acid at residue 116 (Asp116) has been found to play an essential role in AS susceptibility. Here, we systematically investigated the molecular mechanism of the susceptibility difference between the AS-associated subtypes HLA-B*27:02/04/05 and AS-unassociated subtypes HLA-B*27:06/09 to AS at sequence, structure, energetic and dynamic levels. In total seven variable residues were identified among the five studied HLA-B27 subtypes, in which Asp116 can be largely stabilized by a spatially vicinal, positively charged His114 through a salt bridge, while five other variable residues seem to have only a marginal effect on AS susceptibility. We also employed a quantitative structure-activity relationship approach to model the statistical correlation between peptide structure and affinity to HLA-B*27:05, a genetic ancestor of all other HLA-B27 subtypes and associated strongly with AS. The built regression predictor was verified rigorously through both internal cross-validation and external blind validation, and was then employed to identify potential HLA-B*27:05 binders from >20,000 cartilage-derived self-peptides. Subsequently, the binding potency of the top five antigenic peptides to HLA-B*27:05 was assayed in vitro using a FACS-based MHC stabilization experiment. Consequently, two (QRVGSDEFK and LRGAGTNEK) out of the five peptides were determined to have high affinity (BL50 = 5.5 and 15.8 nM, respectively) and, as expected, both of them possess positively charged Lys at the C-terminus.

HIV-1 transmitted drug resistance and genetic diversity among patients from Piauí State, Northeast Brazil.

PubMed

Moura, Maria Edileuza Soares; da Guarda Reis, Mônica Nogueira; Lima, Yanna Andressa Ramos; Eulálio, Kelsen Dantas; Cardoso, Ludimila Paula Vaz; Stefani, Mariane Martins Araújo

2015-05-01

HIV-1 transmitted-drug-resistance and genetic diversity are dynamic and may differ in distinct locations/risk groups. In Brazil, increased AIDS incidence and related mortality have been detected in the Northeast region, differently from the epicenter in the Southeast. This cross-sectional study describes transmitted-dru- resistance and HIV-1 subtypes in protease/PR and reverse transcriptase/RT regions among antiretroviral naïve patients from Piauí State, Northeast Brazil. Among 96 patients recruited 89 (92.7%) had HIV-1 PR/RT regions sequenced: 44 females and 45 males, 22 self-declared as men who have sex with men. Transmitted-drug-resistance was investigated by CPR tool (Stanford HIV-1 Drug Resistance/SDRM). HIV-1 subtypes were assigned by REGA and phylogenetic inference. Overall, transmitted-drug-resistance rate was 11.2% (10/89; CI 95%: 5.8-19.1%); 22.7% among men who have sex with men (5/22; CI 95%: 8.8-43.4%), 10% in heterosexual men (2/20; CI 95%: 1.7-29.3%) and 6.8% in women (3/44; CI 95%: 1.8-17.4%). Singleton mutations to protease-inhibitor/PI, nucleoside-reverse-transcriptase-inhibitor/NRTI or non-nucleoside-reverse-transcriptase-inhibitor/NNRTI predominated (8/10): PI mutations (M46L, V82F, L90M); NRTI mutations (M41L, D67N) and NNRTI mutations (K103N/S). Dual class resistance mutations to NRTI and NNRTI were observed: T215L (NRTI), Y188L (NNRTI) and T215N (NRTI), F227L (NNRTI). Subtype B prevailed (86.6%; 77/89), followed by subtype F1 (1.1%, 1/89) and subtype C (1.1%, 1/89). B/F1 and B/C intersubtype recombinants represented 11.2% (10/89). In Piauí State extensive testing of incidence and transmitted-drug-resistance in all populations with risk behaviors may help control AIDS epidemic locally. © 2015 Wiley Periodicals, Inc.

Childhood Acute Myeloid Leukaemia

PubMed Central

Rubnitz, Jeffrey E.; Inaba, Hiroto

2012-01-01

Summary Although acute myeloid leukaemia (AML) has long been recognized for its morphological and cytogenetic heterogeneity, recent high-resolution genomic profiling has demonstrated a complexity even greater than previously imagined. This complexity can be seen in the number and diversity of genetic alterations, epigenetic modifications, and characteristics of the leukaemic stem cells. The broad range of abnormalities across different AML subtypes suggests that improvements in clinical outcome will require the development of targeted therapies for each subtype of disease and the design of novel clinical trials to test these strategies. It is highly unlikely that further gains in long-term survival rates will be possible by mere intensification of conventional chemotherapy. In this review, we summarize recent studies that provide new insight into the genetics and biology of AML, discuss risk stratification and therapy for this disease, and profile some of the therapeutic agents currently under investigation. PMID:22966788

Parkinsonism in Spinocerebellar Ataxia

PubMed Central

Park, Hyeyoung; Kim, Han-Joon; Jeon, Beom S.

2015-01-01

Spinocerebellar ataxia (SCA) presents heterogeneous clinical phenotypes, and parkinsonism is reported in diverse SCA subtypes. Both levodopa responsive Parkinson disease (PD) like phenotype and atypical parkinsonism have been described especially in SCA2, SCA3, and SCA17 with geographic differences in prevalence. SCA2 is the most frequently reported subtype of SCA related to parkinsonism worldwide. Parkinsonism in SCA2 has unique genetic characteristics, such as low number of expansions and interrupted structures, which may explain the sporadic cases with low penetrance. Parkinsonism in SCA17 is more remarkable in Asian populations especially in Korea. In addition, an unclear cutoff of the pathologic range is the key issue in SCA17 related parkinsonism. SCA3 is more common in western cohorts. SCA6 and SCA8 have also been reported with a PD-like phenotype. Herein, we reviewed the epidemiologic, clinical, genetic, and pathologic features of parkinsonism in SCAs. PMID:25866756

Interplay between HIV-1 and Host Genetic Variation: A Snapshot into Its Impact on AIDS and Therapy Response

PubMed Central

Sampathkumar, Raghavan; Shadabi, Elnaz; Luo, Ma

2012-01-01

As of February 2012, 50 circulating recombinant forms (CRFs) have been reported for HIV-1 while one CRF for HIV-2. Also according to HIV sequence compendium 2011, the HIV sequence database is replete with 414,398 sequences. The fact that there are CRFs, which are an amalgamation of sequences derived from six or more subtypes (CRF27_cpx (cpx refers to complex) is a mosaic with sequences from 6 different subtypes besides an unclassified fragment), serves as a testimony to the continual divergent evolution of the virus with its approximate 1% per year rate of evolution, and this phenomena per se poses tremendous challenge for vaccine development against HIV/AIDS, a devastating disease that has killed 1.8 million patients in 2010. Here, we explore the interaction between HIV-1 and host genetic variation in the context of HIV/AIDS and antiretroviral therapy response. PMID:22666249

Active Surveillance for Avian Influenza Virus, Egypt, 2010–2012

PubMed Central

Kandeil, Ahmed; El-Shesheny, Rabeh; Kayed, Ahmed S.; Gomaa, Mokhtar M.; Maatouq, Asmaa M.; Shehata, Mahmoud M.; Moatasim, Yassmin; Bagato, Ola; Cai, Zhipeng; Rubrum, Adam; Kutkat, Mohamed A.; McKenzie, Pamela P.; Webster, Robert G.; Webby, Richard J.; Ali, Mohamed A.

2014-01-01

Continuous circulation of influenza A(H5N1) virus among poultry in Egypt has created an epicenter in which the viruses evolve into newer subclades and continue to cause disease in humans. To detect influenza viruses in Egypt, since 2009 we have actively surveyed various regions and poultry production sectors. From August 2010 through January 2013, >11,000 swab samples were collected; 10% were positive by matrix gene reverse transcription PCR. During this period, subtype H9N2 viruses emerged, cocirculated with subtype H5N1 viruses, and frequently co-infected the same avian host. Genetic and antigenic analyses of viruses revealed that influenza A(H5N1) clade 2.2.1 viruses are dominant and that all subtype H9N2 viruses are G1-like. Cocirculation of different subtypes poses concern for potential reassortment. Avian influenza continues to threaten public and animal health in Egypt, and continuous surveillance for avian influenza virus is needed. PMID:24655395

Pauci- and Multibacillary Leprosy: Two Distinct, Genetically Neglected Diseases

PubMed Central

Gaschignard, Jean; Grant, Audrey Virginia; Thuc, Nguyen Van; Orlova, Marianna; Cobat, Aurélie; Huong, Nguyen Thu; Ba, Nguyen Ngoc; Thai, Vu Hong; Abel, Laurent; Schurr, Erwin; Alcaïs, Alexandre

2016-01-01

After sustained exposure to Mycobacterium leprae, only a subset of exposed individuals develops clinical leprosy. Moreover, leprosy patients show a wide spectrum of clinical manifestations that extend from the paucibacillary (PB) to the multibacillary (MB) form of the disease. This “polarization” of leprosy has long been a major focus of investigation for immunologists because of the different immune response in these two forms. But while leprosy per se has been shown to be under tight human genetic control, few epidemiological or genetic studies have focused on leprosy subtypes. Using PubMed, we collected available data in English on the epidemiology of leprosy polarization and the possible role of human genetics in its pathophysiology until September 2015. At the genetic level, we assembled a list of 28 genes from the literature that are associated with leprosy subtypes or implicated in the polarization process. Our bibliographical search revealed that improved study designs are needed to identify genes associated with leprosy polarization. Future investigations should not be restricted to a subanalysis of leprosy per se studies but should instead contrast MB to PB individuals. We show the latter approach to be the most powerful design for the identification of genetic polarization determinants. Finally, we bring to light the important resource represented by the nine-banded armadillo model, a unique animal model for leprosy. PMID:27219008

Evolving rule-based systems in two medical domains using genetic programming.

PubMed

Tsakonas, Athanasios; Dounias, Georgios; Jantzen, Jan; Axer, Hubertus; Bjerregaard, Beth; von Keyserlingk, Diedrich Graf

2004-11-01

To demonstrate and compare the application of different genetic programming (GP) based intelligent methodologies for the construction of rule-based systems in two medical domains: the diagnosis of aphasia's subtypes and the classification of pap-smear examinations. Past data representing (a) successful diagnosis of aphasia's subtypes from collaborating medical experts through a free interview per patient, and (b) correctly classified smears (images of cells) by cyto-technologists, previously stained using the Papanicolaou method. Initially a hybrid approach is proposed, which combines standard genetic programming and heuristic hierarchical crisp rule-base construction. Then, genetic programming for the production of crisp rule based systems is attempted. Finally, another hybrid intelligent model is composed by a grammar driven genetic programming system for the generation of fuzzy rule-based systems. Results denote the effectiveness of the proposed systems, while they are also compared for their efficiency, accuracy and comprehensibility, to those of an inductive machine learning approach as well as to those of a standard genetic programming symbolic expression approach. The proposed GP-based intelligent methodologies are able to produce accurate and comprehensible results for medical experts performing competitive to other intelligent approaches. The aim of the authors was the production of accurate but also sensible decision rules that could potentially help medical doctors to extract conclusions, even at the expense of a higher classification score achievement.

Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes

PubMed Central

Engström, Gunnar; Larsson, Susanna C.; Traylor, Matthew; Markus, Hugh S.; Melander, Olle; Orho-Melander, Marju

2018-01-01

Background and Purpose— Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR). Methods— Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance–weighted MR was used to obtain the causal estimates. Inverse-variance–weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias. Results— A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04–1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10–1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67–0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes. Conclusions— LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes. PMID:29535274

Phylogenetic analysis of swine influenza viruses recently isolated in Korea.

PubMed

Lee, C S; Kang, B K; Kim, H K; Park, S J; Park, B K; Jung, K; Song, D S

2008-10-01

Several influenza A viral subtypes were isolated from pigs during a severe outbreak of respiratory disease in Korea during 2005 and 2006. They included a classical swine H1N1 subtype, two swine-human-avian triple-recombinant H1N2 subtypes, and a swine-human-avian triple-recombinant H3N2 subtype. In the current study, genetic characterization to determine the probable origin of these recent isolates was carried out for the first time. Phylogenetic analysis indicated that all the recent Korean isolates of H1N1, H1N2, and H3N2 influenza are closely related to viruses from the United States. Serologic and genetic analysis indicated that the Korean H1N2 viral subtypes were introduced directly from the United States, and did not arise from recombination between Korean H1N1 and H3N2. We suggest that the H1N1, H1N2, and H3N2 viral subtypes that were isolated from the Korean swine population originated in North America, and that these viruses are currently circulating in the Korean swine population.

Non-Ceruloplasmin Copper Distincts Subtypes in Alzheimer's Disease: a Genetic Study of ATP7B Frequency.

PubMed

Squitti, Rosanna; Ventriglia, Mariacarla; Gennarelli, Massimo; Colabufo, Nicola A; El Idrissi, Imane Ghafir; Bucossi, Serena; Mariani, Stefania; Rongioletti, Mauro; Zanetti, Orazio; Congiu, Chiara; Rossini, Paolo M; Bonvicini, Cristian

2017-01-01

Meta-analyses show that serum copper non-bound-to-ceruloplasmin (non-Cp-Cu) is higher in patients with Alzheimer's disease (AD). ATP7B gene variants associate with AD, modulating the size of non-Cp-Cu pool. However, a dedicated genetic study comparing AD patients after stratification for a copper biomarker to demonstrate the existence of a copper subtype of AD has not yet been carried out. An independent patient sample of 287 AD patients was assessed for non-Cp-Cu serum concentrations, rs1801243, rs1061472, and rs732774 ATP7B genetic variants and the APOE4 genotype. Patients were stratified into two groups based on a non-Cp-Cu cutoff (1.9 μM). Single-locus and haplotype-group analyses were performed to define their frequencies in dependence of the non-Cp-Cu group. The two AD subgroups did not differ regarding age, sex, MMSE score, or APOE4 frequency allele, while they did differ regarding non-Cp-Cu concentrations in serum, allele, genotype, and haplotype frequencies of rs1061472 A > G and rs732774 C > T after multiple testing corrections. AD patients with a GG genotype had a 1.76-fold higher risk of having a non-Cp-Cu higher than 1.9 μmol/L (p = 0.029), and those with a TT genotype for rs732774 C > T of 1.8-fold (p = 0.018). After 100,000 permutations for multiple testing corrections, the haplotype containing the AC alleles appeared more frequently in AD patients with normal non-Cp-Cu [43 vs. 33 %; Pm = 0.03], while the haplotype containing the GT risk alleles appeared more frequently in the higher non-Cp-Cu AD (66 vs. 55 %; Pm = 0.01). Genetic heterogeneity sustains a copper AD metabolic subtype; non-Cp-Cu is a marker of this copper AD.

Neurofibromin protein loss in desmoplastic melanoma subtypes: implicating NF1 allelic loss as a distinct genetic driver?

PubMed

Kadokura, Alexander; Frydenlund, Noah; Leone, Dominick A; Yang, Shi; Hoang, Mai P; Deng, April; Hernandez-Perez, Marier; Biswas, Asok; Singh, Rajendra; Yaar, Ron; Mahalingam, Meera

2016-07-01

Loss of the NF1 allele, coding for the protein neurofibromin, and polymorphism in the proto-oncogene RET (RETp) are purportedly common in desmoplastic melanoma (DM). DM is categorized into pure (PDM) and mixed (MDM) subtypes, which differ in prognosis. Most NF1 mutations result in a truncated/absent protein, making immunohistochemical screening for neurofibromin an ideal surrogate for NF1 allelic loss. Using antineurofibromin, our aims were to ascertain the incidence of neurofibromin loss in DM subtypes and to evaluate the relationship with RET, perineural invasion (PNI) and established histopathologic prognosticators. A total of 78 archival samples of DM met criteria for inclusion (54 cases of non-DM serving as controls). Immunohistochemistry was performed for neurofibromin, whereas direct DNA sequencing was used for RETp and BRAF mutation status. Statistical analyses included χ(2) test as well as Fisher exact test. Neurofibromin loss was more common in DM than non-DM (69% versus 54%; P=.02). In DM, significant differences in neurofibromin loss were noted in the following: non-head and neck versus head and neck biopsy site (88% versus 55%) and PDM versus MDM variants (80% versus 56%). No significant associations were noted with sex, presence of a junctional component, Breslow depth, ulceration, mitoses, host response, RETp, BRAF status, or PNI. RETp was marginally associated with PNI-positive DM versus PNI-negative DM (36 versus 18%; P=.08). Our findings, the largest to date investigating neurofibromin in DM, validate the incidence of NF1 mutations/allelic loss in DM and suggest that the DM subtypes have distinct genetic drivers. Published by Elsevier Inc.

Emergence of Cryptosporidium hominis Monkey Genotype II and Novel Subtype Family Ik in the Squirrel Monkey (Saimiri sciureus) in China.

PubMed

Liu, Xuehan; Xie, Na; Li, Wei; Zhou, Ziyao; Zhong, Zhijun; Shen, Liuhong; Cao, Suizhong; Yu, Xingming; Hu, Yanchuan; Chen, Weigang; Peng, Gangneng

2015-01-01

A single Cryptosporidium isolate from a squirrel monkey with no clinical symptoms was obtained from a zoo in Ya'an city, China, and was genotyped by PCR amplification and DNA sequencing of the small-subunit ribosomal RNA (SSU rRNA), 70-kDa heat shock protein (HSP70), Cryptosporidium oocyst wall protein, and actin genes. This multilocus genetic characterization determined that the isolate was Cryptosporidium hominis, but carried 2, 10, and 6 nucleotide differences in the SSU rRNA, HSP70, and actin loci, respectively, which is comparable to the variations at these loci between C. hominis and the previously reported monkey genotype (2, 3, and 3 nucleotide differences). Phylogenetic studies, based on neighbor-joining and maximum likelihood methods, showed that the isolate identified in the current study had a distinctly discordant taxonomic status, distinct from known C. hominis and also from the monkey genotype, with respect to the three loci. Restriction fragment length polymorphisms of the SSU rRNA gene obtained from this study were similar to those of known C. hominis but clearly differentiated from the monkey genotype. Further subtyping was performed by sequence analysis of the gene encoding the 60-kDa glycoprotein (gp60). Maximum homology of only 88.3% to C. hominis subtype IdA10G4 was observed for the current isolate, and phylogenetic analysis demonstrated that this particular isolate belonged to a novel C. hominis subtype family, IkA7G4. This study is the first to report C. hominis infection in the squirrel monkey and, based on the observed genetic characteristics, confirms a new C. hominis genotype, monkey genotype II. Thus, these results provide novel insights into genotypic variation in C. hominis.

Epidemiology and genetic characterization of HIV-1 isolates in the general population of Djibouti (Horn of Africa).

PubMed

Maslin, Jérôme; Rogier, Christophe; Berger, Franck; Khamil, Mohamed Ali; Mattera, Didier; Grandadam, Marc; Caron, Mélanie; Nicand, Elizabeth

2005-06-01

During a national survey in 2002 in Djibouti, serum samples were collected using a valid sampling scheme from 2423 Djiboutians representing the general population of urban and rural districts. The HIV-1 seroprevalence was 2%. The HIV-1 polymerase gene from 53 untreated patients was amplified. Phylogenetic analysis of 34 isolates revealed a majority of subtype C (73%) as well as other subtypes, including CRF02_AG recombinants (18%), subtype D (6%), and subtype A (3%).

Molecular genetics of childhood, adolescent and young adult non-Hodgkin lymphoma.

PubMed

Miles, Rodney R; Shah, Rikin K; Frazer, J Kimble

2016-05-01

Molecular genetic abnormalities are ubiquitous in non-Hodgkin lymphoma (NHL), but genetic changes are not yet used to define specific lymphoma subtypes. Certain recurrent molecular genetic abnormalities in NHL underlie molecular pathogenesis and/or are associated with prognosis or represent potential therapeutic targets. Most molecular genetic studies of B- and T-NHL have been performed on adult patient samples, and the relevance of many of these findings for childhood, adolescent and young adult NHL remains to be demonstrated. In this review, we focus on NHL subtypes that are most common in young patients and emphasize features actually studied in younger NHL patients. This approach highlights what is known about NHL genetics in young patients but also points to gaps that remain, which will require cooperative efforts to collect and share biological specimens for genomic and genetic analyses in order to help predict outcomes and guide therapy in the future. © 2016 John Wiley & Sons Ltd.

Diversity of Group I and II Clostridium botulinum Strains from France Including Recently Identified Subtypes.

PubMed

Mazuet, Christelle; Legeay, Christine; Sautereau, Jean; Ma, Laurence; Bouchier, Christiane; Bouvet, Philippe; Popoff, Michel R

2016-06-13

In France, human botulism is mainly food-borne intoxication, whereas infant botulism is rare. A total of 99 group I and II Clostridium botulinum strains including 59 type A (12 historical isolates [1947-1961], 43 from France [1986-2013], 3 from other countries, and 1 collection strain), 31 type B (3 historical, 23 recent isolates, 4 from other countries, and 1 collection strain), and 9 type E (5 historical, 3 isolates, and 1 collection strain) were investigated by botulinum locus gene sequencing and multilocus sequence typing analysis. Historical C. botulinum A strains mainly belonged to subtype A1 and sequence type (ST) 1, whereas recent strains exhibited a wide genetic diversity: subtype A1 in orfX or ha locus, A1(B), A1(F), A2, A2b2, A5(B2') A5(B3'), as well as the recently identified A7 and A8 subtypes, and were distributed into 25 STs. Clostridium botulinum A1(B) was the most frequent subtype from food-borne botulism and food. Group I C. botulinum type B in France were mainly subtype B2 (14 out of 20 historical and recent strains) and were divided into 19 STs. Food-borne botulism resulting from ham consumption during the recent period was due to group II C. botulinum B4. Type E botulism is rare in France, 5 historical and 1 recent strains were subtype E3. A subtype E12 was recently identified from an unusual ham contamination. Clostridium botulinum strains from human botulism in France showed a wide genetic diversity and seems to result not from a single evolutionary lineage but from multiple and independent genetic rearrangements. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes.

PubMed

Bridge, Julia A; Liu, Jian; Qualman, Stephen J; Suijkerbuijk, Ron; Wenger, Gail; Zhang, Ji; Wan, Xiaoying; Baker, K Scott; Sorensen, Poul; Barr, Frederic G

2002-03-01

In this investigation, we selected PAX3/FKHR and PAX7/FKHR fusion transcript-positive and -negative alveolar rhabdomyosarcomas (ARMSs) and embryonal rhabdomyosarcomas (ERMSs) with and without anaplastic features, to ascertain genomic imbalance differences and/or similarities within these histopathologic and genetic rhabdomyosarcoma (RMS) variants. Comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) studies were performed on 45 rhabdomyosarcoma specimens consisting of 23 ARMSs and 22 ERMSs (12 ERMS cases were included from an earlier study). The anaplastic variant of RMS has not previously been subjected to CGH analysis. Overall, the most prominent imbalances were gain of chromosomes or chromosomal regions 2/2q (40%), 7/7q (31%), 8/8p (53%), 11/11q (31%), 12q13-15 (49%), 13q14 (22%), and 20/20p (31%), and loss of 1p36 (27%), 3p14-21 (22%), 9q21-22 (33%), 10q22-qter (18%), 16q (27%), 17p (22%), and 22 (22%). These gains and losses were distributed equally between ARMS and ERMS histologic subtypes (excluding 7/7q and 11/11q gain that were observed chiefly in ERMS), demonstrating that these entities are similar with respect to recurrent genomic imbalances. Moreover, genomic imbalances were also evenly distributed among the ARMS fusion transcript subtypes, providing evidence for a genetic kinship despite the absence of a fusion transcript in some cases. Genomic amplification was detected in 26% and 23% of the ARMS and ERMS cases, respectively (with nearly all of the latter subset exhibiting anaplastic features). One amplicon, involving 15q25-26, corresponds to the locus of the insulin-like growth factor type I receptor (IGF1R) gene. Amplification of IGF1R was confirmed molecularly in the cases exhibiting a 15q25-26 amplicon. In summary, these results indicate that genomic gains and losses involve alike chromosomes with similar frequencies within the histopathologic and genetic subtypes of rhabdomyosarcoma, that genomic amplification is frequent not only in the alveolar histologic subtype of rhabdomyosarcoma but also in ERMS with anaplasia, and that amplification of IGF1R possibly plays a role in the development or progression of a subset of rhabdomyosarcomas. Copyright 2002 Wiley-Liss, Inc.

The oncocytic subtype is genetically distinct from other pancreatic intraductal papillary mucinous neoplasm subtypes

PubMed Central

Basturk, Olca; Tan, Marcus; Bhanot, Umesh; Allen, Peter; Adsay, Volkan; Scott, Sasinya N; Shah, Ronak; Berger, Michael F; Askan, Gokce; Dikoglu, Esra; Jobanputra, Vaidehi; Wrzeszczynski, Kazimierz O; Sigel, Carlie; Iacobuzio-Donahue, Christine; Klimstra, David S

2017-01-01

In 2010, the World Health Organization reclassified the entity originally described as intraductal oncocytic papillary neoplasm as the ‘oncocytic subtype’ of intraductal papillary mucinous neoplasm. Although several key molecular alterations of other intraductal papillary mucinous neoplasm subtypes have been discovered, including common mutations in KRAS, GNAS, and RNF3, those of oncocytic subtype have not been well characterized. We analyzed 11 pancreatic ‘oncocytic subtype’ of intraductal papillary mucinous neoplasms. Nine pancreatic ‘oncocytic subtype’ of intraductal papillary mucinous neoplasms uniformly exhibited typical entity-defining morphology of arborizing papillae lined by layers of cells with oncocytic cytoplasm, prominent, nucleoli, and intraepithelial lumina. The remaining two were atypical. One lacked the arborizing papilla and had flat oncocytic epithelium only; the other one had focal oncocytic epithelium in a background of predominantly intestinal subtype intraductal papillary mucinous neoplasm. Different components of this case were analyzed separately. Formalin-fixed, paraffin-embedded specimens of all cases were microdissected and subjected to high-depth-targeted next-generation sequencing for a panel of 300 key cancer-associated genes in a platform that enabled the identification of sequence mutations, copy number alterations, and select structural rearrangements involving all targeted genes. Fresh frozen specimens of two cases were also subjected to whole-genome sequencing. For the nine typical pancreatic ‘oncocytic subtype’ of intraductal papillary mucinous neoplasms, the number of mutations per case, identified by next-generation sequencing, ranged from 1 to 10 (median = 4). None of these cases had KRAS or GNAS mutations and only one had both RNF43 and PIK3R1 mutations. ARHGAP26, ASXL1, EPHA8, and ERBB4 genes were somatically altered in more than one of these typical ‘oncocytic subtype’ of intraductal papillary mucinous neoplasms but not in the other two atypical ones. In the neoplasm with flat oncocytic epithelium, the only mutated gene was KRAS. All components of the intestinal subtype intraductal papillary mucinous neoplasms with focal oncocytic epithelium manifested TP53, GNAS, and RNF43 mutations. In conclusion, this study elucidates that ‘oncocytic subtype’ of intraductal papillary mucinous neoplasm is not only morphologically distinct but also genetically distinct from other intraductal papillary mucinous neoplasm subtypes. Considering that now its biologic behavior is also being found to be different than other intraductal papillary mucinous neoplasm subtypes, ‘oncocytic subtype’ of intraductal papillary mucinous neoplasm warrants being recognized separately. PMID:27282351

Subtype Distribution of Blastocystis Isolates in Sebha, Libya

PubMed Central

Abdulsalam, Awatif M.; Ithoi, Init; Al-Mekhlafi, Hesham M.; Al-Mekhlafi, Abdulsalam M.; Ahmed, Abdulhamid; Surin, Johari

2013-01-01

Background Blastocystis is a genetically diverse and a common intestinal parasite of humans with a controversial pathogenic potential. This study was carried out to identify the Blastocystis subtypes and their association with demographic and socioeconomic factors among outpatients living in Sebha city, Libya. Methods/Findings Blastocystis in stool samples were cultured followed by isolation, PCR amplification of a partial SSU rDNA gene, cloning, and sequencing. The DNA sequences of isolated clones showed 98.3% to 100% identity with the reference Blastocystis isolates from the Genbank. Multiple sequence alignment showed polymorphism from one to seven base substitution and/or insertion/deletion in several groups of non-identical nucleotides clones. Phylogenetic analysis revealed three assemblage subtypes (ST) with ST1 as the most prevalent (51.1%) followed by ST2 (24.4%), ST3 (17.8%) and mixed infections of two concurrent subtypes (6.7%). Blastocystis ST1 infection was significantly associated with female (P = 0.009) and low educational level (P = 0.034). ST2 was also significantly associated with low educational level (P= 0.008) and ST3 with diarrhoea (P = 0.008). Conclusion Phylogenetic analysis of Libyan Blastocystis isolates identified three different subtypes; with ST1 being the predominant subtype and its infection was significantly associated with female gender and low educational level. More extensive studies are needed in order to relate each Blastocystis subtype with clinical symptoms and potential transmission sources in this community. PMID:24376805

Subtype distribution of Blastocystis isolates in Sebha, Libya.

PubMed

Abdulsalam, Awatif M; Ithoi, Init; Al-Mekhlafi, Hesham M; Al-Mekhlafi, Abdulsalam M; Ahmed, Abdulhamid; Surin, Johari

2013-01-01

Blastocystis is a genetically diverse and a common intestinal parasite of humans with a controversial pathogenic potential. This study was carried out to identify the Blastocystis subtypes and their association with demographic and socioeconomic factors among outpatients living in Sebha city, Libya. Blastocystis in stool samples were cultured followed by isolation, PCR amplification of a partial SSU rDNA gene, cloning, and sequencing. The DNA sequences of isolated clones showed 98.3% to 100% identity with the reference Blastocystis isolates from the Genbank. Multiple sequence alignment showed polymorphism from one to seven base substitution and/or insertion/deletion in several groups of non-identical nucleotides clones. Phylogenetic analysis revealed three assemblage subtypes (ST) with ST1 as the most prevalent (51.1%) followed by ST2 (24.4%), ST3 (17.8%) and mixed infections of two concurrent subtypes (6.7%). ST1 infection was significantly associated with female (P = 0.009) and low educational level (P = 0.034). ST2 was also significantly associated with low educational level (P= 0.008) and ST3 with diarrhoea (P = 0.008). Phylogenetic analysis of Libyan Blastocystis isolates identified three different subtypes; with ST1 being the predominant subtype and its infection was significantly associated with female gender and low educational level. More extensive studies are needed in order to relate each Blastocystis subtype with clinical symptoms and potential transmission sources in this community.

Identification of cancer genes that are independent of dominant proliferation and lineage programs

PubMed Central

Selfors, Laura M.; Stover, Daniel G.; Harris, Isaac S.; Brugge, Joan S.; Coloff, Jonathan L.

2017-01-01

Large, multidimensional cancer datasets provide a resource that can be mined to identify candidate therapeutic targets for specific subgroups of tumors. Here, we analyzed human breast cancer data to identify transcriptional programs associated with tumors bearing specific genetic driver alterations. Using an unbiased approach, we identified thousands of genes whose expression was enriched in tumors with specific genetic alterations. However, expression of the vast majority of these genes was not enriched if associations were analyzed within individual breast tumor molecular subtypes, across multiple tumor types, or after gene expression was normalized to account for differences in proliferation or tumor lineage. Together with linear modeling results, these findings suggest that most transcriptional programs associated with specific genetic alterations in oncogenes and tumor suppressors are highly context-dependent and are predominantly linked to differences in proliferation programs between distinct breast cancer subtypes. We demonstrate that such proliferation-dependent gene expression dominates tumor transcriptional programs relative to matched normal tissues. However, we also identified a relatively small group of cancer-associated genes that are both proliferation- and lineage-independent. A subset of these genes are attractive candidate targets for combination therapy because they are essential in breast cancer cell lines, druggable, enriched in stem-like breast cancer cells, and resistant to chemotherapy-induced down-regulation. PMID:29229826

New insights into prevalence, genetic diversity, and proviral load of human T-cell leukemia virus types 1 and 2 in pregnant women in Gabon in equatorial central Africa.

PubMed

Etenna, Sonia Lekana-Douki; Caron, Mélanie; Besson, Guillaume; Makuwa, Maria; Gessain, Antoine; Mahé, Antoine; Kazanji, Mirdad

2008-11-01

Human T-cell leukemia virus type 1 (HTLV-1) is highly endemic in areas of central Africa; mother-to-child transmission and sexual transmission are considered to be the predominant routes. To determine the prevalence and subtypes of HTLV-1/2 in pregnant women in Gabon, we conducted an epidemiological survey in the five main cities of the country. In 907 samples, the HTLV-1 seroprevalence was 2.1%, which is lower than that previously reported. Only one case of HTLV-2 infection was found. The HTLV-1 seroprevalence increased with age and differed between regions (P

Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies

PubMed Central

Pérez-Palma, Eduardo; Helbig, Ingo; Klein, Karl Martin; Anttila, Verneri; Horn, Heiko; Reinthaler, Eva Maria; Gormley, Padhraig; Ganna, Andrea; Byrnes, Andrea; Pernhorst, Katharina; Toliat, Mohammad R; Saarentaus, Elmo; Howrigan, Daniel P; Hoffman, Per; Miquel, Juan Francisco; De Ferrari, Giancarlo V; Nürnberg, Peter; Lerche, Holger; Zimprich, Fritz; Neubauer, Bern A; Becker, Albert J; Rosenow, Felix; Perucca, Emilio; Zara, Federico; Weber, Yvonne G; Lal, Dennis

2017-01-01

Background Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement ‘hotspot’ loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained. Objective To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype. Methods We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls. Results When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10−6,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10−12, OR 7.45, 95% CI 4.20–13.5). Outside hotspots , microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10−3,OR 2.85, 95% CI 1.62–4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes across epilepsy subtypes that were not deleted in controls. Conclusions Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE. PMID:28756411

Distribution and phylogenetic analysis of Blastocystis sp. subtypes isolated from IBD patients and healthy individuals in Iran.

PubMed

Mirjalali, H; Abbasi, M R; Naderi, N; Hasani, Z; Mirsamadi, E S; Stensvold, C R; Balaii, H; Asadzadeh Aghdaei, H; Zali, M R

2017-12-01

Blastocystis is a single-celled intestinal parasite commonly found in humans and a broad range of animals all over the world. In humans, its role in health and disease remains unsettled. The aim of our study was to investigate the distribution of Blastocystis and Blastocystis subtypes (ST) in patients with inflammatory bowel disease (IBD) and control subjects. A total of 71 stool samples were collected from IBD patients, 69 and 2 of whom had ulcerative colitis (UC) and Crohn's Disease (CD), respectively. Moreover, 166 stool samples from healthy subjects were included as control samples. All stool samples were cultivated, and 550-bp fragments of the small subunit ribosomal RNA gene was amplified from Blastocystis-positive cultures. All PCR-positive samples were sequenced. Blastocystis was observed in 9 (12.67%) and 35 (21.1%) IBD patients and healthy controls, respectively. There was no statistically significant correlation between IBD and presence of Blastocystis (P = 0.147). There was a statistically significant correlation between age and Blastocystis colonization in the IBD group (P < 0.05), but not among healthy controls. No significant correlation between gender and colonization was observed. ST1 and ST3 were obtained from 1 (12.5%) and 7 (87.5%) IBD patients, respectively, while in the healthy control group, subtypes 1, 2, and 3 were found in 14 (40%), 12 (34.28%), and 9 (25.72%), respectively. Phylogenetic analysis showed no variation in the distribution of subtypes nor intra-subtype genetic diversity between samples acquired from IBD patients and healthy controls. This study showed a trend towards a lower prevalence of Blastocystis in IBD patients than in control subjects. ST3 sequences isolated from IBD patients and control individuals did not appear to differ genetically.

Distribution and clinical manifestations of Cryptosporidium species and subtypes in HIV/AIDS patients in Ethiopia.

PubMed

Adamu, Haileeyesus; Petros, Beyene; Zhang, Guoqing; Kassa, Hailu; Amer, Said; Ye, Jianbin; Feng, Yaoyu; Xiao, Lihua

2014-04-01

Cryptosporidiosis is an important cause for chronic diarrhea and death in HIV/AIDS patients. Among common Cryptosporidium species in humans, C. parvum is responsible for most zoonotic infections in industrialized nations. Nevertheless, the clinical significance of C. parvum and role of zoonotic transmission in cryptosporidiosis epidemiology in developing countries remain unclear. In this cross-sectional study, 520 HIV/AIDS patients were examined for Cryptosporidium presence in stool samples using genotyping and subtyping techniques. Altogether, 140 (26.9%) patients were positive for Cryptosporidium spp. by PCR-RFLP analysis of the small subunit rRNA gene, belonging to C. parvum (92 patients), C. hominis (25 patients), C. viatorum (10 patients), C. felis (5 patients), C. meleagridis (3 patients), C. canis (2 patients), C. xiaoi (2 patients), and mixture of C. parvum and C. hominis (1 patient). Sequence analyses of the 60 kDa glycoprotein gene revealed a high genetic diversity within the 82 C. parvum and 19 C. hominis specimens subtyped, including C. parvum zoonotic subtype families IIa (71) and IId (5) and anthroponotic subtype families IIc (2), IIb (1), IIe (1) and If-like (2), and C. hominis subtype families Id (13), Ie (5), and Ib (1). Overall, Cryptosporidium infection was associated with the occurrence of diarrhea and vomiting. Diarrhea was attributable mostly to C. parvum subtype family IIa and C. hominis, whereas vomiting was largely attributable to C. hominis and rare Cryptosporidium species. Calf contact was identified as a significant risk factor for infection with Cryptosporidium spp., especially C. parvum subtype family IIa. Results of the study indicate that C. parvum is a major cause of cryptosporidiosis in HIV-positive patients and zoonotic transmission is important in cryptosporidiosis epidemiology in Ethiopia. In addition, they confirm that different Cryptosporidium species and subtypes are linked to different clinical manifestations.

Genomic investigation of Staphylococcus aureus isolates from bulk tank milk and dairy cows with clinical mastitis.

PubMed

Ronco, Troels; Klaas, Ilka C; Stegger, Marc; Svennesen, Line; Astrup, Lærke B; Farre, Michael; Pedersen, Karl

2018-02-01

Staphylococcus aureus is one of the most common pathogens that cause mastitis in dairy cows. Various subtypes, virulence genes and mobile genetic elements have been associated with isolates from bulk tank milk and clinical mastitis. So far, no Danish cattle associated S. aureus isolates have been whole-genome sequenced and further analyzed. Thus, the main objective was to investigate the population structure and genomic content of isolates from bulk tank milk and clinical mastitis, using whole-genome sequencing. This may reveal the origin of strains that cause clinical mastitis. S. aureus isolates from bulk tank milk (n = 94) and clinical mastitis (n = 63) were collected from 91 and 24 different farms, respectively and whole-genome sequenced. The genomic content was analyzed and a phylogenetic tree based on single nucleotide polymorphisms was constructed. In general, the isolates from both bulk tank milk and clinical mastitis were of similar genetic background. This suggests that dairy cows are natural carriers of the S. aureus subtypes that cause clinical mastitis if the right conditions are present and that a broad range of subtypes cause mastitis. A phylogenetic cluster that mostly consisted of ST151 isolates carried three mobile genetic elements that were primarily found in this group. The prevalence of resistance genes was generally low. However, the first ST398 methicillin resistant S. aureus isolate from a Danish dairy cow with clinical mastitis was detected. Copyright © 2018 Elsevier B.V. All rights reserved.

Intrinsic Molecular Subtypes of Glioma Are Prognostic and Predict Benefit From Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Combination With Other Prognostic Factors in Anaplastic Oligodendroglial Brain Tumors: A Report From EORTC Study 26951

PubMed Central

Erdem-Eraslan, Lale; Gravendeel, Lonneke A.; de Rooi, Johan; Eilers, Paul H.C.; Idbaih, Ahmed; Spliet, Wim G.M.; den Dunnen, Wilfred F.A.; Teepen, Johannes L.; Wesseling, Pieter; Sillevis Smitt, Peter A.E.; Kros, Johan M.; Gorlia, Thierry; van den Bent, Martin J.; French, Pim J.

2013-01-01

Purpose Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a randomized phase III clinical trial investigating adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study includes gene expression profiles of formalin-fixed, paraffin-embedded (FFPE) clinical trial samples. Patients and Methods Gene expression profiling was performed in 140 samples, 47 fresh frozen samples and 93 FFPE samples, on HU133_Plus_2.0 and HuEx_1.0_st arrays, respectively. Results All previously identified six IGSs are present in EORTC 26951. This confirms that different molecular subtypes are present within a well-defined histologic subtype. Intrinsic subtypes are highly prognostic for overall survival (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance status, and tumor location), molecular (1p/19q loss of heterozygosity [LOH], IDH1 mutation, and MGMT methylation), and histologic parameters. Combining known molecular (1p/19q LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (proportion of explained variation, 30% v 23% for each individual group of factors). Specific genetic changes (IDH1, 1p/19q LOH, and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p/19q LOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone versus 12.8 years after RT/PCV (P = .0349; hazard ratio, 2.18; 95% CI, 1.06 to 4.50). Conclusion Intrinsic subtypes are highly prognostic in EORTC 26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV. PMID:23269986

Neurobiology of anxious depression: a review.

PubMed

Ionescu, Dawn F; Niciu, Mark J; Mathews, Daniel C; Richards, Erica M; Zarate, Carlos A

2013-04-01

Anxious depression is a common, distinct clinical subtype of major depressive disorder (MDD). This review summarizes current neurobiological knowledge regarding anxious depression. Peer-reviewed articles, published January 1970 through September 2012, were identified via PUBMED, EMBASE, and Cochrane Library, using the following key words: anxious depression electroencephalography (EEG), anxious depression functional magnetic resonance imaging (fMRI), anxious depression genetics, anxious depression neurobiology, and anxious melancholia neurobiology. Despite a general dearth of neurobiological research, the results suggest that anxious depression-when defined either syndromally or dimensionally-has distinct neurobiological findings that separate it from nonanxious depression. Structural neuroimaging, EEG, genetics, and neuropsychiatric studies revealed differences in subjects with anxious depression compared to other groups. Endocrine differences between individuals with anxious depression and those with nonanxious depression have also been noted, as evidenced by abnormal responses elicited by exogenous stimulation of the system. Despite these findings, heterogeneity in the definition of anxious depression complicates the results. Because exploring the neurobiology of this depressive subtype is important for improving diagnosis, prognosis, and treatment, enrichment strategies to decrease heterogeneity within the field should be employed for future research. © 2013 Wiley Periodicals, Inc.

Familial aggregation and heritability of the melancholic and atypical subtypes of depression.

PubMed

Lamers, Femke; Cui, Lihong; Hickie, Ian B; Roca, Catherine; Machado-Vieira, Rodrigo; Zarate, Carlos A; Merikangas, Kathleen R

2016-11-01

The heterogeneity of mood disorders has been a challenge to our understanding of their underlying biologic and genetic pathways. This report examines the specificity of the familial aggregation of atypical and melancholic subtypes of depression and their clinical correlates in a large community based family study of affective spectrum disorders. The sample includes 457 probands and their directly interviewed adult first degree relatives from the National Institute of Mental Health (NIMH) Family Study of Affective Spectrum Disorder. Depression subtypes were based on best estimate diagnoses using information from semi-structured diagnostic interviews by experienced clinical interviews and multiple family history reports. Atypical depression in probands was significantly associated with the atypical subtype of depression in relatives (OR 1.75 [95%CI 1.02-3.02], p=0.04), independent of proband and relative comorbid disorders. Melancholic depression in probands was not associated with melancholic depression in relatives (OR 1.25 [95%CI 0.62-2.55], p=.53). The familial heritability of the atypical subtype was 0.46 (95%CI 0.21-0.71), whereas that of the melancholic subtype was 0.33 (95%CI 0.21-0.45). Melancholic depression was associated with greater severity in terms of treatment, global functioning, suicide attempts, comorbid disorders, and an earlier age at onset of depression. The subsample of interviewed relatives necessary to assess specific subtypes of depression reduced the power to detect the specificity of mood disorder subtypes. The results indicate that the atypical subtype should be incorporated in future treatment, genetic and other etiologic studies of major depression. Findings further suggest that melancholic subtype may be an indicator of clinical severity of depression. Published by Elsevier B.V.

Polygenic Risk for Depression Increases Risk of Ischemic Stroke: From the Stroke Genetics Network Study.

PubMed

Wassertheil-Smoller, Sylvia; Qi, Qibin; Dave, Tushar; Mitchell, Braxton D; Jackson, Rebecca D; Liu, Simin; Park, Ki; Salinas, Joel; Dunn, Erin C; Leira, Enrique C; Xu, Huichun; Ryan, Kathleen; Smoller, Jordan W

2018-03-01

Although depression is a risk factor for stroke in large prospective studies, it is unknown whether these conditions have a shared genetic basis. We applied a polygenic risk score (PRS) for major depressive disorder derived from European ancestry analyses by the Psychiatric Genomics Consortium to a genome-wide association study of ischemic stroke in the Stroke Genetics Network of National Institute of Neurological Disorders and Stroke. Included in separate analyses were 12 577 stroke cases and 25 643 controls of European ancestry and 1353 cases and 2383 controls of African ancestry. We examined the association between depression PRS and ischemic stroke overall and with pathogenic subtypes using logistic regression analyses. The depression PRS was associated with higher risk of ischemic stroke overall in both European ( P =0.025) and African ancestry ( P =0.011) samples from the Stroke Genetics Network. Ischemic stroke risk increased by 3.0% (odds ratio, 1.03; 95% confidence interval, 1.00-1.05) for every 1 SD increase in PRS for those of European ancestry and by 8% (odds ratio, 1.08; 95% confidence interval, 1.04-1.13) for those of African ancestry. Among stroke subtypes, elevated risk of small artery occlusion was observed in both European and African ancestry samples. Depression PRS was also associated with higher risk of cardioembolic stroke in European ancestry and large artery atherosclerosis in African ancestry persons. Higher polygenic risk for major depressive disorder is associated with increased risk of ischemic stroke overall and with small artery occlusion. Additional associations with ischemic stroke subtypes differed by ancestry. © 2018 American Heart Association, Inc.

The varied clinical presentations of major depressive disorder.

PubMed

Rush, A John

2007-01-01

DSM-IV major depressive disorder (MDD) is a clinical syndrome notable for heterogeneity of its clinical presentation, genetics, neurobiology, clinical course, and treatment responsiveness. In an attempt to make sense of this heterogeneity, clinicians and researchers have proposed a number of MDD "subtypes" based on differences in characteristic symptoms (e.g., atypical, melancholic, psychotic), onset (e.g., early vs. late, post-partum, seasonal), course of illness (e.g., single vs. recurrent, chronic, double), and severity. This article provides a brief review of the status of several of the most common subtypes in terms of their clinical features, biological correlates, course of illness, and treatment implications.

Gene‐set and multivariate genome‐wide association analysis of oppositional defiant behavior subtypes in attention‐deficit/hyperactivity disorder

PubMed Central

van Donkelaar, Marjolein M. J.; Poelmans, Geert; Buitelaar, Jan K.; Sonuga‐Barke, Edmund J. S.; Stringaris, Argyris; consortium, IMAGE; Faraone, Stephen V.; Franke, Barbara; Steinhausen, Hans‐Christoph; van Hulzen, Kimm J. E.

2015-01-01

Oppositional defiant disorder (ODD) is a frequent psychiatric disorder seen in children and adolescents with attention‐deficit‐hyperactivity disorder (ADHD). ODD is also a common antecedent to both affective disorders and aggressive behaviors. Although the heritability of ODD has been estimated to be around 0.60, there has been little research into the molecular genetics of ODD. The present study examined the association of irritable and defiant/vindictive dimensions and categorical subtypes of ODD (based on latent class analyses) with previously described specific polymorphisms (DRD4 exon3 VNTR, 5‐HTTLPR, and seven OXTR SNPs) as well as with dopamine, serotonin, and oxytocin genes and pathways in a clinical sample of children and adolescents with ADHD. In addition, we performed a multivariate genome‐wide association study (GWAS) of the aforementioned ODD dimensions and subtypes. Apart from adjusting the analyses for age and sex, we controlled for “parental ability to cope with disruptive behavior.” None of the hypothesis‐driven analyses revealed a significant association with ODD dimensions and subtypes. Inadequate parenting behavior was significantly associated with all ODD dimensions and subtypes, most strongly with defiant/vindictive behaviors. In addition, the GWAS did not result in genome‐wide significant findings but bioinformatics and literature analyses revealed that the proteins encoded by 28 of the 53 top‐ranked genes functionally interact in a molecular landscape centered around Beta‐catenin signaling and involved in the regulation of neurite outgrowth. Our findings provide new insights into the molecular basis of ODD and inform future genetic studies of oppositional behavior. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID:26184070

Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

PubMed Central

Morton, Lindsay M.; Slager, Susan L.; Cerhan, James R.; Wang, Sophia S.; Vajdic, Claire M.; Skibola, Christine F.; Bracci, Paige M.; de Sanjosé, Silvia; Smedby, Karin E.; Chiu, Brian C. H.; Zhang, Yawei; Mbulaiteye, Sam M.; Monnereau, Alain; Turner, Jennifer J.; Clavel, Jacqueline; Adami, Hans-Olov; Chang, Ellen T.; Glimelius, Bengt; Hjalgrim, Henrik; Melbye, Mads; Crosignani, Paolo; di Lollo, Simonetta; Miligi, Lucia; Nanni, Oriana; Ramazzotti, Valerio; Rodella, Stefania; Costantini, Adele Seniori; Stagnaro, Emanuele; Tumino, Rosario; Vindigni, Carla; Vineis, Paolo; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Cocco, Pierluigi; Foretova, Lenka; Maynadié, Marc; Nieters, Alexandra; Staines, Anthony; Colt, Joanne S.; Cozen, Wendy; Davis, Scott; de Roos, Anneclaire J.; Hartge, Patricia; Rothman, Nathaniel; Severson, Richard K.; Holly, Elizabeth A.; Call, Timothy G.; Feldman, Andrew L.; Habermann, Thomas M.; Liebow, Mark; Blair, Aaron; Cantor, Kenneth P.; Kane, Eleanor V.; Lightfoot, Tracy; Roman, Eve; Smith, Alex; Brooks-Wilson, Angela; Connors, Joseph M.; Gascoyne, Randy D.; Spinelli, John J.; Armstrong, Bruce K.; Kricker, Anne; Holford, Theodore R.; Lan, Qing; Zheng, Tongzhang; Orsi, Laurent; Dal Maso, Luigino; Franceschi, Silvia; La Vecchia, Carlo; Negri, Eva; Serraino, Diego; Bernstein, Leslie; Levine, Alexandra; Friedberg, Jonathan W.; Kelly, Jennifer L.; Berndt, Sonja I.; Birmann, Brenda M.; Clarke, Christina A.; Flowers, Christopher R.; Foran, James M.; Kadin, Marshall E.; Paltiel, Ora; Weisenburger, Dennis D.; Linet, Martha S.; Sampson, Joshua N.

2014-01-01

Background Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes. Methods We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case–control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE). Results Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10−4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10−4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Conclusions Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility. PMID:25174034

Genetic dissection of GABAergic neural circuits in mouse neocortex

PubMed Central

Taniguchi, Hiroki

2014-01-01

Diverse and flexible cortical functions rely on the ability of neural circuits to perform multiple types of neuronal computations. GABAergic inhibitory interneurons significantly contribute to this task by regulating the balance of activity, synaptic integration, spiking, synchrony, and oscillation in a neural ensemble. GABAergic interneurons display a high degree of cellular diversity in morphology, physiology, connectivity, and gene expression. A considerable number of subtypes of GABAergic interneurons diversify modes of cortical inhibition, enabling various types of information processing in the cortex. Thus, comprehensively understanding fate specification, circuit assembly, and physiological function of GABAergic interneurons is a key to elucidate the principles of cortical wiring and function. Recent advances in genetically encoded molecular tools have made a breakthrough to systematically study cortical circuitry at the molecular, cellular, circuit, and whole animal levels. However, the biggest obstacle to fully applying the power of these to analysis of GABAergic circuits was that there were no efficient and reliable methods to express them in subtypes of GABAergic interneurons. Here, I first summarize cortical interneuron diversity and current understanding of mechanisms, by which distinct classes of GABAergic interneurons are generated. I then review recent development in genetically encoded molecular tools for neural circuit research, and genetic targeting of GABAergic interneuron subtypes, particularly focusing on our recent effort to develop and characterize Cre/CreER knockin lines. Finally, I highlight recent success in genetic targeting of chandelier cells, the most unique and distinct GABAergic interneuron subtype, and discuss what kind of questions need to be addressed to understand development and function of cortical inhibitory circuits. PMID:24478631

Severe congenital neutropenia, a genetically heterogeneous disease group with an increased risk of AML/MDS

PubMed Central

Vandenberghe, Peter; Beel, Karolien

2011-01-01

Over the past decade, enormous progress has been made in the understanding of severe congenital neutropenia (SCN), by identification of several causal gene mutations: in ELANE, GFI1, HAX1, WAS and G3PC3. SCN is a preleukemic condition, independent of the genetic subtype. Acquired CSF3R mutations are specific for SCN and are strongly associated with malignant progression. In this review, we describe the known genetic subtypes of SCN, their molecular basis and clinical presentation and summarize the available evidence on CSF3R mutations and monosomy 7 in malignant conversion. PMID:22053285

Host Genetic Variation Does Not Determine Spatio-Temporal Patterns of European Bat 1 Lyssavirus

PubMed Central

Picard-Meyer, Evelyne; Dellicour, Simon; Casademont, Isabelle; Kergoat, Lauriane; Lepelletier, Anthony; Dacheux, Laurent; Baele, Guy; Monchâtre-Leroy, Elodie; Cliquet, Florence; Lemey, Philippe

2017-01-01

Abstract The majority of bat rabies cases in Europe are attributed to European bat 1 lyssavirus (EBLV-1), circulating mainly in serotine bats (Eptesicus serotinus). Two subtypes have been defined (EBLV-1a and EBLV-1b), each associated with a different geographical distribution. In this study, we undertake a comprehensive sequence analysis based on 80 newly obtained EBLV-1 nearly complete genome sequences from nine European countries over a 45-year period to infer selection pressures, rates of nucleotide substitution, and evolutionary time scale of these two subtypes in Europe. Our results suggest that the current lineage of EBLV-1 arose in Europe ∼600 years ago and the virus has evolved at an estimated average substitution rate of ∼4.19×10−5 subs/site/year, which is among the lowest recorded for RNA viruses. In parallel, we investigate the genetic structure of French serotine bats at both the nuclear and mitochondrial level and find that they constitute a single genetic cluster. Furthermore, Mantel tests based on interindividual distances reveal the absence of correlation between genetic distances estimated between viruses and between host individuals. Taken together, this indicates that the genetic diversity observed in our E. serotinus samples does not account for EBLV-1a and -1b segregation and dispersal in Europe. PMID:29165566

[Distal hereditary motor neuropathy].

PubMed

Devic, P; Petiot, P

2011-11-01

Distal hereditary motor neuropathy (dHMN), also known as spinal muscular atrophy, represents a group of clinically and genetically heterogeneous diseases caused by degenerations of spinal motor neurons and leading to distal muscle weakness and wasting. Nerve conduction studies reveal a pure motor axonopathy and needle examination shows chronic denervation. dHMN were initially subdivided into seven subtypes according to mode of inheritance, age at onset, and clinical evolution. Recent studies have shown that these subtypes are still heterogeneous at the molecular genetic level and novel clinical and genetic entities have been characterized. To date, mutations in 11 different genes have been identified for autosomal-dominant, autosomal-recessive, and X-linked recessive dHMN. Most of the genes encode protein involved in housekeeping functions, endosomal trafficking, axonal transport, translation synthesis, RNA processing, oxidative stress response and apoptosis. The pathophysiological mechanisms underlying dHMN seem to be related to the "length-dependent" death of motor neurons of the anterior horn of the spinal cord, likely because their large axons have higher metabolic requirements for maintenance. dHMN remain heterogeneous at the clinical and molecular genetic level. The molecular pathomechanisms explaining why mutations in these ubiquitously expressed housekeeping genes result in the selective involvement of spinal motor neurons remain to be unravelled. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

De novo point mutations in patients diagnosed with ataxic cerebral palsy.

PubMed

Parolin Schnekenberg, Ricardo; Perkins, Emma M; Miller, Jack W; Davies, Wayne I L; D'Adamo, Maria Cristina; Pessia, Mauro; Fawcett, Katherine A; Sims, David; Gillard, Elodie; Hudspith, Karl; Skehel, Paul; Williams, Jonathan; O'Regan, Mary; Jayawant, Sandeep; Jefferson, Rosalind; Hughes, Sarah; Lustenberger, Andrea; Ragoussis, Jiannis; Jackson, Mandy; Tucker, Stephen J; Németh, Andrea H

2015-07-01

Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

Highly complex neutralization determinants on a monophyletic lineage of newly transmitted subtype C HIV-1 Env clones from India.

PubMed

Kulkarni, Smita S; Lapedes, Alan; Tang, Haili; Gnanakaran, S; Daniels, Marcus G; Zhang, Ming; Bhattacharya, Tanmoy; Li, Ming; Polonis, Victoria R; McCutchan, Francine E; Morris, Lynn; Ellenberger, Dennis; Butera, Salvatore T; Bollinger, Robert C; Korber, Bette T; Paranjape, Ramesh S; Montefiori, David C

2009-03-15

Little is known about the neutralization properties of HIV-1 in India to optimally design and test vaccines. For this reason, a functional Env clone was obtained from each of ten newly acquired, heterosexually transmitted HIV-1 infections in Pune, Maharashtra. These clones formed a phylogenetically distinct genetic lineage within subtype C. As Env-pseudotyped viruses the clones were mostly resistant to IgG1b12, 2G12 and 2F5 but all were sensitive to 4E10. When compared to a large multi-subtype panel of Env-pseudotyped viruses (subtypes B, C and CRF02_AG) in neutralization assays with a multi-subtype panel of HIV-1-positive plasma samples, the Indian Envs were remarkably complex. With the exception of the Indian Envs, results of a hierarchical clustering analysis showed a strong subtype association with the patterns of neutralization susceptibility. From these patterns we were able to identify 19 neutralization cluster-associated amino acid signatures in gp120 and 14 signatures in the ectodomain and cytoplasmic tail of gp41. We conclude that newly transmitted Indian Envs are antigenically complex in spite of close genetic similarity. Delineation of neutralization-associated amino acid signatures provides a deeper understanding of the antigenic structure of HIV-1 Env.

Developmental changes in genetic and environmental influences on rule-breaking and aggression: age and pubertal development.

PubMed

Harden, K Paige; Patterson, Megan W; Briley, Daniel A; Engelhardt, Laura E; Kretsch, Natalie; Mann, Frank D; Tackett, Jennifer L; Tucker-Drob, Elliot M

2015-12-01

Antisocial behavior (ASB) can be meaningfully divided into nonaggressive rule-breaking versus aggressive dimensions, which differ in developmental course and etiology. Previous research has found that genetic influences on rule-breaking, but not aggression, increase from late childhood to mid-adolescence. This study tested the extent to which the developmental increase in genetic influence on rule-breaking was associated with pubertal development compared to chronological age. Child and adolescent twins (n = 1,031), ranging in age from 8 to 20 years (M age = 13.5 years), were recruited from public schools as part of the Texas Twin Project. Participants reported on their pubertal development using the Pubertal Development Scale and on their involvement in ASB on items from the Child Behavior Checklist. Measurement invariance of ASB subtypes across age groups (≤12 years vs. >12 years old) was tested using confirmatory factor analyses. Quantitative genetic modeling was used to test whether the genetic and environmental influences on aggression and rule-breaking were moderated by age, pubertal status, or both. Quantitative genetic modeling indicated that genetic influences specific to rule-breaking increased as a function of pubertal development controlling for age (a gene × puberty interaction), but did not vary as a function of age controlling for pubertal status. There were no developmental differences in the genetic etiology of aggression. Family-level environmental influences common to aggression and rule-breaking decreased with age, further contributing to the differentiation between these subtypes of ASB from childhood to adolescence. Future research should discriminate between alternative possible mechanisms underlying gene × puberty interactions on rule-breaking forms of antisocial behavior, including possible effects of pubertal hormones on gene expression. © 2015 Association for Child and Adolescent Mental Health.

New genetic lineage within the Siberian subtype of tick-borne encephalitis virus found in Western Siberia, Russia.

PubMed

Tkachev, Sergey E; Chicherina, Galina S; Golovljova, Irina; Belokopytova, Polina S; Tikunov, Artem Yu; Zadora, Oksana V; Glupov, Victor V; Tikunova, Nina V

2017-12-01

Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is a causative agent of a severe neurological disease. There are three main TBEV subtypes: the European (TBEV-Eu), Far Eastern (TBEV-FE), and Siberian (TBEV-Sib). Currently, three lineages within TBEV-Sib have been recorded. In this study, the genetic and biological characteristics of a new original strain, TBEV-2871, isolated in the Novosibirsk province of Western Siberia, Russia were investigated. The strain has low neuroinvasiveness in mice. Phylogenetic analysis demonstrated that TBEV-2871 belongs to TBEV-Sib, but does not cluster with any of the TBEV-Sib lineages. The TBEV-2871 strain has 88-89% nucleotide sequence identity with the other TBEV-Sib strains, 84-86% nucleotide sequence identity with the TBEV-FE and TBEV-Eu subtypes and is genetically close to the subtype division border. The TBEV-2871 polyprotein sequence includes 43 unique amino acid substitutions, 30 of which are recorded at positions that are conserved among all TBEV subtypes. Strain TBEV-2871 and two similar but not identical isolates found in Kemerovo province, Western Siberia are separated into a new lineage tentatively named Obskaya after the name of Ob riber, in the vicinity of which the TBEV-2871 was first found. A molecular evolution investigation demonstrated that within TBEV-Sib, the Obskaya lineage likely separated 1535years ago, which is even earlier than the Baltic lineage. Copyright © 2017 Elsevier B.V. All rights reserved.

Investigation of FANCA mutations in Greek patients.

PubMed

Selenti, Nikoletta; Sofocleous, Christalena; Kattamis, Antonis; Kolialexi, Aggeliki; Kitsiou, Sophia; Fryssira, Elena; Polychronopoulou, Sophia; Kanavakis, Emmanouel; Mavrou, Ariadni

2013-08-01

Fanconi anemia (FA) is a rare genetic disease characterized by considerable heterogeneity. Fifteen subtypes are currently recognised and deletions of the Fanconi anemia complementation group A (FANCA) gene account for more than 65% of FA cases. We report on the results from a cohort of 166 patients referred to the Department of Medical Genetics of Athens University for genetic investigation after the clinical suspicion of FA. For clastogen-induced chromosome damage, cultures were set up with the addition of mitomycin C (MMC) and diepoxybutane (DEB), respectively. Following a positive cytogenetic result, molecular analysis was performed to allow identification of causative mutations in the FANCA gene. A total of 13/166 patients were diagnosed with FA and 8/13 belonged to the FA-A subtype. A novel point mutation was identified in exon 26 of FANCA gene. In our study 62% of FA patients were classified in the FA-A subtype and a point mutation in exon 26 was noted for the first time.

Genetic characterization of influenza A virus subtype H12N1 isolated from a watercock and lesser whistling ducks in Thailand.

PubMed

Wongphatcharachai, Manoosak; Wisedchanwet, Trong; Lapkuntod, Jiradej; Nonthabenjawan, Nutthawan; Jairak, Waleemas; Amonsin, Alongkorn

2012-06-01

Monitoring of influenza A virus (IAV) was conducted in wild bird species in central Thailand. Four IAV subtype H12N1 strains were isolated from a watercock (order Gruiformes, family Rallidae) (n = 1) and lesser whistling ducks (order Anseriformes, family Anatidae) (n = 3). All H12N1 viruses were characterized by whole-genome sequencing. Phylogenetic analysis of all eight genes of the Thai H12N1 viruses indicated that they are most closely related to the Eurasian strains. Analysis of the HA gene revealed the strains to be of low pathogenicity. This study is the first to report the circulation of IAV subtype H12N1 in Thailand and to describe the genetic characteristics of H12N1 in Eurasia. Moreover, the genetic information obtained on H12N1 has contributed a new Eurasian strain of H12N1 to the GenBank database.

PDI Coamplified Genes in Ovarian Cancer

DTIC Science & Technology

2017-08-01

ORGANIZATION: University of Michigan Ann Arbor, MI 48109 REPORT DATE: August 2017 TYPE OF REPORT: Final PREPARED FOR: U.S. Army Medical Research ...Michigan Ann Arbor, MI 48109 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) U.S. Army Medical Research and...distinct subtypes having different tissues of origin, diverse genetic landscapes, and respond differently to therapy.1-3 For example , serous EOC is

Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies.

PubMed

Kao, Chung-Feng; Chen, Hui-Wen; Chen, Hsi-Chung; Yang, Jenn-Hwai; Huang, Ming-Chyi; Chiu, Yi-Hang; Lin, Shih-Ku; Lee, Ya-Chin; Liu, Chih-Min; Chuang, Li-Chung; Chen, Chien-Hsiun; Wu, Jer-Yuarn; Lu, Ru-Band; Kuo, Po-Hsiu

2016-12-01

This study aimed to identify susceptible loci and enriched pathways for bipolar disorder subtype II. We conducted a genome-wide association scan in discovery samples with 189 bipolar disorder subtype II patients and 1773 controls, and replication samples with 283 bipolar disorder subtype II patients and 500 controls in a Taiwanese Han population using Affymetrix Axiom Genome-Wide CHB1 Array. We performed single-marker and gene-based association analyses, as well as calculated polygeneic risk scores for bipolar disorder subtype II. Pathway enrichment analyses were employed to reveal significant biological pathways. Seven markers were found to be associated with bipolar disorder subtype II in meta-analysis combining both discovery and replication samples (P<5.0×10 -6 ), including markers in or close to MYO16, HSP90AB3P, noncoding gene LOC100507632, and markers in chromosomes 4 and 10. A novel locus, ETF1, was associated with bipolar disorder subtype II (P<6.0×10 -3 ) in gene-based association tests. Results of risk evaluation demonstrated that higher genetic risk scores were able to distinguish bipolar disorder subtype II patients from healthy controls in both discovery (P=3.9×10 -4 ~1.0×10 -3 ) and replication samples (2.8×10 -4 ~1.7×10 -3 ). Genetic variance explained by chip markers for bipolar disorder subtype II was substantial in the discovery (55.1%) and replication (60.5%) samples. Moreover, pathways related to neurodevelopmental function, signal transduction, neuronal system, and cell adhesion molecules were significantly associated with bipolar disorder subtype II. We reported novel susceptible loci for pure bipolar subtype II disorder that is less addressed in the literature. Future studies are needed to confirm the roles of these loci for bipolar disorder subtype II. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Molecular epidemiology of HIV-1 infection in Europe: An overview.

PubMed

Beloukas, Apostolos; Psarris, Alexandros; Giannelou, Polina; Kostaki, Evangelia; Hatzakis, Angelos; Paraskevis, Dimitrios

2016-12-01

Human Immunodeficiency Virus type 1 (HIV-1) is characterised by vast genetic diversity. Globally circulating HIV-1 viruses are classified into distinct phylogenetic strains (subtypes, sub-subtypes) and several recombinant forms. Here we describe the characteristics and evolution of European HIV-1 epidemic over time through a review of published literature and updated queries of existing HIV-1 sequence databases. HIV-1 in Western and Central Europe was introduced in the early-1980s in the form of subtype B, which is still the predominant clade. However, in Eastern Europe (Former Soviet Union (FSU) countries and Russia) the predominant strain, introduced into Ukraine in the mid-1990s, is subtype A (A FSU ) with transmission mostly occurring in People Who Inject Drugs (PWID). In recent years, the epidemic is evolving towards a complex tapestry with an increase in the prevalence of non-B subtypes and recombinants in Western and Central Europe. Non-B epidemics are mainly associated with immigrants, heterosexuals and females but more recently, non-B clades have also spread amongst groups where non-B strains were previously absent - non-immigrant European populations and amongst men having sex with men (MSM). In some countries, non-B clades have spread amongst the native population, for example subtype G in Portugal and subtype A in Greece, Albania and Cyprus. Romania provides a unique case where sub-subtype F1 has predominated throughout the epidemic. In contrast, HIV-1 epidemic in FSU countries remains more homogeneous with A FSU clade predominating in all countries. The differences between the evolution of the Western epidemic and the Eastern epidemic may be attributable to differences in transmission risk behaviours, lifestyle and the patterns of human mobility. The study of HIV-1 epidemic diversity provides a useful tool by which we can understand the history of the pandemic in addition to allowing us to monitor the spread and growth of the epidemic over time. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparison of the genetic variability of Blastocystis subtypes between human carriers from two contrasting climatic regions of México.

PubMed

Villegas-Gómez, Isaac; Martínez-Hernández, Fernando; Urrea-Quezada, Alejandro; González-Díaz, Mariana; Durazo, María; Hernández, Jesús; Orozco-Mosqueda, Guadalupe Erendira; Villalobos, Guiehdani; Maravilla, Pablo; Valenzuela, Olivia

2016-10-01

Blastocystis sp. is an anaerobic intestinal microorganism commonly identified in the feces of several animals, including humans. Blastocystis exhibits high genetic polymorphism and at least 17 subtypes (ST) have been identified; ST1-ST3 are frequently found in the Americas. Furthermore, in vitro assays have shown that temperature and humidity can affect the viability of Blastocystis cysts. In this study, we describe the genetic variability and genetic differentiation among and within Blastocystis STs in adults and children from the cities of Hermosillo and Morelia cities, which represent arid and humid subtropical climatic regions of México, respectively. Phylogenetic and genetic diversity was assessed by analyzing a region of the small subunit ribosomal DNA (SSU rDNA) gene as a marker. Blastocystis ST3 and ST1 were associated with children from Hermosillo and Morelia, respectively. An analysis of the nucleotide diversity (π) and haplotype polymorphism (θ) indexes showed that they were similar within each ST, but different between ST1 and ST3. Interestingly, the group of symptomatic carriers from Hermosillo showed scarce mean nucleotide diversity compared to the asymptomatic carriers (0.0039±0.0030 and 0.0329±0.0286, respectively). Furthermore, the gene flow and genetic differentiation indexes between the children and adults suggested that the Blastocystis haplotypes in the adult carriers were "highly mobile" among humans, while the haplotypes found in the children were more isolated and genetically differentiated between them. Copyright © 2016 Elsevier B.V. All rights reserved.

[Molecular updates on Usher syndrome].

PubMed

Roux, A-F

2005-01-01

Usher syndrome (USH) is an autosomal recessive disorder characterized by the association of sensorineural hearing loss and retinitis pigmentosa (RP). Usher syndrome is both clinically and genetically heterogeneous. Three clinical subtypes are defined with respect to vestibular dysfunction and the degree of hearing loss. Type I (USH1) patients have profound hearing loss and vestibular dysfunction from birth. Type II (USH2) is the most frequent and patients tend to have less severe hearing impairment and normal vestibular response. Type III (USH3) is characterized by a progressive loss of hearing and is found more frequently among Finnish patients. Recently, major breakthroughs have been made in the molecular genetics of Usher syndrome as a number of chromosomal loci and causative genes have been identified in each clinical subtype. Twelve loci are known and the corresponding genes have been cloned for six of them. Although their functions are not always clearly established, a common role is emerging for the proteins identified within each subtype. As a result, each subtype could emanate from defects affecting distinct cellular mechanisms.

Identification and genetic characterization of unique HIV-1 A1/C recombinant strain in South Africa.

PubMed

Musyoki, Andrew M; Rakgole, Johnny N; Selabe, Gloria; Mphahlele, Jeffrey

2015-03-01

HIV isolates from South Africa are predominantly subtype C. Sporadic isolation of non-C strains has been reported mainly in cosmopolitan cities. HIV isolate j51 was recovered from a rural South African heterosexual female aged 51 years. Near full length amplification of the genome was attempted using PCR with primers targeting overlapping segments of the HIV genome. Analysis of 5593 bp (gag to vpu) at a bootstrap value greater than 70% found that all but the vpu gene was HIV-1 subtype A1. The vpu gene was assigned HIV-1 subtype C. The recombination breaking point was estimated at position 6035+/- 15 bp with reference to the beginning of the HXB2 reference strain. Isolate j51 revealed a unique genome constellation to previously reported recombinant strains with parental A/C backbones from South Africa though a common recombination with subtype C within the vpu gene. Identification of recombinant strains supports continued surveillance of HIV genetic diversity.

Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer.

PubMed

Castellanos, Emily; Feld, Emily; Horn, Leora

2017-04-01

EGFR-mutated NSCLC is a genetically heterogeneous disease that includes more than 200 distinct mutations. The implications of mutational subtype for both prognostic and predictive value are being increasingly understood. Although the most common EGFR mutations-exon 19 deletions or L858R mutations-predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), it is now being recognized that outcomes may be improved in patients with exon 19 deletions. Additionally, 10% of patients will have an uncommon EGFR mutation, and response to EGFR TKI therapy is highly variable depending on the mutation. Given the growing recognition of the genetic and clinical variation seen in this disease, the development of comprehensive bioinformatics-driven tools to both analyze response in uncommon mutation subtypes and inform clinical decision making will be increasingly important. Clinical trials of novel EGFR TKIs should prospectively account for the presence of uncommon mutation subtypes in study design. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

HNF1 alpha gene coding regions mutations screening, in a Caucasian population clinically characterized as MODY from Argentina.

PubMed

Lopez, Ariel Pablo; Foscaldi, Sabrina Andrea; Perez, Maria Silvia; Rodriguez, Martín; Traversa, Mercedes; Puchulu, Félix Miguel; Bergada, Ignacio; Frechtel, Gustavo Daniel

2011-02-01

There are at least six subtypes of Maturity Onset Diabetes of the Young (MODY) with distinctive genetic causes. MODY 3 is caused by mutations in HNF1A gene, an insulin transcription factor, so mutations in this gene are associated with impaired insulin secretion. MODY 3 prevalence differs according to the population analyzed, but it is one of the most frequent subtypes. Therefore, our aims in this work were to find mutations present in the HNF1A gene and provide information on their prevalence. Mutations screening was done in a group of 80 unrelated patients (average age 17.1 years) selected by clinical characterization of MODY, by SSCP electrophoresis followed by sequenciation. We found eight mutations, of which six were novel and four sequence variants, which were all novel. Therefore the prevalence of MODY 3 in this group was 10%. Compared clinical data between the non-MODY 3 patients and the MODY 3 diagnosed patients did not show any significant difference. Eight patients were diagnosed as MODY 3 and new data about the prevalence of that subtype is provided. Our results contribute to reveal novel mutations, providing new data about the prevalence of that subtype. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Isolation and Functional Characterization of the Novel Clostridium botulinum Neurotoxin A8 Subtype

PubMed Central

Kull, Skadi; Schulz, K. Melanie; Strotmeier, Jasmin Weisemann née; Kirchner, Sebastian; Schreiber, Tanja; Bollenbach, Alexander; Dabrowski, P. Wojtek; Nitsche, Andreas; Kalb, Suzanne R.; Dorner, Martin B.; Barr, John R.; Rummel, Andreas; Dorner, Brigitte G.

2015-01-01

Botulism is a severe neurological disease caused by the complex family of botulinum neurotoxins (BoNT). Based on the different serotypes known today, a classification of serotype variants termed subtypes has been proposed according to sequence diversity and immunological properties. However, the relevance of BoNT subtypes is currently not well understood. Here we describe the isolation of a novel Clostridium botulinum strain from a food-borne botulism outbreak near Chemnitz, Germany. Comparison of its botulinum neurotoxin gene sequence with published sequences identified it to be a novel subtype within the BoNT/A serotype designated BoNT/A8. The neurotoxin gene is located within an ha-orfX+ cluster and showed highest homology to BoNT/A1, A2, A5, and A6. Unexpectedly, we found an arginine insertion located in the HC domain of the heavy chain, which is unique compared to all other BoNT/A subtypes known so far. Functional characterization revealed that the binding characteristics to its main neuronal protein receptor SV2C seemed unaffected, whereas binding to membrane-incorporated gangliosides was reduced in comparison to BoNT/A1. Moreover, we found significantly lower enzymatic activity of the natural, full-length neurotoxin and the recombinant light chain of BoNT/A8 compared to BoNT/A1 in different endopeptidase assays. Both reduced ganglioside binding and enzymatic activity may contribute to the considerably lower biological activity of BoNT/A8 as measured in a mouse phrenic nerve hemidiaphragm assay. Despite its reduced activity the novel BoNT/A8 subtype caused severe botulism in a 63-year-old male. To our knowledge, this is the first description and a comprehensive characterization of a novel BoNT/A subtype which combines genetic information on the neurotoxin gene cluster with an in-depth functional analysis using different technical approaches. Our results show that subtyping of BoNT is highly relevant and that understanding of the detailed toxin function might pave the way for the development of novel therapeutics and tailor-made antitoxins. PMID:25658638

Isolation and functional characterization of the novel Clostridium botulinum neurotoxin A8 subtype.

PubMed

Kull, Skadi; Schulz, K Melanie; Weisemann, Jasmin; Kirchner, Sebastian; Schreiber, Tanja; Bollenbach, Alexander; Dabrowski, P Wojtek; Nitsche, Andreas; Kalb, Suzanne R; Dorner, Martin B; Barr, John R; Rummel, Andreas; Dorner, Brigitte G

2015-01-01

Botulism is a severe neurological disease caused by the complex family of botulinum neurotoxins (BoNT). Based on the different serotypes known today, a classification of serotype variants termed subtypes has been proposed according to sequence diversity and immunological properties. However, the relevance of BoNT subtypes is currently not well understood. Here we describe the isolation of a novel Clostridium botulinum strain from a food-borne botulism outbreak near Chemnitz, Germany. Comparison of its botulinum neurotoxin gene sequence with published sequences identified it to be a novel subtype within the BoNT/A serotype designated BoNT/A8. The neurotoxin gene is located within an ha-orfX+ cluster and showed highest homology to BoNT/A1, A2, A5, and A6. Unexpectedly, we found an arginine insertion located in the HC domain of the heavy chain, which is unique compared to all other BoNT/A subtypes known so far. Functional characterization revealed that the binding characteristics to its main neuronal protein receptor SV2C seemed unaffected, whereas binding to membrane-incorporated gangliosides was reduced in comparison to BoNT/A1. Moreover, we found significantly lower enzymatic activity of the natural, full-length neurotoxin and the recombinant light chain of BoNT/A8 compared to BoNT/A1 in different endopeptidase assays. Both reduced ganglioside binding and enzymatic activity may contribute to the considerably lower biological activity of BoNT/A8 as measured in a mouse phrenic nerve hemidiaphragm assay. Despite its reduced activity the novel BoNT/A8 subtype caused severe botulism in a 63-year-old male. To our knowledge, this is the first description and a comprehensive characterization of a novel BoNT/A subtype which combines genetic information on the neurotoxin gene cluster with an in-depth functional analysis using different technical approaches. Our results show that subtyping of BoNT is highly relevant and that understanding of the detailed toxin function might pave the way for the development of novel therapeutics and tailor-made antitoxins.

Familial Renal Cancer: Molecular Genetics and Surgical Management

PubMed Central

Barrisford, Glen W.; Singer, Eric A.; Rosner, Inger L.; Linehan, W. Marston; Bratslavsky, Gennady

2011-01-01

Familial renal cancer (FRC) is a heterogeneous disorder comprised of a variety of subtypes. Each subtype is known to have unique histologic features, genetic alterations, and response to therapy. Through the study of families affected by hereditary forms of kidney cancer, insights into the genetic basis of this disease have been identified. This has resulted in the elucidation of a number of kidney cancer gene pathways. Study of these pathways has led to the development of novel targeted molecular treatments for patients affected by systemic disease. As a result, the treatments for families affected by von Hippel-Lindau (VHL), hereditary papillary renal carcinoma (HPRC), hereditary leiomyomatosis renal cell carcinoma (HLRCC), and Birt-Hogg-Dubé (BHD) are rapidly changing. We review the genetics and contemporary surgical management of familial forms of kidney cancer. PMID:22312516

Phylogenetic analysis of feline immunodeficiency virus strains from naturally infected cats in Belgium and The Netherlands.

PubMed

Roukaerts, Inge D M; Theuns, Sebastiaan; Taffin, Elien R L; Daminet, Sylvie; Nauwynck, Hans J

2015-01-22

Feline immunodeficiency virus (FIV) is a major pathogen in feline populations worldwide, with seroprevalences up to 26%. Virus strains circulating in domestic cats are subdivided into different phylogenetic clades (A-E), based on the genetic diversity of the V3-V4 region of the env gene. In this report, a phylogenetic analysis of the V3-V4 env region, and a variable region in the gag gene was made for 36 FIV strains isolated in Belgium and The Netherlands. All newly generated gag sequences clustered together with previously known clade A FIV viruses, confirming the dominance of clade A viruses in Northern Europe. The same was true for the obtained env sequences, with only one sample of an unknown env subtype. Overall, the genetic diversity of FIV strains sequenced in this report was low. This indicates a relatively recent introduction of FIV in Belgium and The Netherlands. However, the sample with an unknown env subtype indicates that new introductions of FIV from unknown origin do occur and this will likely increase genetic variability in time. Copyright © 2014 Elsevier B.V. All rights reserved.

Integrative Network-based Analysis of Magnetic Resonance Spectroscopy and Genome Wide Expression in Glioblastoma multiforme

PubMed Central

Heiland, Dieter Henrik; Mader, Irina; Schlosser, Pascal; Pfeifer, Dietmar; Carro, Maria Stella; Lange, Thomas; Schwarzwald, Ralf; Vasilikos, Ioannis; Urbach, Horst; Weyerbrock, Astrid

2016-01-01

The goal of this study was to identify correlations between metabolites from proton MR spectroscopy and genetic pathway activity in glioblastoma multiforme (GBM). Twenty patients with primary GBM were analysed by short echo-time chemical shift imaging and genome-wide expression analyses. Weighed Gene Co-Expression Analysis was used for an integrative analysis of imaging and genetic data. N-acetylaspartate, normalised to the contralateral healthy side (nNAA), was significantly correlated to oligodendrocytic and neural development. For normalised creatine (nCr), a group with low nCr was linked to the mesenchymal subtype, while high nCr could be assigned to the proneural subtype. Moreover, clustering of normalised glutamine and glutamate (nGlx) revealed two groups, one with high nGlx being attributed to the neural subtype, and one with low nGlx associated with the classical subtype. Hence, the metabolites nNAA, nCr, and nGlx correlate with a specific gene expression pattern reflecting the previously described subtypes of GBM. Moreover high nNAA was associated with better clinical prognosis, whereas patients with lower nNAA revealed a shorter progression-free survival (PFS). PMID:27350391

Divergent Cryptosporidium parvum subtype and Enterocytozoon bieneusi genotypes in dromedary camels in Algeria.

PubMed

Baroudi, Djamel; Zhang, Hongwei; Amer, Said; Khelef, Djamel; Roellig, Dawn M; Wang, Yuanfei; Feng, Yaoyu; Xiao, Lihua

2018-03-01

Little information is available on the occurrence of the zoonotic protists Cryptosporidium spp. and none on Enterocytozoon bieneusi in camels. This preliminary study was conducted to examine the identity of Cryptosporidium subtypes and E. bieneusi genotypes in dromedary camels in Algeria. A total of 39 fecal specimens were collected from young camels. PCR-sequence analysis of the small subunit rRNA was used to detect and genotype Cryptosporidium spp. Cryptosporidium parvum present was further subtyped by sequence analysis of the 60 kDa glycoprotein gene. PCR-sequence analysis of the ribosomal internal transcribed spacer gene was used to detect and genotype E. bieneusi. Altogether, two and eight of the specimens analyzed were positive for C. parvum and E. bieneusi, respectively. The former was identified as a new subtype that is genetically related to the C. hominis If subtype family, whereas the latter was identified as two related genotypes (Macaque1 and a novel genotype) in the newly assigned E. bieneusi genotype group 8. Although they are not known hosts for C. parvum and E. bieneusi, camels are apparently infected with genetically distinct variants of these pathogens.

Changes in drug resistance patterns following the introduction of HIV type 1 non-B subtypes in Spain.

PubMed

De Mendoza, Carmen; Garrido, Carolina; Poveda, Eva; Corral, Angélica; Zahonero, Natalia; Treviño, Ana; Anta, Lourdes; Soriano, Vincent

2009-10-01

Natural genetic variability at the pol gene may account for differences in drug susceptibility and selection of resistance patterns across HIV-1 clades. Spread of non-B subtypes along with changes in antiretroviral drug use may have modified drug resistance patterns in recent years. All HIV-1 clinical samples sent to a reference laboratory located in Madrid for drug resistance testing since January 2000 were analyzed. The pol gene was sequenced and HIV-1 subtypes were assigned using the Stanford algorithm and phylogenetic analyses for non-B subtypes. Drug resistance mutations were recorded using the IAS-USA mutation list (April 2008). A total of 3034 specimens from 730 antiretroviral-naive individuals (92 with non-B subtypes) and 1569 antiretroviral-experienced patients (97 with non-B subtypes) were examined. The prevalence of HIV-1 non-B subtypes in the study period increased from 4.4% (2000-2003) to 10.1% (2004-2007) (p < 0.01). The most predominant variants were CRF02_AG (41.8%) and G (17.5%). Thymidine analogue mutations (TAMs) were more prevalent in B than non-B subtypes, in both drug-naive (6.2% vs. 1%; p < 0.01) and treatment-experienced patients (49% vs. 30%, p < 0.01). K103N was most frequent in B than non-B subtypes (34% vs. 21%; p < 0.01); conversely, 106A/M was more prevalent in non-B than B clades (11% vs. 5%). Codon 179 mutations associated with etravirine resistance were more frequent in non-B than B subtypes. Finally, secondary protease resistance mutations were more common in non-B than B clades, with a potentially significant impact at least on tipranavir. The prevalence of HIV-1 non-B subtypes has increased since the year 2000 in a large drug resistance database in Spain, determining changes in drug resistance patterns that may influence the susceptibility to new antiretroviral drugs and have an impact on genotypic drug resistance interpretation algorithms.

BCR-ABL1-like acute lymphoblastic leukaemia: From bench to bedside.

PubMed

Boer, Judith M; den Boer, Monique L

2017-09-01

Acute lymphoblastic leukaemia (ALL) occurs in approximately 1:1500 children and is less frequently found in adults. The most common immunophenotype of ALL is the B cell lineage and within B cell precursor ALL, specific genetic aberrations define subtypes with distinct biological and clinical characteristics. With more advanced genetic analysis methods such as whole genome and transcriptome sequencing, novel genetic subtypes have recently been discovered. One novel class of genetic aberrations comprises tyrosine kinase-activating lesions, including translocations and rearrangements of tyrosine kinase and cytokine receptor genes. These newly discovered genetic aberrations are harder to detect by standard diagnostic methods such as karyotyping, fluorescent in situ hybridisation (FISH) or polymerase chain reaction (PCR) because they are diverse and often cryptic. These lesions involve one of several tyrosine kinase genes (among others, v-abl Abelson murine leukaemia viral oncogene homologue 1 (ABL1), v-abl Abelson murine leukaemia viral oncogene homologue 2 (ABL2), platelet-derived growth factor receptor beta polypeptide (PDGFRB)), each of which can be fused to up to 15 partner genes. Together, they compose 2-3% of B cell precursor ALL (BCP-ALL), which is similar in size to the well-known fusion gene BCR-ABL1 subtype. These so-called BCR-ABL1-like fusions are mutually exclusive with the sentinel translocations in BCP-ALL (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, and KMT2A (MLL) rearrangements) and have the promising prospect to be sensitive to tyrosine kinase inhibitors similar to BCR-ABL1. In this review, we discuss the types of tyrosine kinase-activating lesions discovered, and the preclinical and clinical evidence for the use of tyrosine kinase inhibitors in the treatment of this novel subtype of ALL. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prolonged Co-circulation of Two Distinct Dengue Virus Type 3 Lineages in the Hyperendemic Area of Medellín, Colombia

PubMed Central

Ospina, Marta C.; Diaz, Francisco J.; Osorio, Jorge E.

2010-01-01

During the past two decades, Dengue virus-3 (DENV-3) has re-emerged in the Western Hemisphere causing significant epidemics of dengue fever (DF) and dengue hemorrhagic fever (DHF). In an effort to understand the molecular evolution of DENV-3 and their relationships to other DENV-3 circulating in the western hemisphere, we conducted a phylogenetic study on DENV-3 isolates made between 2002 and 2007 in the metropolitan area of Medellín, Colombia. An unexpected co-circulation of two different variants of DENV-3 subtype III during at least 5 years in Medellín was found. In addition, a more complete analysis of DENV-3 viruses isolated in other South American regions revealed the existence of three different subtype III lineages, all derived from independent introductions. This study documents significant genetic diversity of circulating viruses within the same subtype and an unusual capacity of the population of this city to support continuous circulation of multiple variants of dengue virus. PMID:20810837

Deep Brain Stimulation for Dystonia: A Novel Perspective on the Value of Genetic Testing

PubMed Central

Jinnah, H. A.; Alterman, Ron; Klein, Christine; Krauss, Joachim K.; Moro, Elena; Vidailhet, Marie; Raike, Robert

2017-01-01

The dystonias are a group of disorders characterized by excessive muscle contractions leading to abnormal movements and postures. There are many different clinical manifestations and underlying causes. Deep brain stimulation (DBS) provides an effect treatment, but outcomes can vary considerably among the different subtypes of dystonia. Several variables are thought to contribute to this variation including age of onset and duration of dystonia, specific characteristics of the dystonic movements, location of stimulation and stimulator settings, and others. The potential contributions of genetic factors have received little attention. In this review, we summarize evidence that some of the variation in DBS outcomes for dystonia is due to genetic factors. The evidence suggests that more methodical genetic testing may provide useful information in the assessment of potential surgical candidates, and in advancing our understanding of the biological mechanisms that influence DBS outcomes. PMID:28160152

Impact of immigration on HIV-1 molecular epidemiology in West Africa, Maghreb and Southern Europe.

PubMed

Miri, Lamia; Wakrim, Lahcen; Kassar, Hassène; Hemminki, Kari; Khyatti, Meriem

2014-01-01

There is global concern about the relation between international migration and the course of the AIDS epidemic. Maghreb is a North African region, which lies between sub-Saharan Africa and Europe. It has been turned recently into a region of immigration, since there are more and more flows of West African migrants hoping to reach European countries. Here we provide an overview on HIV-1 molecular epidemiology particularly in West African countries, Maghreb (Morocco, Algeria, Tunisia) and southern European countries (Spain, France, and Italy). The studies conducted in several countries of the region revealed different features of HIV-1 molecular epidemiology, especially for the distribution of viral subtypes and for transmitted drug resistance profiles. Furthermore, migration from West Africa to Europe seems to be a potential source of non-B subtype mobility to Maghreb and eventually to southern Europe, where HIV-1 non-B variants significantly increased in the last 10 to 15 years. As genetic differences between subtypes might impact the drug resistance pathways, it is important to provide continuous surveillance programs for the early detection of new variants spreading in the population before they become more prevalent, and to identify resistance profiles in different infected populations, especially migrants.

Nuclear and Chloroplast DNA Variation Provides Insights into Population Structure and Multiple Origin of Native Aromatic Rices of Odisha, India

PubMed Central

Roy, Pritesh Sundar; Rao, Gundimeda Jwala Narasimha; Patnaik, Ashok; Patnaik, Sasank Sekhar Chyau; Jambhulkar, Nitiprasad Namdeorao; Sharma, Srigopal; Mohapatra, Trilochan

2016-01-01

A large number of short grain aromatic rice suited to the agro-climatic conditions and local preferences are grown in niche areas of different parts of India and their diversity is evolved over centuries as a result of selection by traditional farmers. Systematic characterization of these specialty rices has not been attempted. An effort was made to characterize 126 aromatic short grain rice landraces, collected from 19 different districts in the State of Odisha, from eastern India. High level of variation for grain quality and agronomic traits among these aromatic rices was observed and genotypes having desirable phenotypic traits like erect flag leaf, thick culm, compact and dense panicles, short plant stature, early duration, superior yield and grain quality traits were identified. A total of 24 SSR markers corresponding to the hyper variable regions of rice chromosomes were used to understand the genetic diversity and to establish the genetic relationship among the aromatic short grain rice landraces at nuclear genome level. SSR analysis of 126 genotypes from Odisha and 10 genotypes from other states revealed 110 alleles with an average of 4.583 and the Nei’s genetic diversity value (He) was in the range of 0.034–0.880 revealing two sub-populations SP 1 (membership percentage-27.1%) and SP 2 (72.9%). At the organelle genomic level for the C/A repeats in PS1D sequence of chloroplasts, eight different plastid sub types and 33 haplotypes were detected. The japonica (Nipponbare) subtype (6C7A) was detected in 100 genotypes followed by O. rufipogon (KF428978) subtype (6C6A) in 13 genotypes while indica (93–11) sub type (8C8A) was seen in 14 genotypes. The tree constructed based on haplotypes suggests that short grain aromatic landraces might have independent origin of these plastid subtypes. Notably a wide range of diversity was observed among these landraces cultivated in different parts confined to the State of Odisha. PMID:27598392

Metabolic profiling in Maturity-onset diabetes of the young (MODY) and young onset type 2 diabetes fails to detect robust urinary biomarkers.

PubMed

Gloyn, Anna L; Faber, Johan H; Malmodin, Daniel; Thanabalasingham, Gaya; Lam, Francis; Ueland, Per Magne; McCarthy, Mark I; Owen, Katharine R; Baunsgaard, Dorrit

2012-01-01

It is important to identify patients with Maturity-onset diabetes of the young (MODY) as a molecular diagnosis determines both treatment and prognosis. Genetic testing is currently expensive and many patients are therefore not assessed and are misclassified as having either type 1 or type 2 diabetes. Biomarkers could facilitate the prioritisation of patients for genetic testing. We hypothesised that patients with different underlying genetic aetiologies for their diabetes could have distinct metabolic profiles which may uncover novel biomarkers. The aim of this study was to perform metabolic profiling in urine from patients with MODY due to mutations in the genes encoding glucokinase (GCK) or hepatocyte nuclear factor 1 alpha (HNF1A), type 2 diabetes (T2D) and normoglycaemic control subjects. Urinary metabolic profiling by Nuclear Magnetic Resonance (NMR) and ultra performance liquid chromatography hyphenated to Q-TOF mass spectrometry (UPLC-MS) was performed in a Discovery set of subjects with HNF1A-MODY (n = 14), GCK-MODY (n = 17), T2D (n = 14) and normoglycaemic controls (n = 34). Data were used to build a valid partial least squares discriminate analysis (PLS-DA) model where HNF1A-MODY subjects could be separated from the other diabetes subtypes. No single metabolite contributed significantly to the separation of the patient groups. However, betaine, valine, glycine and glucose were elevated in the urine of HNF1A-MODY subjects compared to the other subgroups. Direct measurements of urinary amino acids and betaine in an extended dataset did not support differences between patients groups. Elevated urinary glucose in HNF1A-MODY is consistent with the previously reported low renal threshold for glucose in this genetic subtype. In conclusion, we report the first metabolic profiling study in monogenic diabetes and show that, despite the distinct biochemical pathways affected, there are unlikely to be robust urinary biomarkers which distinguish monogenic subtypes from T2D. Our results have implications for studies investigating metabolic profiles in complex traits including T2D.

Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing | Office of Cancer Genomics

Cancer.gov

Abstract: Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous cancer comprising at least two molecular subtypes that differ in gene expression and distribution of mutations. Recently, application of genome/exome sequencing and RNA-seq to DLBCL has revealed numerous genes that are recurrent targets of somatic point mutation in this disease.

Dysregulation of HIF2α and autophagy in renal cell carcinoma

PubMed Central

Liu, Xian-De; Zhu, Haifeng; DePavia, Adela; Jonasch, Eric

2015-01-01

Our recent study shows that autophagy collaborates with proteasomes to degrade endothelial PAS domain-containing protein 1 (EPAS1, also known as HIF2α) in a manner dependent on Von Hippel-Lindau (VHL) and sequestosome 1 (SQSTM1/p62). The genetic dysregulation of autophagy is a common feature of different subtypes of renal cell carcinoma (RCC). PMID:27308417

Host Genetic Variation Does Not Determine Spatio-Temporal Patterns of European Bat 1 Lyssavirus.

PubMed

Troupin, Cécile; Picard-Meyer, Evelyne; Dellicour, Simon; Casademont, Isabelle; Kergoat, Lauriane; Lepelletier, Anthony; Dacheux, Laurent; Baele, Guy; Monchâtre-Leroy, Elodie; Cliquet, Florence; Lemey, Philippe; Bourhy, Hervé

2017-11-01

The majority of bat rabies cases in Europe are attributed to European bat 1 lyssavirus (EBLV-1), circulating mainly in serotine bats (Eptesicus serotinus). Two subtypes have been defined (EBLV-1a and EBLV-1b), each associated with a different geographical distribution. In this study, we undertake a comprehensive sequence analysis based on 80 newly obtained EBLV-1 nearly complete genome sequences from nine European countries over a 45-year period to infer selection pressures, rates of nucleotide substitution, and evolutionary time scale of these two subtypes in Europe. Our results suggest that the current lineage of EBLV-1 arose in Europe ∼600 years ago and the virus has evolved at an estimated average substitution rate of ∼4.19×10-5 subs/site/year, which is among the lowest recorded for RNA viruses. In parallel, we investigate the genetic structure of French serotine bats at both the nuclear and mitochondrial level and find that they constitute a single genetic cluster. Furthermore, Mantel tests based on interindividual distances reveal the absence of correlation between genetic distances estimated between viruses and between host individuals. Taken together, this indicates that the genetic diversity observed in our E. serotinus samples does not account for EBLV-1a and -1b segregation and dispersal in Europe. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Assessing local stromal alterations in human ovarian cancer subtypes via second harmonic generation microscopy and analysis

NASA Astrophysics Data System (ADS)

Campbell, Kirby R.; Campagnola, Paul J.

2017-11-01

The collagen architecture in all human ovarian cancers is substantially remodeled, where these alterations are manifested in different fiber widths, fiber patterns, and fibril size and packing. Second harmonic generation (SHG) microscopy has differentiated normal tissues from high-grade serous (HGS) tumors with high accuracy; however, the classification between low-grade serous, endometrioid, and benign tumors was less successful. We postulate this is due to known higher genetic variation in these tissues relative to HGS tumors, which are genetically similar, and this results in more heterogeneous collagen remodeling in the respective matrix. Here, we examine fiber widths and SHG emission intensity and directionality locally within images (e.g., 10×10 microns) and show that normal tissues and HGS tumors are more uniform in fiber properties as well as in fibril size and packing than the other tissues. Moreover, these distributions are in good agreement with phase matching considerations relating SHG emission directionality and intensity. The findings show that in addition to average collagen assembly properties the intrinsic heterogeneity must also be considered as another aspect of characterization. These local analyses showed differences not shown in pure intensity-based image analyses and may provide further insight into disease etiology of the different tumor subtypes.

New Subtypes and Genetic Recombination in HIV Type 1-Infecting Patients with Highly Active Antiretroviral Therapy in Peru (2008–2010)

PubMed Central

Acuña, Maribel; Gazzo, Cecilia; Salinas, Gabriela; Cárdenas, Fanny; Valverde, Ada; Romero, Soledad

2012-01-01

Abstract HIV-1 subtype B is the most frequent strain in Peru. However, there is no available data about the genetic diversity of HIV-infected patients receiving highly active antiretroviral therapy (HAART) here. A group of 267 patients in the Peruvian National Treatment Program with virologic failure were tested for genotypic evidence of HIV drug resistance at the Instituto Nacional de Salud (INS) of Peru between March 2008 and December 2010. Viral RNA was extracted from plasma and the segments of the protease (PR) and reverse transcriptase (RT) genes were amplified by reverse transcriptase polymerase chain reaction (RT-PCR), purified, and fully sequenced. Consensus sequences were submitted to the HIVdb Genotypic Resistance Interpretation Algorithm Database from Stanford University, and then aligned using Clustal X v.2.0 to generate a phylogenetic tree using the maximum likelihood method. Intrasubtype and intersubtype recombination analyses were performed using the SCUEAL program (Subtype Classification by Evolutionary ALgo-rithms). A total of 245 samples (91%) were successfully genotyped. The analysis obtained from the HIVdb program showed 81.5% resistance cases (n=198). The phylogenetic analysis revealed that subtype B was predominant in the population (98.8%), except for new cases of A, C, and H subtypes (n=4). Of these cases, only subtype C was imported. Likewise, recombination analysis revealed nine intersubtype and 20 intrasubtype recombinant cases. This is the first report of the presence of HIV-1 subtypes C and H in Peru. The introduction of new subtypes and circulating recombinants forms can make it difficult to distinguish resistance profiles in patients and consequently affect future treatment strategies against HIV in this country. PMID:22559065

New subtypes and genetic recombination in HIV type 1-infecting patients with highly active antiretroviral therapy in Peru (2008-2010).

PubMed

Yabar, Carlos Augusto; Acuña, Maribel; Gazzo, Cecilia; Salinas, Gabriela; Cárdenas, Fanny; Valverde, Ada; Romero, Soledad

2012-12-01

HIV-1 subtype B is the most frequent strain in Peru. However, there is no available data about the genetic diversity of HIV-infected patients receiving highly active antiretroviral therapy (HAART) here. A group of 267 patients in the Peruvian National Treatment Program with virologic failure were tested for genotypic evidence of HIV drug resistance at the Instituto Nacional de Salud (INS) of Peru between March 2008 and December 2010. Viral RNA was extracted from plasma and the segments of the protease (PR) and reverse transcriptase (RT) genes were amplified by reverse transcriptase polymerase chain reaction (RT-PCR), purified, and fully sequenced. Consensus sequences were submitted to the HIVdb Genotypic Resistance Interpretation Algorithm Database from Stanford University, and then aligned using Clustal X v.2.0 to generate a phylogenetic tree using the maximum likelihood method. Intrasubtype and intersubtype recombination analyses were performed using the SCUEAL program (Subtype Classification by Evolutionary ALgo-rithms). A total of 245 samples (91%) were successfully genotyped. The analysis obtained from the HIVdb program showed 81.5% resistance cases (n=198). The phylogenetic analysis revealed that subtype B was predominant in the population (98.8%), except for new cases of A, C, and H subtypes (n=4). Of these cases, only subtype C was imported. Likewise, recombination analysis revealed nine intersubtype and 20 intrasubtype recombinant cases. This is the first report of the presence of HIV-1 subtypes C and H in Peru. The introduction of new subtypes and circulating recombinants forms can make it difficult to distinguish resistance profiles in patients and consequently affect future treatment strategies against HIV in this country.

Prevalence and control of H7 avian influenza viruses in birds and humans.

PubMed

Abdelwhab, E M; Veits, J; Mettenleiter, T C

2014-05-01

The H7 subtype HA gene has been found in combination with all nine NA subtype genes. Most exhibit low pathogenicity and only rarely high pathogenicity in poultry (and humans). During the past few years infections of poultry and humans with H7 subtypes have increased markedly. This review summarizes the emergence of avian influenza virus H7 subtypes in birds and humans, and the possibilities of its control in poultry. All H7Nx combinations were reported from wild birds, the natural reservoir of the virus. Geographically, the most prevalent subtype is H7N7, which is endemic in wild birds in Europe and was frequently reported in domestic poultry, whereas subtype H7N3 is mostly isolated from the Americas. In humans, mild to fatal infections were caused by subtypes H7N2, H7N3, H7N7 and H7N9. While infections of humans have been associated mostly with exposure to domestic poultry, infections of poultry have been linked to wild birds or live-bird markets. Generally, depopulation of infected poultry was the main control tool; however, inactivated vaccines were also used. In contrast to recent cases caused by subtype H7N9, human infections were usually self-limiting and rarely required antiviral medication. Close genetic and antigenic relatedness of H7 viruses of different origins may be helpful in development of universal vaccines and diagnostics for both animals and humans. Due to the wide spread of H7 viruses and their zoonotic importance more research is required to better understand the epidemiology, pathobiology and virulence determinants of these viruses and to develop improved control tools.

Distribution of Cryptosporidium subtypes in humans and domestic and wild ruminants in Portugal.

PubMed

Alves, Margarida; Xiao, Lihua; Antunes, Francisco; Matos, Olga

2006-08-01

To investigate the transmission of cryptosporidiosis in Portugal, Cryptosporidium hominis and Cryptosporidium parvum from HIV-infected patients, cattle, and wild ruminants were characterized by sequence analysis of the 60-kDa glycoprotein (GP60) gene. Fourteen subtypes within nine subtype families were identified, and three of the subtype families (If, IIb, and IId) were restricted or largely limited to Portugal. Parasites from cattle from various regions in Portugal and wild ruminants in Lisbon showed limited genetic heterogeneity (only two subtype families). All wild ruminants had the same subtype, which was also the predominant subtype in cattle all over Portugal and was found in nine HIV-infected patients in Lisbon. Two other C. parvum subtypes were only restricted to limited locations. In contrast, human parasites displayed 13 subtypes in nine subtype families, with most of the infections caused by parasites in Ib, IIa, IIc, and IId families. Two of the C. parvum subtype families (IIc and IIb) had only been found in humans. The high overall parasite diversity and high percentage of C. hominis infections attributable to Ib and C. parvum infections to IId represent unique characteristics of Cryptosporidium transmission in humans in Portugal.

Genetics of Human and Canine Dilated Cardiomyopathy

PubMed Central

Simpson, Siobhan; Edwards, Jennifer; Ferguson-Mignan, Thomas F. N.; Cobb, Malcolm; Mongan, Nigel P.; Rutland, Catrin S.

2015-01-01

Cardiovascular disease is a leading cause of death in both humans and dogs. Dilated cardiomyopathy (DCM) accounts for a large number of these cases, reported to be the third most common form of cardiac disease in humans and the second most common in dogs. In human studies of DCM there are more than 50 genetic loci associated with the disease. Despite canine DCM having similar disease progression to human DCM studies into the genetic basis of canine DCM lag far behind those of human DCM. In this review the aetiology, epidemiology, and clinical characteristics of canine DCM are examined, along with highlighting possible different subtypes of canine DCM and their potential relevance to human DCM. Finally the current position of genetic research into canine and human DCM, including the genetic loci, is identified and the reasons many studies may have failed to find a genetic association with canine DCM are reviewed. PMID:26266250

Genetics of Human and Canine Dilated Cardiomyopathy.

PubMed

Simpson, Siobhan; Edwards, Jennifer; Ferguson-Mignan, Thomas F N; Cobb, Malcolm; Mongan, Nigel P; Rutland, Catrin S

2015-01-01

Cardiovascular disease is a leading cause of death in both humans and dogs. Dilated cardiomyopathy (DCM) accounts for a large number of these cases, reported to be the third most common form of cardiac disease in humans and the second most common in dogs. In human studies of DCM there are more than 50 genetic loci associated with the disease. Despite canine DCM having similar disease progression to human DCM studies into the genetic basis of canine DCM lag far behind those of human DCM. In this review the aetiology, epidemiology, and clinical characteristics of canine DCM are examined, along with highlighting possible different subtypes of canine DCM and their potential relevance to human DCM. Finally the current position of genetic research into canine and human DCM, including the genetic loci, is identified and the reasons many studies may have failed to find a genetic association with canine DCM are reviewed.

Copy number abnormality of acute lymphoblastic leukemia cell lines based on their genetic subtypes.

PubMed

Tomoyasu, Chihiro; Imamura, Toshihiko; Tomii, Toshihiro; Yano, Mio; Asai, Daisuke; Goto, Hiroaki; Shimada, Akira; Sanada, Masashi; Iwamoto, Shotaro; Takita, Junko; Minegishi, Masayoshi; Inukai, Takeshi; Sugita, Kanji; Hosoi, Hajime

2018-05-21

In this study, we performed genetic analysis of 83 B cell precursor acute lymphoblastic leukemia (B-ALL) cell lines. First, we performed multiplex ligation-dependent probe amplification analysis to identify copy number abnormalities (CNAs) in eight genes associated with B-ALL according to genetic subtype. In Ph + B-ALL cell lines, the frequencies of IKZF1, CDKN2A/2B, BTG1, and PAX5 deletion were significantly higher than those in Ph - B-ALL cell lines. The frequency of CDKN2A/2B deletion in KMT2A rearranged cell lines was significantly lower than that in non-KMT2A rearranged cell lines. These findings suggest that CNAs are correlated with genetic subtype in B-ALL cell lines. In addition, we determined that three B-other ALL cell lines had IKZF1 deletions (YCUB-5, KOPN49, and KOPN75); we therefore performed comprehensive genetic analysis of these cell lines. YCUB-5, KOPN49, and KOPN75 had P2RY8-CRLF2, IgH-CRLF2, and PAX5-ETV6 fusions, respectively. Moreover, targeted capture sequencing revealed that YCUB-5 had JAK2 R683I and KRAS G12D, and KOPN49 had JAK2 R683G and KRAS G13D mutations. These data may contribute to progress in the field of leukemia research.

Associations of Genetic Variants at Nongenic Susceptibility Loci with Breast Cancer Risk and Heterogeneity by Tumor Subtype in Southern Han Chinese Women

PubMed Central

Liang, Huiying; Li, Hong; Yang, Xuexi; Chen, Lujia; Zhu, Anna; Sun, Minying; Ye, Changsheng; Li, Ming

2016-01-01

Current understanding of cancer genomes is mainly “gene centric.” However, GWAS have identified some nongenic breast cancer susceptibility loci. Validation studies showed inconsistent results among different populations. To further explore this inconsistency and to investigate associations by intrinsic subtype (Luminal-A, Luminal-B, ER−&PR−&HER2+, and triple negative) among Southern Han Chinese women, we genotyped five nongenic polymorphisms (2q35: rs13387042, 5p12: rs981782 and rs4415084, and 8q24: rs1562430 and rs13281615) using MassARRAY IPLEX platform in 609 patients and 882 controls. Significant associations with breast cancer were observed for rs13387042 and rs4415084 with OR (95% CI) per-allele 1.29 (1.00–1.66) and 0.83 (0.71–0.97), respectively. In subtype specific analysis, rs13387042 (per-allele adjusted OR = 1.36, 95% CI = 1.00–1.87) and rs4415084 (per-allele adjusted OR = 0.82, 95% CI = 0.66–1.00) showed slightly significant association with Luminal-A subtype; however, only rs13387042 was associated with ER−&PR−&HER2+ tumors (per-allele adjusted OR = 1.55, 95% CI = 1.00–2.40), and none of them were linked to Luminal-B and triple negative subtype. Collectively, nongenic SNPs were heterogeneous according to the intrinsic subtype. Further studies with larger datasets along with intrinsic subtype categorization should explore and confirm the role of these variants in increasing breast cancer risk. PMID:27022606

Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma.

PubMed

Wu, Xin; Serna, Vanida A; Thomas, Justin; Qiang, Wenan; Blumenfeld, Michael L; Kurita, Takeshi

2017-12-15

Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here, we report the elucidation of the biological characteristics of the two most prevalent uterine leiomyoma subtypes, MED12-mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) uterine leiomyomas. Because each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-uterine leiomyoma were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF). Paradoxically, TAF carried no mutations in MED12, suggesting an interaction between SMC and TAF to coordinate their growth. The higher amount of extracellular matrix in MED12-LM than HMGA2-LM was partially due to the high concentration of collagen-producing TAF. SMC growth in a xenograft assay was driven by progesterone in both uterine leiomyoma subtypes. In contrast, TAF in MED12-LM proliferated in response to estradiol, whereas progesterone had no effect. The high concentration of estrogen-responsive TAF in MED12-LM explains the inconsistent discoveries between in vivo and in vitro studies on the mitogenic effect of estrogen and raises questions regarding the accuracy of previous studies utilizing MED12-LM cell culture. In addition, the differential effects of estradiol and progesterone on these uterine leiomyoma subtypes emphasize the importance of subtypes and genotypes in designing nonsurgical therapeutic strategies for uterine leiomyoma. Cancer Res; 77(24); 6891-901. ©2017 AACR . ©2017 American Association for Cancer Research.

Genetic analysis and antigenic characterization of swine origin influenza viruses isolated from humans in the United States, 1990-2010.

PubMed

Shu, Bo; Garten, Rebecca; Emery, Shannon; Balish, Amanda; Cooper, Lynn; Sessions, Wendy; Deyde, Varough; Smith, Catherine; Berman, LaShondra; Klimov, Alexander; Lindstrom, Stephen; Xu, Xiyan

2012-01-05

Swine influenza viruses (SIV) have been recognized as important pathogens for pigs and occasional human infections with swine origin influenza viruses (SOIV) have been reported. Between 1990 and 2010, a total of twenty seven human cases of SOIV infections have been identified in the United States. Six viruses isolated from 1990 to 1995 were recognized as classical SOIV (cSOIV) A(H1N1). After 1998, twenty-one SOIV recovered from human cases were characterized as triple reassortant (tr_SOIV) inheriting genes from classical swine, avian and human influenza viruses. Of those twenty-one tr_SOIV, thirteen were of A(H1N1), one of A(H1N2), and seven of A(H3N2) subtype. SOIV characterized were antigenically and genetically closely related to the subtypes of influenza viruses circulating in pigs but distinct from contemporary influenza viruses circulating in humans. The diversity of subtypes and genetic lineages in SOIV cases highlights the importance of continued surveillance at the animal-human interface. Copyright © 2011. Published by Elsevier Inc.

NCI study offers genetic insights into common lymphoma

Cancer.gov

An NCI study identifies genetic subtypes of diffuse large B-cell lymphoma (DLBCL), helping explain why only some patients with this most common lymphoma respond to treatment, and offering a path toward targeted therapies.

Study Points to Genetic Subtypes of Esophageal Cancer

Cancer.gov

A Cancer Currents blog post about a study by The Cancer Genome Atlas Research Network that identified distinct genetic and molecular changes in esophageal cancers that could improve their classification and identify potential new treatments.

Zoonotic Potential and Molecular Epidemiology of Giardia Species and Giardiasis†

PubMed Central

Feng, Yaoyu; Xiao, Lihua

2011-01-01

Summary: Molecular diagnostic tools have been used recently in assessing the taxonomy, zoonotic potential, and transmission of Giardia species and giardiasis in humans and animals. The results of these studies have firmly established giardiasis as a zoonotic disease, although host adaptation at the genotype and subtype levels has reduced the likelihood of zoonotic transmission. These studies have also identified variations in the distribution of Giardia duodenalis genotypes among geographic areas and between domestic and wild ruminants and differences in clinical manifestations and outbreak potentials of assemblages A and B. Nevertheless, our efforts in characterizing the molecular epidemiology of giardiasis and the roles of various animals in the transmission of human giardiasis are compromised by the lack of case-control and longitudinal cohort studies and the sampling and testing of humans and animals living in the same community, the frequent occurrence of infections with mixed genotypes and subtypes, and the apparent heterozygosity at some genetic loci for some G. duodenalis genotypes. With the increased usage of multilocus genotyping tools, the development of next-generation subtyping tools, the integration of molecular analysis in epidemiological studies, and an improved understanding of the population genetics of G. duodenalis in humans and animals, we should soon have a better appreciation of the molecular epidemiology of giardiasis, the disease burden of zoonotic transmission, the taxonomy status and virulences of various G. duodenalis genotypes, and the ecology of environmental contamination. PMID:21233509

Typing and Subtyping of 83 Clinical Isolates Purified from Surgically Implanted Silicone Feeding Tubes by Random Amplified Polymorphic DNA Amplification

PubMed Central

Dautle, Melanie P.; Ulrich, Ricky L.; Hughes, Thomas A.

2002-01-01

In this study, 83 clinical isolates purified from biofilms colonizing 18 silicone gastrostomy devices (12 “buttons” and six tubes converted to skin level devices) were selected for subtype characterization utilizing genetic analysis. The tubes, previously used for feeding, remained in place for 3 to 47 months (mean, 20.0 months) in children ranging in age from 6 months to 17 years. Classification of specific microbes using random amplified polymorphic DNA (RAPD) analysis revealed genetic similarities and differences among isolates belonging to the same genus. Both gram-positive and -negative bacteria were investigated, including 2 isolates of Bacillus brevis, 4 isolates of Bacillus licheniformis, 2 isolates of Bacillus pumilus, 3 isolates of Enterococcus durans, 19 isolates of Enterococcus faecalis, 8 isolates of Enterococcus faecium, 2 isolates of Enterococcus hirae, 7 isolates of Escherichia coli, 8 isolates of Lactobacillus plantarum, 19 isolates of Staphylococcus aureus, 2 isolates of Staphylococcus epidermidis, and 7 isolates of Staphylococcus saprophyticus. Amplified DNA fragments (amplicons) provided species-specific fingerprints for comparison by agarose gel electrophoresis. A total of 62 distinct RAPD types were categorized from the five genera studied. Typing analysis suggested cross acquisition of E. coli, E. faecalis, and S. aureus in three patient pairs. Genomic polymorphism detection proved efficient and reliable for classifying bacterial subtypes isolated from biofilms adhering to various portions of commonly employed enteral access tubes. PMID:11825951

Isolation and Genetic Characterization of Avian Influenza Viruses Isolated from Wild Birds in the Azov-Black Sea Region of Ukraine (2001-2012).

PubMed

Muzyka, Denys; Pantin-Jackwood, Mary; Spackman, Erica; Smith, Diane; Rula, Oleksandr; Muzyka, Nataliia; Stegniy, Borys

2016-05-01

Wild bird surveillance for avian influenza virus (AIV) was conducted from 2001 to 2012 in the Azov - Black Sea region of the Ukraine, considered part of the transcontinental wild bird migration routes from northern Asia and Europe to the Mediterranean, Africa, and southwest Asia. A total of 6281 samples were collected from wild birds representing 27 families and eight orders for virus isolation. From these samples, 69 AIVs belonging to 15 of the 16 known hemagglutinin (HA) subtypes and seven of nine known neuraminidase (NA) subtypes were isolated. No H14, N5, or N9 subtypes were identified. In total, nine H6, eight H1, nine H5, seven H7, six H11, six H4, five H3, five H10, four H8, three H2, three H9, one H12, one H13, one H15, and one H16 HA subtypes were isolated. As for the NA subtypes, twelve N2, nine N6, eight N8, seven N7, six N3, four N4, and one undetermined were isolated. There were 27 HA and NA antigen combinations. All isolates were low pathogenic AIV except for eight highly pathogenic (HP) AIVs that were isolated during the H5N1 HPAI outbreaks of 2006-08. Sequencing and phylogenetic analysis of the HA genes revealed epidemiological connections between the Azov-Black Sea regions and Europe, Russia, Mongolia, and Southeast Asia. H1, H2, H3, H7, H8, H6, H9, and H13 AIV subtypes were closely related to European, Russian, Mongolian, and Georgian AIV isolates. H10, H11, and H12 AIV subtypes were epidemiologically linked to viruses from Europe and Southeast Asia. Serology conducted on serum and egg yolk samples also demonstrated previous exposure of many wild bird species to different AIVs. Our results demonstrate the great genetic diversity of AIVs in wild birds in the Azov-Black Sea region as well as the importance of this region for monitoring and studying the ecology of influenza viruses. This information furthers our understanding of the ecology of avian influenza viruses in wild bird species.

Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies

PubMed Central

2014-01-01

Summary Background The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10−8. Findings We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10−10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10−9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10−9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. Interpretation This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes). Funding International League Against Epilepsy and multiple governmental and philanthropic agencies. PMID:25087078

The Classification, Natural History and Treatment of the Limb Girdle Muscular Dystrophies

PubMed Central

Murphy, Alexander Peter; Straub, Volker

2015-01-01

Abstract Over sixty years ago John Walton and Frederick Nattrass defined limb girdle muscular dystrophy (LGMD) as a separate entity from the X-linked dystrophinopathies such as Duchenne and Becker muscular dystrophies. LGMD is a highly heterogeneous group of very rare neuromuscular disorders whose common factor is their autosomal inheritance. Sixty years later, with the development of increasingly advanced molecular genetic investigations, a more precise classification and understanding of the pathogenesis is possible. To date, over 30 distinct subtypes of LGMD have been identified, most of them inherited in an autosomal recessive fashion. There are significant differences in the frequency of subtypes of LGMD between different ethnic populations, providing evidence of founder mutations. Clinically there is phenotypic heterogeneity between subtypes of LGMD with varying severity and age of onset of symptoms. The first natural history studies into subtypes of LGMD are in process, but large scale longitudinal data have been lacking due to the rare nature of these diseases. Following natural history data collection, the next challenge is to develop more effective, disease specific treatments. Current management is focussed on symptomatic and supportive treatments. Advances in the application of new omics technologies and the generation of large-scale biomedical data will help to better understand disease mechanisms in LGMD and should ultimately help to accelerate the development of novel and more effective therapeutic approaches. PMID:27858764

The Classification, Natural History and Treatment of the Limb Girdle Muscular Dystrophies.

PubMed

Murphy, Alexander Peter; Straub, Volker

2015-07-22

Over sixty years ago John Walton and Frederick Nattrass defined limb girdle muscular dystrophy (LGMD) as a separate entity from the X-linked dystrophinopathies such as Duchenne and Becker muscular dystrophies. LGMD is a highly heterogeneous group of very rare neuromuscular disorders whose common factor is their autosomal inheritance. Sixty years later, with the development of increasingly advanced molecular genetic investigations, a more precise classification and understanding of the pathogenesis is possible.To date, over 30 distinct subtypes of LGMD have been identified, most of them inherited in an autosomal recessive fashion. There are significant differences in the frequency of subtypes of LGMD between different ethnic populations, providing evidence of founder mutations. Clinically there is phenotypic heterogeneity between subtypes of LGMD with varying severity and age of onset of symptoms. The first natural history studies into subtypes of LGMD are in process, but large scale longitudinal data have been lacking due to the rare nature of these diseases. Following natural history data collection, the next challenge is to develop more effective, disease specific treatments. Current management is focussed on symptomatic and supportive treatments. Advances in the application of new omics technologies and the generation of large-scale biomedical data will help to better understand disease mechanisms in LGMD and should ultimately help to accelerate the development of novel and more effective therapeutic approaches.

Differential perinatal risk factors in children with attention-deficit/hyperactivity disorder by subtype.

PubMed

Park, Subin; Cho, Soo-Churl; Kim, Jae-Won; Shin, Min-Sup; Yoo, Hee-Jeong; Oh, Seung Min; Han, Doug Hyun; Cheong, Jae Hoon; Kim, Bung-Nyun

2014-11-30

We compared the attention-deficit/hyperactivity disorder(ADHD) combined subtype (ADHD-C) to the ADHD inattentive subtype (ADHD-I) in terms of genetic, perinatal, and developmental risk factors as well as clinical and neuropsychological characteristics. A total of 147 children diagnosed with ADHD between the ages of 6 and 15 years participated in this study. The parents of the children completed the structured diagnostic interview, the ADHD Rating Scale-IV, the Children's Behavior Checklist, and structured questionnaires on perinatal risk factors, and the children underwent a neuropsychological test and were genotyped. A total of 502 children without ADHD were recruited from the community as a healthy control group. The ADHD-C children showed more severe externalizing symptoms, showed more deficits in a continuous performance test, and were more likely to have comorbid disorders. Maternal stress during pregnancy, postpartum depression, and changes in the primary caretaker during first 3 years were significantly associated with both ADHD-I and ADHD-C. The ADHD-I group was less likely to have received regular prenatal check-ups and more likely to have had postnatal medical illness than the ADHD-C group. There were no significant differences in the genotype frequencies of the dopamine transporter (DAT1) and the serotonin transporter -linked polymorphic region (5-HTTLPR) polymorphisms between ADHD-I and ADHD-C groups. This study shows that the inattentive subtype of ADHD is different from the combined subtype in many parameters including severity of symptoms, comorbidity, neuropsychological characteristics, and environmental risk factors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Memory in intellectually matched groups of young participants with 22q11.2 deletion syndrome and those with schizophrenia.

PubMed

Kravariti, Eugenia; Jacobson, Clare; Morris, Robin; Frangou, Sophia; Murray, Robin M; Tsakanikos, Elias; Habel, Alex; Shearer, Jo

2010-01-01

The 22q11.2 deletion syndrome (22qDS) and schizophrenia have genetic and neuropsychological similarities, but are likely to differ in memory profile. Confirming differences in memory function between the two disorders, and identifying their genetic determinants, can help to define genetic subtypes in both syndromes, identify genetic risk factors for the emergence of psychosis, and develop pharmacological interventions for cognitive dysfunction. However, no study has compared memory function between 22qDS and schizophrenia, while indirect comparisons are confounded by marked differences in IQ between the two populations. We compared verbal and visual memory in 29 children and adolescents with 22qDS and 15 intellectually matched youths with schizophrenia using age-appropriate, directly comparable, Wechsler scales. Verbal memory was markedly superior in the 22qDS group by 21 points. There were no group differences in visual memory. The inherently low COMT activity in 22qDS merits investigation as a potential protective factor for verbal memory. 2010 Elsevier Ltd. All rights reserved.

Subtyping of Canadian isolates of Salmonella Enteritidis using Multiple Locus Variable Number Tandem Repeat Analysis (MLVA) alone and in combination with Pulsed-Field Gel Electrophoresis (PFGE) and phage typing.

PubMed

Ziebell, Kim; Chui, Linda; King, Robin; Johnson, Suzanne; Boerlin, Patrick; Johnson, Roger P

2017-08-01

Salmonella enterica subspecies enterica serovar Enteritidis (SE) is one of the most common causes of human salmonellosis and in Canada currently accounts for over 40% of human cases. Reliable subtyping of isolates is required for outbreak detection and source attribution. However, Pulsed-Field Gel Electrophoresis (PFGE), the current standard subtyping method for Salmonella spp., is compromised by the high genetic homogeneity of SE. Multiple Locus Variable Number Tandem Repeat Analysis (MLVA) was introduced to supplement PFGE, although there is a lack of data on the ability of MLVA to subtype Canadian isolates of SE. Three subtyping methods, PFGE, MLVA and phage typing were compared for their discriminatory power when applied to three panels of Canadian SE isolates: Panel 1: 70 isolates representing the diversity of phage types (PTs) and PFGE subtypes within these PTs; Panel 2: 214 apparently unrelated SE isolates of the most common PTs; and Panel 3: 27 isolates from 10 groups of epidemiologically related strains. For Panel 2 isolates, four MLVA subtypes were shared among 74% of unrelated isolates and in Panel 3 isolates, one MLVA subtype accounted for 62% of the isolates. For all panels, combining results from PFGE, MLVA and PT gave the best discrimination, except in Panel 1, where the combination of PT and PFGE was equally as high, due to the selection criteria for this panel. However, none of these methods is sufficiently discriminatory alone for reliable outbreak detection or source attribution, and must be applied together to achieve sufficient discrimination for practical purposes. Even then, some large clusters were not differentiated adequately. More discriminatory methods are required for reliable subtyping of this genetically highly homogeneous serovar. This need will likely be met by whole genome sequence analysis given the recent promising reports and as more laboratories implement this tool for outbreak response and surveillance. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparative proteomic profiling of soleus, extensor digitorum longus, flexor digitorum brevis and interosseus muscles from the mdx mouse model of Duchenne muscular dystrophy.

PubMed

Carberry, Steven; Brinkmeier, Heinrich; Zhang, Yaxin; Winkler, Claudia K; Ohlendieck, Kay

2013-09-01

Duchenne muscular dystrophy is due to genetic abnormalities in the dystrophin gene and represents one of the most frequent genetic childhood diseases. In the X-linked muscular dystrophy (mdx) mouse model of dystrophinopathy, different subtypes of skeletal muscles are affected to a varying degree albeit the same single base substitution within exon 23 of the dystrophin gene. Thus, to determine potential muscle subtype-specific differences in secondary alterations due to a deficiency in dystrophin, in this study, we carried out a comparative histological and proteomic survey of mdx muscles. We intentionally included the skeletal muscles that are often used for studying the pathomechanism of muscular dystrophy. Histological examinations revealed a significantly higher degree of central nucleation in the soleus and extensor digitorum longus muscles compared with the flexor digitorum brevis and interosseus muscles. Muscular hypertrophy of 20-25% was likewise only observed in the soleus and extensor digitorum longus muscles from mdx mice, but not in the flexor digitorum brevis and interosseus muscles. For proteomic analysis, muscle protein extracts were separated by fluorescence two-dimensional (2D) gel electrophoresis. Proteins with a significant change in their expression were identified by mass spectrometry. Proteomic profiling established an altered abundance of 24, 17, 19 and 5 protein species in the dystrophin-deficient soleus, extensor digitorum longus, flexor digitorum brevis and interosseus muscle, respectively. The key proteomic findings were verified by immunoblot analysis. The identified proteins are involved in the contraction-relaxation cycle, metabolite transport, muscle metabolism and the cellular stress response. Thus, histological and proteomic profiling of muscle subtypes from mdx mice indicated that distinct skeletal muscles are differentially affected by the loss of the membrane cytoskeletal protein, dystrophin. Varying degrees of perturbed protein expression patterns in the muscle subtypes from mdx mice may be due to dissimilar downstream events, including differences in muscle structure or compensatory mechanisms that counteract pathophysiological processes. The interosseus muscle from mdx mice possibly represents a naturally protected phenotype.

Comparative proteomic profiling of soleus, extensor digitorum longus, flexor digitorum brevis and interosseus muscles from the mdx mouse model of Duchenne muscular dystrophy

PubMed Central

CARBERRY, STEVEN; BRINKMEIER, HEINRICH; ZHANG, YAXIN; WINKLER, CLAUDIA K.; OHLENDIECK, KAY

2013-01-01

Duchenne muscular dystrophy is due to genetic abnormalities in the dystrophin gene and represents one of the most frequent genetic childhood diseases. In the X-linked muscular dystrophy (mdx) mouse model of dystrophinopathy, different subtypes of skeletal muscles are affected to a varying degree albeit the same single base substitution within exon 23 of the dystrophin gene. Thus, to determine potential muscle subtype-specific differences in secondary alterations due to a deficiency in dystrophin, in this study, we carried out a comparative histological and proteomic survey of mdx muscles. We intentionally included the skeletal muscles that are often used for studying the pathomechanism of muscular dystrophy. Histological examinations revealed a significantly higher degree of central nucleation in the soleus and extensor digitorum longus muscles compared with the flexor digitorum brevis and interosseus muscles. Muscular hypertrophy of 20–25% was likewise only observed in the soleus and extensor digitorum longus muscles from mdx mice, but not in the flexor digitorum brevis and interosseus muscles. For proteomic analysis, muscle protein extracts were separated by fluorescence two-dimensional (2D) gel electrophoresis. Proteins with a significant change in their expression were identified by mass spectrometry. Proteomic profiling established an altered abundance of 24, 17, 19 and 5 protein species in the dystrophin-deficient soleus, extensor digitorum longus, flexor digitorum brevis and interosseus muscle, respectively. The key proteomic findings were verified by immunoblot analysis. The identified proteins are involved in the contraction-relaxation cycle, metabolite transport, muscle metabolism and the cellular stress response. Thus, histological and proteomic profiling of muscle subtypes from mdx mice indicated that distinct skeletal muscles are differentially affected by the loss of the membrane cytoskeletal protein, dystrophin. Varying degrees of perturbed protein expression patterns in the muscle subtypes from mdx mice may be due to dissimilar downstream events, including differences in muscle structure or compensatory mechanisms that counteract pathophysiological processes. The interosseus muscle from mdx mice possibly represents a naturally protected phenotype. PMID:23828267

Subtyping of STEC by MLVA in Argentina.

PubMed

Bustamante, Ana V; Sanso, Andrea M; Parma, Alberto E; Lucchesi, Paula M A

2012-01-01

Shiga toxin-producing Escherichia coli (STEC) causes serious human illness such as hemolytic uremic syndrome (HUS). Argentina has the world's highest rate of this syndrome, which is the leading cause of acute renal failure among children. E. coli O157:H7 is the most common cause of HUS, but a substantial and growing proportion of this illness is caused by infection due to non-O157 strains. Multiple-locus variable-number tandem repeat analysis (MLVA) has become an established technique to subtype STEC. This review will address the use of routine STEC subtyping by MLVA in order to type this group of isolates and to get insight into the genetic diversity of native STEC. With regard to these objectives we modified and adapted two MLVA protocols, one exclusive for O157 and the other, a generic E. coli assay. A total of 202 STEC isolates, from different sources and corresponding to 20 serotypes, have been MLVA genotyped in our laboratory. In our experience, MLVA constitutes a very sensitive tool and enables us to perform an efficient STEC subtyping. The diversity found in many serotypes may be useful for future epidemiological studies of STEC clonality, applied to O157 as well as to non-O157 isolates.

A dual affinity-tag strategy for the expression and purification of human linker histone H1.4 in Escherichia coli.

PubMed

Ryan, Daniel P; Tremethick, David J

2016-04-01

Linker histones are an abundant and critical component of the eukaryotic chromatin landscape. They play key roles in regulating the higher order structure of chromatin and many genetic processes. Higher eukaryotes possess a number of different linker histone subtypes and new data are consistently emerging that indicate these subtypes are functionally distinct. We were interested in studying one of the most abundant human linker histone subtypes, H1.4. We have produced recombinant full-length H1.4 in Escherichia coli. An N-terminal Glutathione-S-Transferase tag was used to promote soluble expression and was combined with a C-terminal hexahistidine tag to facilitate a simple non-denaturing two-step affinity chromatography procedure that results in highly pure full-length H1.4. The purified H1.4 was shown to be functional via in vitro chromatin assembly experiments and remains active after extended storage at -80 °C. Copyright © 2015 Elsevier Inc. All rights reserved.

Diversity and evolution of class 2 CRISPR–Cas systems

PubMed Central

Shmakov, Sergey; Smargon, Aaron; Scott, David; Cox, David; Pyzocha, Neena; Yan, Winston; Abudayyeh, Omar O.; Gootenberg, Jonathan S.; Makarova, Kira S.; Wolf, Yuri I.; Severinov, Konstantin; Zhang, Feng; Koonin, Eugene V.

2018-01-01

Class 2 CRISPR–Cas systems are characterized by effector modules that consist of a single multidomain protein, such as Cas9 or Cpf1. We designed a computational pipeline for the discovery of novel class 2 variants and used it to identify six new CRISPR–Cas subtypes. The diverse properties of these new systems provide potential for the development of versatile tools for genome editing and regulation. In this Analysis article, we present a comprehensive census of class 2 types and class 2 subtypes in complete and draft bacterial and archaeal genomes, outline evolutionary scenarios for the independent origin of different class 2 CRISPR–Cas systems from mobile genetic elements, and propose an amended classification and nomenclature of CRISPR–Cas. PMID:28111461

Novel reassortant influenza viruses between pandemic (H1N1) 2009 and other influenza viruses pose a risk to public health.

PubMed

Kong, Weili; Wang, Feibing; Dong, Bin; Ou, Changbo; Meng, Demei; Liu, Jinhua; Fan, Zhen-Chuan

2015-12-01

Influenza A virus (IAV) is characterized by eight single-stranded, negative sense RNA segments, which allows for gene reassortment among different IAV subtypes when they co-infect a single host cell simultaneously. Genetic reassortment is an important way to favor the evolution of influenza virus. Novel reassortant virus may pose a pandemic among humans. In history, three human pandemic influenza viruses were caused by genetic reassortment between avian, human and swine influenza viruses. Since 2009, pandemic (H1N1) 2009 (pdm/09 H1N1) influenza virus composed of two swine influenza virus genes highlighted the genetic reassortment again. Due to wide host species and high transmission of the pdm/09 H1N1 influenza virus, many different avian, human or swine influenza virus subtypes may reassert with it to generate novel reassortant viruses, which may result in a next pandemic among humans. So, it is necessary to understand the potential threat of current reassortant viruses between the pdm/09 H1N1 and other influenza viruses to public health. This study summarized the status of the reassortant viruses between the pdm/09 H1N1 and other influenza viruses of different species origins in natural and experimental conditions. The aim of this summarization is to facilitate us to further understand the potential threats of novel reassortant influenza viruses to public health and to make effective prevention and control strategies for these pathogens. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Collaborative Study of the Etiology of Breast Cancer Subtypes in African American Women: the AMBER Consortium

PubMed Central

Palmer, Julie R.; Ambrosone, Christine B.; Olshan, Andrew F.

2014-01-01

Purpose Breast cancer is a heterogeneous disease, with at least five intrinsic subtypes defined by molecular characteristics. Tumors that express the estrogen receptor (ER+) have better outcomes than ER− tumors, due in part to the success of hormonal therapies that target ER+ tumors. The incidence of ER− breast cancer, and the subset of ER− cancers that are basal-like, is about twice as high among African American (AA) women as among U.S. women of European descent (EA). This disparity appears to explain, in part, the disproportionately high mortality from breast cancer that occurs in AA women. Epidemiologic research on breast cancer in AA women lags behind research in EA women. Here, we review differences in the etiology of breast cancer subtypes among AA women and describe a new consortium of ongoing studies of breast cancer in AA women. Methods We combined samples and data from four large epidemiologic studies of breast cancer in AA women, two cohort and two case-control, creating the AMBER consortium. Tumor tissue is obtained and stored in tissue microarrays, with assays of molecular markers carried out at a pathology core. Genotyping, carried out centrally, includes a whole exome SNP array and over 180,000 custom SNPs for fine-mapping of GWAS loci and candidate pathways. Results To date, questionnaire data from 5,739 breast cancer cases and 14,273 controls have been harmonized. Genotyping of the first 3,200 cases and 3,700 controls is underway, with a total of 6,000 each expected by the end of the study period. Conclusions The new consortium will likely have sufficient statistical power to assess potential risk factors, both genetic and non-genetic in relation to specific subtypes of breast cancer in AA women. PMID:24343304

Lack of Postprandial Peak in Brain-Derived Neurotrophic Factor in Adults with Prader-Willi Syndrome

PubMed Central

Bueno, Marta; Esteba-Castillo, Susanna; Novell, Ramon; Giménez-Palop, Olga; Coronas, Ramon; Gabau, Elisabeth; Corripio, Raquel; Baena, Neus; Viñas-Jornet, Marina; Guitart, Míriam; Torrents-Rodas, David; Deus, Joan; Pujol, Jesús; Rigla, Mercedes

2016-01-01

Context Prader-Willi syndrome (PWS) is characterized by severe hyperphagia. Brain-derived neurotrophic factor (BDNF) and leptin are reciprocally involved in energy homeostasis. Objectives To analyze the role of BDNF and leptin in satiety in genetic subtypes of PWS. Design Experimental study. Setting University hospital. Subjects 90 adults: 30 PWS patients; 30 age-sex-BMI-matched obese controls; and 30 age-sex-matched lean controls. Interventions Subjects ingested a liquid meal after fasting ≥10 hours. Main Outcome Measures Leptin and BDNF levels in plasma extracted before ingestion and 30’, 60’, and 120’ after ingestion. Hunger, measured on a 100-point visual analogue scale before ingestion and 60’ and 120’ after ingestion. Results Fasting BDNF levels were lower in PWS than in controls (p = 0.05). Postprandially, PWS patients showed only a truncated early peak in BDNF, and their BDNF levels at 60' and 120' were lower compared with lean controls (p<0.05). Leptin was higher in PWS patients than in controls at all time points (p<0.001). PWS patients were hungrier than controls before and after eating. The probability of being hungry was associated with baseline BDNF levels: every 50-unit increment in BDNF decreased the odds of being hungry by 22% (OR: 0.78, 95%CI: 0.65–0.94). In uniparental disomy, the odds of being hungry decreased by 66% (OR: 0.34, 90%CI: 0.13–0.9). Postprandial leptin patterns did no differ among genetic subtypes. Conclusions Low baseline BDNF levels and lack of postprandial peak may contribute to persistent hunger after meals. Uniparental disomy is the genetic subtype of PWS least affected by these factors. PMID:27685845

Reviewing the history of HIV-1: spread of subtype B in the Americas.

PubMed

Junqueira, Dennis Maletich; de Medeiros, Rúbia Marília; Matte, Maria Cristina Cotta; Araújo, Leonardo Augusto Luvison; Chies, Jose Artur Bogo; Ashton-Prolla, Patricia; Almeida, Sabrina Esteves de Matos

2011-01-01

The dispersal of HIV-1 subtype B (HIV-1B) is a reflection of the movement of human populations in response to social, political, and geographical issues. The initial dissemination of HIV-1B outside Africa seems to have included the passive involvement of human populations from the Caribbean in spreading the virus to the United States. However, the exact pathways taken during the establishment of the pandemic in the Americas remain unclear. Here, we propose a geographical scenario for the dissemination of HIV-1B in the Americas, based on phylogenetic and genetic statistical analyses of 313 available sequences of the pol gene from 27 countries. Maximum likelihood and bayesian inference methods were used to explore the phylogenetic relationships between HIV-1B sequences, and molecular variance estimates were analyzed to infer the genetic structure of the viral population. We found that the initial dissemination and subsequent spread of subtype B in the Americas occurred via a single introduction event in the Caribbean around 1964 (1950-1967). Phylogenetic trees present evidence of several primary outbreaks in countries in South America, directly seeded by the Caribbean epidemic. Cuba is an exception insofar as its epidemic seems to have been introduced from South America. One clade comprising isolates from different countries emerged in the most-derived branches, reflecting the intense circulation of the virus throughout the American continents. Statistical analysis supports the genetic compartmentalization of the virus among the Americas, with a close relationship between the South American and Caribbean epidemics. These findings reflect the complex establishment of the HIV-1B pandemic and contribute to our understanding between the migration process of human populations and virus diffusion.

Reviewing the History of HIV-1: Spread of Subtype B in the Americas

PubMed Central

Junqueira, Dennis Maletich; de Medeiros, Rúbia Marília; Matte, Maria Cristina Cotta; Araújo, Leonardo Augusto Luvison; Chies, Jose Artur Bogo; Ashton-Prolla, Patricia; Almeida, Sabrina Esteves de Matos

2011-01-01

The dispersal of HIV-1 subtype B (HIV-1B) is a reflection of the movement of human populations in response to social, political, and geographical issues. The initial dissemination of HIV-1B outside Africa seems to have included the passive involvement of human populations from the Caribbean in spreading the virus to the United States. However, the exact pathways taken during the establishment of the pandemic in the Americas remain unclear. Here, we propose a geographical scenario for the dissemination of HIV-1B in the Americas, based on phylogenetic and genetic statistical analyses of 313 available sequences of the pol gene from 27 countries. Maximum likelihood and Bayesian inference methods were used to explore the phylogenetic relationships between HIV-1B sequences, and molecular variance estimates were analyzed to infer the genetic structure of the viral population. We found that the initial dissemination and subsequent spread of subtype B in the Americas occurred via a single introduction event in the Caribbean around 1964 (1950–1967). Phylogenetic trees present evidence of several primary outbreaks in countries in South America, directly seeded by the Caribbean epidemic. Cuba is an exception insofar as its epidemic seems to have been introduced from South America. One clade comprising isolates from different countries emerged in the most-derived branches, reflecting the intense circulation of the virus throughout the American continents. Statistical analysis supports the genetic compartmentalization of the virus among the Americas, with a close relationship between the South American and Caribbean epidemics. These findings reflect the complex establishment of the HIV-1B pandemic and contribute to our understanding between the migration process of human populations and virus diffusion. PMID:22132104

A computationally optimized broadly reactive H5 hemagglutinin vaccine provides protection against homologous and heterologous H5N1 highly pathogenic avian influenza virus infection in chickens

USDA-ARS?s Scientific Manuscript database

Since its emergence in 1996 in China, H5N1 highly pathogenic avian influenza (HPAI) virus has continuously evolved into different genetic clades that have created challenges to maintaining antigenically relevant H5N1 vaccine seeds. Therefore, a universal (multi-hemagglutinin [HA] subtype) or more c...

Stroke subtyping for genetic association studies? A comparison of the CCS and TOAST classifications.

PubMed

Lanfranconi, Silvia; Markus, Hugh S

2013-12-01

A reliable and reproducible classification system of stroke subtype is essential for epidemiological and genetic studies. The Causative Classification of Stroke system is an evidence-based computerized algorithm with excellent inter-rater reliability. It has been suggested that, compared to the Trial of ORG 10172 in Acute Stroke Treatment classification, it increases the proportion of cases with defined subtype that may increase power in genetic association studies. We compared Trial of ORG 10172 in Acute Stroke Treatment and Causative Classification of Stroke system classifications in a large cohort of well-phenotyped stroke patients. Six hundred ninety consecutively recruited patients with first-ever ischemic stroke were classified, using review of clinical data and original imaging, according to the Trial of ORG 10172 in Acute Stroke Treatment and Causative Classification of Stroke system classifications. There was excellent agreement subtype assigned by between Trial of ORG 10172 in Acute Stroke Treatment and Causative Classification of Stroke system (kappa = 0·85). The agreement was excellent for the major individual subtypes: large artery atherosclerosis kappa = 0·888, small-artery occlusion kappa = 0·869, cardiac embolism kappa = 0·89, and undetermined category kappa = 0·884. There was only moderate agreement (kappa = 0·41) for the subjects with at least two competing underlying mechanism. Thirty-five (5·8%) patients classified as undetermined by Trial of ORG 10172 in Acute Stroke Treatment were assigned to a definite subtype by Causative Classification of Stroke system. Thirty-two subjects assigned to a definite subtype by Trial of ORG 10172 in Acute Stroke Treatment were classified as undetermined by Causative Classification of Stroke system. There is excellent agreement between classification using Trial of ORG 10172 in Acute Stroke Treatment and Causative Classification of Stroke systems but no evidence that Causative Classification of Stroke system reduced the proportion of patients classified to undetermined subtypes. The excellent inter-rater reproducibility and web-based semiautomated nature make Causative Classification of Stroke system suitable for multicenter studies, but the benefit of reclassifying cases already classified using the Trial of ORG 10172 in Acute Stroke Treatment system on existing databases is likely to be small. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.

First report of Blastocystis infections in cattle in China.

PubMed

Zhu, Weining; Tao, Wei; Gong, Binbin; Yang, Hang; Li, Yijing; Song, Mingxin; Lu, Yixin; Li, Wei

2017-11-15

Blastocystis is one of the most common intestinal protists of humans and can also infect a variety of other mammals and birds. Blastocystis infections and subtype distribution in cattle have been documented, while nothing is known about those in China. Herein, a total of 526 dairy cattle from northeast China were sampled and investigated for the prevalence and genetic characteristics of Blastocystis and the potential role of bovine animals in zoonotic transmission of Blastocystis. The parasite was identified in 54 (10.3%) fecal specimens by nested PCR and DNA sequencing of the small subunit ribosomal RNA gene. Sequence analysis enabled identification of four Blastocystis subtypes (STs). Among those, subtype ST10 (75.9%, 41/54) has the highest frequency, followed by ST14 (18.5%, 10/54), ST4 (3.7%, 2/54), and ST5 (1.9%, 1/54). High prevalence and widespread distribution of ST10 and ST14 in cattle observed herein, together with analysis of their host distribution patterns in earlier studies, indicated some host-adapted potential in the two subtypes. The identification of human-pathogenic subtypes ST4 and ST5 might imply a potential zoonotic risk of cattle origin. This is the first study exploring the prevalence and genetic characteristics of Blastocystis in cattle in China. The host range of subtype ST4 was extended. The findings of this study should be helpful for a better understanding of the epidemiology and public health potential of Blastocystis. Copyright © 2017 Elsevier B.V. All rights reserved.

Differences in incidence and trends of haematological malignancies in Japan and the United States

PubMed Central

Chihara, Dai; Ito, Hidemi; Matsuda, Tomohiro; Shibata, Akiko; Katsumi, Akira; Nakamura, Shigeo; Tomotaka, Sobue; Morton, Lindsay M; Weisenburger, Dennis D; Matsuo, Keitaro

2014-01-01

The incidence of a malignant disease reflects the genetic and cumulative exposure to the environment of a population. Therefore, evaluation of the incidence and trends of a disease in different populations may provide insights into its aetiology and pathogenesis. To evaluate the incidence of haematological malignancies according to specific subtypes, we used population-based registry data in Japan (N = 125 148) and the United States (US; N = 172 925) from 1993 to 2008. The age-adjusted incidence of haematological malignancies in Japan was approximately one-half that in the US but has been increasing significantly, whereas no significant change was seen in the US [annual percent change (95% C confidence interval): Japan, +2·4% (1·7, 3·1); US, +0·1% (−0·1, 0·2)]. Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) showed the largest differences in incidence, with the most remarkable differences observed for chronic lymphocytic leukaemia, HL-nodular sclerosis, mycosis fungoides and cutaneous T-cell lymphoma. HL and NHL are increasing substantially in Japan but not in the US, suggesting that environmental exposures, such as Westernization of the life style may be causing this increase. Differences in the incidence and trends for specific subtypes also showed a marked contrast across subtypes, which, in turn, may provide significant new insights into disease aetiology in the future. PMID:24245986

Genetic and environmental influences on relationship between anxiety sensitivity and anxiety subscales in children

PubMed Central

Waszczuk, M.A.; Zavos, H.M.S.; Eley, T.C.

2013-01-01

Anxiety sensitivity, a belief that symptoms of anxiety are harmful, has been proposed to influence development of panic disorder. Recent research suggests it may be a vulnerability factor for many anxiety subtypes. Moderate genetic influences have been implicated for both anxiety sensitivity and anxiety, however, little is known about the aetiology of the relationship between these traits in children. Self-reports of anxiety sensitivity and anxiety symptoms were collected from approximately 300 twin pairs at two time points. Partial correlations indicated that anxiety sensitivity at age 8 was broadly associated with most anxiety subtypes at age 10 (r = 0.11–0.17, p < 0.05). The associations were largely unidirectional, underpinned by stable genetic influences. Non-shared environment had unique influences on variables. Phenotypic results showed that anxiety sensitivity is a broad predictor of anxiety symptoms in childhood. Genetic results suggest that childhood is a developmental period characterised by genetic stability and time-specific environmental influences on anxiety-related traits. PMID:23872507

Genetic characterization of canine parvovirus type 2 subtypes in Maputo, Mozambique.

PubMed

Figueiredo, J; Miranda, C; Souto, R; Silva, E; Fafetine, J; Thompson, G

2017-05-01

Canine parvovirus type 2 (CPV-2) comprises three antigenic subtypes (2a, 2b and 2c) that have been reported in many countries. These subtypes cause serious disease in dogs with characteristic gastroenteritis signs. Little information has been documented in Africa about the genetic characterization of CPV-2. The aim of this study was to detect and to characterize the CPV-2 subtypes circulating in dogs admitted to Veterinary Clinics from two cities of Mozambique, Maputo and Matola, in 2010. A total of 40 field fecal samples were collected and tested for CPV-2 by polymerase chain reaction assay. The partial length VP2 gene of the positive samples were sequenced and genetically analyzed. Twenty-six (65%) fecal samples were positive for CPV-2. The restriction fragment length polymorphism analysis was also performed from positive samples and did not reveal the presence of CPV-2c subtype. The results of the sequencing revealed the presence of CPV-2a (n = 9) and CPV-2b (n = 17). No CPV-2 and CPV-2c were detected. Sequence analysis comparison showed nucleotide identities of 99.6-100% among our CPV-2 isolates. Amino acid analysis showed predicted amino acid changes. Phylogenetically, all of the CPV-2a strains isolated formed a cluster together with South African and Nigerian isolates. Most of Mozambican CPV-2b isolates also tended to cluster together with South African isolates; however, four were more closely related to French strain and one isolates to the American strain. The present study was the first to characterize the CPV-2 circulating in the Mozambican dog population.

Behavioral phenotype in adults with Prader-Willi syndrome.

PubMed

Sinnema, Margje; Einfeld, Stewart L; Schrander-Stumpel, Constance T R M; Maaskant, Marian A; Boer, Harm; Curfs, Leopold M G

2011-01-01

Prader-Willi syndrome (PWS) is characterized by temper tantrums, impulsivity, mood fluctuations, difficulty with change in routine, skinpicking, stubbornness and aggression. Many studies on behavior in PWS are limited by sample size, age range, a lack of genetically confirmed diagnosis of PWS and inconsistent assessment of behavior. The aim of this study was to explore systematically the relation between behavioral problems and age groups, genetic subtypes and BMI categories in an adult PWS population. Participants were contacted via the Dutch Prader-Willi Parent Association and through physicians specialized in persons with ID. Behaviors were studied using the Developmental Behavior Checklist for Adults (DBC-A). The forms were completed by the main caregivers of 98 adults with a genetically confirmed diagnosis of PWS. Differences between age groups were statistically significant (ANOVA, p=0.03). DBC-A total scores were higher in the consecutive age groups, with the most behavioral problems in the oldest age groups. Differences between genetic subtypes were also statistically significant (ANOVA, p<0.01). Persons with mUPD had higher total scores on the DBC-A than persons with a deletion. Those with a Type I deletion showed higher total DBC-A scores than persons with a Type II deletion. There were no statistically significant differences in DBC-A total scores between the different BMI categories. Individuals with a BMI<25 had higher scores on the self-absorbed subscale compared to persons with a BMI between 25 and 30. Unlike previous descriptions of the behavioral phenotype in adults with PWS, we did not find a reduction in behavioral problems in older adults. Therefore, special attention should be paid to behavioral problems as part of general management of adults with PWS. Longitudinal studies are warranted to gain more insight into the natural history and course of behavioral problems in adults and older people with PWS over the long term and possible risk and preventive factors. Copyright © 2010 Elsevier Ltd. All rights reserved.

Distinguishing Low-Risk Luminal A Breast Cancer Subtypes with Ki-67 and p53 Is More Predictive of Long-Term Survival

PubMed Central

Lee, Se Kyung; Bae, Soo Youn; Lee, Jun Ho; Lee, Hyun-Chul; Yi, Hawoo; Kil, Won Ho; Lee, Jeong Eon; Kim, Seok Won; Nam, Seok Jin

2015-01-01

Overexpression of p53 is the most frequent genetic alteration in breast cancer. Recently, many studies have shown that the expression of mutant p53 differs for each subtype of breast cancer and is associated with different prognoses. In this study, we aimed to determine the suitable cut-off value to predict the clinical outcome of p53 overexpression and its usefulness as a prognostic factor in each subtype of breast cancer, especially in luminal A breast cancer. Approval was granted by the Institutional Review Board of Samsung Medical Center. We analyzed a total of 7,739 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between Dec 1995 and Apr 2013. Luminal A subtype was defined as ER&PR + and HER2- and was further subclassified according to Ki-67 and p53 expression as follows: luminal A (Ki-67-,p53-), luminal A (Ki-67+, p53-), luminal A (Ki-67 -, p53+) and luminal A (Ki-67+, p53+). Low-risk luminal A subtype was defined as negative for both Ki-67 and p53 (luminal A [ki-67-, p53-]), and others subtypes were considered to be high-risk luminal A breast cancer. A cut-off value of 10% for p53 was a good predictor of clinical outcome in all patients and luminal A breast cancer patients. The prognostic role of p53 overexpression for OS and DFS was only significant in luminal A subtype. The combination of p53 and Ki-67 has been shown to have the best predictive power as calculated by the area under curve (AUC), especially for long-term overall survival. In this study, we have shown that overexpression of p53 and Ki-67 could be used to discriminate low-risk luminal A subtype in breast cancer. Therefore, using the combination of p53 and Ki-67 expression in discriminating low-risk luminal A breast cancer may improve the prognostic power and provide the greatest clinical utility. PMID:26241661

Distinguishing Low-Risk Luminal A Breast Cancer Subtypes with Ki-67 and p53 Is More Predictive of Long-Term Survival.

PubMed

Lee, Se Kyung; Bae, Soo Youn; Lee, Jun Ho; Lee, Hyun-Chul; Yi, Hawoo; Kil, Won Ho; Lee, Jeong Eon; Kim, Seok Won; Nam, Seok Jin

2015-01-01

Overexpression of p53 is the most frequent genetic alteration in breast cancer. Recently, many studies have shown that the expression of mutant p53 differs for each subtype of breast cancer and is associated with different prognoses. In this study, we aimed to determine the suitable cut-off value to predict the clinical outcome of p53 overexpression and its usefulness as a prognostic factor in each subtype of breast cancer, especially in luminal A breast cancer. Approval was granted by the Institutional Review Board of Samsung Medical Center. We analyzed a total of 7,739 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between Dec 1995 and Apr 2013. Luminal A subtype was defined as ER&PR + and HER2- and was further subclassified according to Ki-67 and p53 expression as follows: luminal A (Ki-67-,p53-), luminal A (Ki-67+, p53-), luminal A (Ki-67 -, p53+) and luminal A (Ki-67+, p53+). Low-risk luminal A subtype was defined as negative for both Ki-67 and p53 (luminal A [ki-67-, p53-]), and others subtypes were considered to be high-risk luminal A breast cancer. A cut-off value of 10% for p53 was a good predictor of clinical outcome in all patients and luminal A breast cancer patients. The prognostic role of p53 overexpression for OS and DFS was only significant in luminal A subtype. The combination of p53 and Ki-67 has been shown to have the best predictive power as calculated by the area under curve (AUC), especially for long-term overall survival. In this study, we have shown that overexpression of p53 and Ki-67 could be used to discriminate low-risk luminal A subtype in breast cancer. Therefore, using the combination of p53 and Ki-67 expression in discriminating low-risk luminal A breast cancer may improve the prognostic power and provide the greatest clinical utility.

Updated strategies for the management, pathogenesis and molecular genetics of different forms of ichthyosis syndromes with prominent hair abnormalities.

PubMed

Rasheed, Madiha; Shahzad, Shaheen; Zaeem, Afifa; Afzal, Imran; Gul, Asma; Khalid, Sumbal

2017-12-01

Syndromic ichthyosis is rare inherited disorders of cornification with varied disease complications. This disorder appears in seventeen subtypes associated with severe systematic manifestations along with medical, cosmetic and social problems. Syndromic ichthyosis with prominent hair abnormalities covers five major subtypes: Netherton syndrome, trichothiodystrophy, ichthyosis hypotrichosis syndrome, ichthyosis hypotrichosis sclerosing cholangitis and ichthyosis follicularis atrichia photophobia syndrome. These syndromes mostly prevail in high consanguinity states, with distinctive clinical features. The known pathogenic molecules involved in ichthyosis syndromes with prominent hair abnormalities include SPINK5, ERCC2, ERCC3, GTF2H5, MPLKIP, ST14, CLDN1 and MBTPS2. Despite underlying genetic origin, most of the health professionals solely rely on phenotypic expression of these disorders that leads to improper management of patients, hence making these patients living an orphanage life. After dermal features, association of other systems such as nervous system, skeletal system, hair abnormalities or liver problems may sometimes give clues for diagnosis but still leaving place for molecular screening for efficient diagnosis. In this paper, we have presented a review of ichthyosis syndrome with prominent hair abnormalities, with special emphasis on their updated genetic consequences and disease management. Additionally, we aim to update health professionals about the practice of molecular screening in ichthyosis syndromes for appropriate diagnosis and treatment.

Developmental Trajectories of DSM-IV Symptoms of Attention-Deficit/Hyperactivity Disorder: Genetic Effects, Family Risk and Associated Psychopathology

ERIC Educational Resources Information Center

Larsson, Henrik; Dilshad, Rezin; Lichtenstein, Paul; Barker, Edward D.

2011-01-01

Background: DSM-IV specifies three ADHD subtypes; the combined, the hyperactive-impulsive and the inattentive. Little is known about the developmental relationships underlying these subtypes. The objective of this study was to describe the development of parent-reported hyperactivity-impulsivity and inattention symptoms from childhood to…

Collaborative Analysis of DRD4 and DAT Genotypes in Population-Defined ADHD Subtypes

ERIC Educational Resources Information Center

Todd, Richard D.; Huang, Hongyan; Smalley, Susan L.; Nelson, Stanley F.; Willcutt, Erik G.; Pennington, Bruce F.; Smith, Shelley D.; Faraone, Stephen V.; Neuman, Rosalind J.

2005-01-01

Background: It has been proposed that some of the variability in reporting of associations between attention deficit hyperactivity disorder (ADHD) and candidate genes may result from mixing of genetically heterogeneous forms of ADHD using DSM-IV criteria. The goal of the current study is to test whether population-based ADHD subtypes defined by…

Genetically Diverse Low Pathogenicity Avian Influenza A Virus Subtypes Co-Circulate among Poultry in Bangladesh.

PubMed

Gerloff, Nancy A; Khan, Salah Uddin; Zanders, Natosha; Balish, Amanda; Haider, Najmul; Islam, Ausraful; Chowdhury, Sukanta; Rahman, Mahmudur Ziaur; Haque, Ainul; Hosseini, Parviez; Gurley, Emily S; Luby, Stephen P; Wentworth, David E; Donis, Ruben O; Sturm-Ramirez, Katharine; Davis, C Todd

2016-01-01

Influenza virus surveillance, poultry outbreak investigations and genomic sequencing were assessed to understand the ecology and evolution of low pathogenicity avian influenza (LPAI) A viruses in Bangladesh from 2007 to 2013. We analyzed 506 avian specimens collected from poultry in live bird markets and backyard flocks to identify influenza A viruses. Virus isolation-positive specimens (n = 50) were subtyped and their coding-complete genomes were sequenced. The most frequently identified subtypes among LPAI isolates were H9N2, H11N3, H4N6, and H1N1. Less frequently detected subtypes included H1N3, H2N4, H3N2, H3N6, H3N8, H4N2, H5N2, H6N1, H6N7, and H7N9. Gene sequences were compared to publicly available sequences using phylogenetic inference approaches. Among the 14 subtypes identified, the majority of viral gene segments were most closely related to poultry or wild bird viruses commonly found in Southeast Asia, Europe, and/or northern Africa. LPAI subtypes were distributed over several geographic locations in Bangladesh, and surface and internal protein gene segments clustered phylogenetically with a diverse number of viral subtypes suggesting extensive reassortment among these LPAI viruses. H9N2 subtype viruses differed from other LPAI subtypes because genes from these viruses consistently clustered together, indicating this subtype is enzootic in Bangladesh. The H9N2 strains identified in Bangladesh were phylogenetically and antigenically related to previous human-derived H9N2 viruses detected in Bangladesh representing a potential source for human infection. In contrast, the circulating LPAI H5N2 and H7N9 viruses were both phylogenetically and antigenically unrelated to H5 viruses identified previously in humans in Bangladesh and H7N9 strains isolated from humans in China. In Bangladesh, domestic poultry sold in live bird markets carried a wide range of LPAI virus subtypes and a high diversity of genotypes. These findings, combined with the seven year timeframe of sampling, indicate a continuous circulation of these viruses in the country.

Genetically Diverse Low Pathogenicity Avian Influenza A Virus Subtypes Co-Circulate among Poultry in Bangladesh

PubMed Central

Gerloff, Nancy A.; Khan, Salah Uddin; Zanders, Natosha; Balish, Amanda; Haider, Najmul; Islam, Ausraful; Chowdhury, Sukanta; Rahman, Mahmudur Ziaur; Haque, Ainul; Hosseini, Parviez; Gurley, Emily S.; Luby, Stephen P.; Wentworth, David E.; Donis, Ruben O.; Sturm-Ramirez, Katharine; Davis, C. Todd

2016-01-01

Influenza virus surveillance, poultry outbreak investigations and genomic sequencing were assessed to understand the ecology and evolution of low pathogenicity avian influenza (LPAI) A viruses in Bangladesh from 2007 to 2013. We analyzed 506 avian specimens collected from poultry in live bird markets and backyard flocks to identify influenza A viruses. Virus isolation-positive specimens (n = 50) were subtyped and their coding-complete genomes were sequenced. The most frequently identified subtypes among LPAI isolates were H9N2, H11N3, H4N6, and H1N1. Less frequently detected subtypes included H1N3, H2N4, H3N2, H3N6, H3N8, H4N2, H5N2, H6N1, H6N7, and H7N9. Gene sequences were compared to publicly available sequences using phylogenetic inference approaches. Among the 14 subtypes identified, the majority of viral gene segments were most closely related to poultry or wild bird viruses commonly found in Southeast Asia, Europe, and/or northern Africa. LPAI subtypes were distributed over several geographic locations in Bangladesh, and surface and internal protein gene segments clustered phylogenetically with a diverse number of viral subtypes suggesting extensive reassortment among these LPAI viruses. H9N2 subtype viruses differed from other LPAI subtypes because genes from these viruses consistently clustered together, indicating this subtype is enzootic in Bangladesh. The H9N2 strains identified in Bangladesh were phylogenetically and antigenically related to previous human-derived H9N2 viruses detected in Bangladesh representing a potential source for human infection. In contrast, the circulating LPAI H5N2 and H7N9 viruses were both phylogenetically and antigenically unrelated to H5 viruses identified previously in humans in Bangladesh and H7N9 strains isolated from humans in China. In Bangladesh, domestic poultry sold in live bird markets carried a wide range of LPAI virus subtypes and a high diversity of genotypes. These findings, combined with the seven year timeframe of sampling, indicate a continuous circulation of these viruses in the country. PMID:27010791

Nonallelic heterogeneity in autosomal dominant retinitis pigmentosa with incomplete penetrance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, S.K.; Berson, E.L.; Dryja, T.P.

1994-08-01

Retinitis pigmentosa is a group of retinal diseases in which photoreceptor cells throughout the retina degenerate. Although there is considerable genetic heterogeneity (autosomal dominant, autosomal recessive, and X-linked forms exist), there is a possibility that some clinically defined subtypes of the disease may be the result of mutations at the same locus. One possible clinically defined subtype is that of autosomal dominant retinitis pigmentosa (ADRP) with incomplete penetrance. Whereas in most families with ADRP, carriers can be clearly identified because of visual loss, ophthalmological findings, or abnormal electroretinograms (ERGs), in occasional families some obligate carriers are asymptomatic and have normalmore » or nearly normal ERGs even late in life. A recent paper reported the mapping of the diseases locus in one pedigree (designated adRP7) with ADRP with incomplete penetrance to chromosome 7p. To test the idea that ADRP with incomplete penetrance may be genetically homogeneous, we have evaluated whether a different family with incomplete penetrance also has a disease gene linked to the same region. 4 refs., 1 fig., 1 tab.« less

Epigenetic and genetic diagnosis of Silver-Russell syndrome.

PubMed

Eggermann, Thomas; Spengler, Sabrina; Gogiel, Magdalena; Begemann, Matthias; Elbracht, Miriam

2012-06-01

Silver-Russell syndrome (SRS) is a congenital imprinting disorder characterized by intrauterine and postnatal growth restriction and further characteristic features. SRS is genetically heterogenous: 7-10% of patients carry a maternal uniparental disomy of chromosome 7; >38% show a hypomethylation in imprinting control region 1 in 11p15; and a further class of mutations are copy number variations affecting different chromosomes, but mainly 11p15 and 7. The diagnostic work-up should thus aim to detect these three molecular subtypes. Numerous techniques are currently applied in genetic SRS testing, but none of them covers all known (epi)mutations, and they should therefore be used synergistically. However, future next-generation sequencing approaches will allow a comprehensive analysis of all types of alterations in SRS.

Cryptosporidiosis outbreak in a child day-care center caused by an unusual Cryptosporidium hominis subtype.

PubMed

Goñi, Pilar; Almagro-Nievas, Diego; Cieloszyk, Joanna; Lóbez, Silvia; Navarro-Marí, José María; Gutiérrez-Fernández, José

2015-12-01

This work describes the genetic characterization of Cryptosporidium and Giardia involved in an outbreak in a nursery school in Granada, Spain, that affected seven children under the age of 4. Nucleic acids were extracted from the seven stool samples positive to Cryptosporidium or Giardia by microscopy and/or immunochromatography. The species and subtypes of Cryptosporidium were identified by PCR-RFLP and PCR of the SSUrRNA and gp60 genes, respectively. The assemblages of Giardia duodenalis isolates were characterized by PCR of the tpi gene. PCR products were sequenced and analyzed. All of the isolates were positive for Cryptosporidium hominis. Five of them belonged to subtype IaA11R2, one to subtype IbA10G2R2, and the other could not be identified. Three of these samples were positive for G. duodenalis by PCR, two belonging to the assemblage A, and the other one to assemblage B. This is the first report of Cryptosporidium hominis subtype IaA11R2 as a cause of an outbreak in Europe where subtype IbA10G2R2 is the most frequently identified. In the case of Giardia, an outbreak could not be confirmed because of the low number of positive samples and the low genetic variability of the amplified fragments for assemblage A of tpi gene. A new subtype, of Cryptosporidium hominis named IaA11R2, has been described as a cause of an outbreak in a nursery school in Granada, Spain. However an outbreak of giardiasis could not be confirmed. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Nucleic acid amplification of HIV-1 integrase sequence subtypes CRF01_AE and B for development of HIV anti-integrase drug resistance genotyping assay

NASA Astrophysics Data System (ADS)

Adlar, F. R.; Bela, B.

2017-08-01

To anticipate the potential use of anti-integrase drugs in Indonesia for treatment of HIV-1 infection, the development of a drug resistance genotyping assay for anti-integrase is crucial in identifying the genetic drug resistance profile of Indonesian HIV-1 strains. This experiment aimed to amplify a target region in the integrase gene of Indonesian HIV-1 subtypes CRF01_AE and B that contain genetic mutations known to confer resistance to anti-integrase drug. Eleven archived plasma samples from individuals living with HIV-1 were obtained from the Virology and Cancer Pathobiology Research Center for Health Service (VCPRC FKUI-RSCM) laboratory. One of the plasma samples contained HIV-1 subtype B, and the remaining plasma samples contained subtype CRF01_AE. The target regions for all samples were amplified through RT-PCR, with an annealing temperature of 55 °C, using the primer pair AE_POL 4086F and AE_POL 5232R that were designed by VCPRC FKUI-RSCM. The results of this experiment show that 18.2% (2/11) of the samples were successfully amplified using the one-step RT-PCR. While the primer pair was effective in amplifying the target region in the integrase gene sequence for subtype B (100%; 1/1), it had a low efficacy (10%, 1/10) for subtype CRF01_AE. In conclusion, the primer pair can be used to amplify the target region in Indonesian HIV-1 strain subtypes CRF01_AE and B. However, optimization of the PCR condition and an increased number of samples would help to determine an accurate representation of the efficacy of the primer pair.

A 5-year course of predominantly obsessive vs. mixed subtypes of obsessive-compulsive disorder

PubMed Central

Math, S. B.; Thoduguli, Jaideep; Janardhan Reddy, Y. C.; Manoj, P. N.; Zutshi, A.; Rajkumar, R. P.; Adarsh, A. M.

2007-01-01

Background: Obsessive-compulsive disorder (OCD) is considered a heterogeneous disorder. One of the traditional approaches to subtype OCD is based on the predominance of obsessions, compulsions or both. Some studies suggest that the “predominantly obsessive” subtype of OCD may have poor outcome, whereas few other studies suggest that “mixed” OCD is associated with poor outcome. Therefore, it is not clear if the long-term course of “predominantly obsessive” subjects is different from those with “mixed” OCD. In the establishment of diagnostic validity of psychiatric conditions, differential course is an important validating factor. Aim: This study compares the 5-6 year course of the “predominantly obsessive” subtype with that of the “mixed” subtype of OCD with the objective of determining if the course of OCD differs according to subtypes and whether course could be a validating factor for subtyping OCD based on predominance of obsessions, compulsions or both. Setting and Design: Tertiary hospital, institutional setting. The study has a retrospective cohort design. Materials and Methods: Fifty-four subjects with “predominantly obsessions” and an equal number of the “mixed” subtype of OCD were recruited from the database of a specialty OCD clinic of a major psychiatric hospital. They were followed up after 5-6 years. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) checklist and severity rating scale was used for assessing OCD. The course of OCD was determined according to predefined criteria. Statistics: The Chi-square/Fisher's exact test and the independent samples “t” test were used to compare categorical and continuous variables, respectively. Correlations were tested using the Pearson's correlation analysis. Results: Thirty-eight “predominantly obsessive” (70%) and 39 “mixed” (72%) OCD subjects could be traced and evaluated. The course of illness was similar in the two subtypes. A majority of the sample (72%) did not have clinical OCD at follow-up. Conclusions: “Predominantly obsessive” subjects have a course similar to those with “mixed” OCD. Clinically, it is reassuring to know that obsessive subjects do not have an unfavorable course as was suggested by some previous studies. In this sample, course did not validate the subtyping method employed, but it would be premature to conclude that the subtyping method employed is incorrect based on the course alone. Prospective study of the course in larger samples and neurobiological and family-genetic data may help further validation. PMID:20680136

Describing the genetic architecture of epilepsy through heritability analysis.

PubMed

Speed, Doug; O'Brien, Terence J; Palotie, Aarno; Shkura, Kirill; Marson, Anthony G; Balding, David J; Johnson, Michael R

2014-10-01

Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

Molecular epidemiology of Mycobacterium avium subsp. paratuberculosis isolated from sheep, cattle and deer on New Zealand pastoral farms.

PubMed

Verdugo, Cristobal; Pleydell, Eve; Price-Carter, Marian; Prattley, Deborah; Collins, Desmond; de Lisle, Geoffrey; Vogue, Hinrich; Wilson, Peter; Heuer, Cord

2014-12-01

The present study aimed to describe the molecular diversity of Mycobacterium avium subsp. paratuberculosis (MAP) isolates obtained from sheep, cattle (beef and dairy) and deer farms in New Zealand. A total of 206 independent MAP isolates (15 beef cattle, 89 dairy cattle, 35 deer, 67 sheep) were sourced from 172 species-mobs (15 beef cattle, 66 dairy cattle, 31 deer, 60 sheep). Seventeen subtypes were identified, using a combination of variable number of tandem repeats (VNTR) and short sequence repeat (SSR) methods. Rarefaction analysis, analysis of molecular variance (AMOVA), Fst pairwise comparisons and proportional similarity index (PSI) were used to describe subtype population richness, genetic structure and potential associations between livestock sectors and New Zealand two main islands (North and South). The rarefaction analysis suggests a significantly higher subtype richness in dairy cattle herds when compared to the other livestock sectors. AMOVA results indicate that the main source of subtype variation is attributable to the livestock sector from which samples were sourced suggesting that subtypes are generally sector-specific. The pairwise Fst results were similar, with low Fst values for island differences within a livestock sector when compared to between sector analyses, representing a low subtype differentiation between islands. However, for a given island, potential associations were seen between dominant subtypes and specific livestock sectors. Three subtypes accounted for 76% of the isolates. The most common of these was isolated from sheep and beef cattle in the North Island, the second most frequent subtype was mainly isolated from dairy cattle (either island), while the third most common subtype was associated with deer farmed in the South Island. The PSI analysis suggests similarities in subtypes sourced from sheep and beef cattle. This contrasted with the isolates sourced from other livestock sectors, which tended to present sector-specific subtypes. Sheep and beef cattle were mainly infected with MAP Type I, while dairy cattle and deer were almost exclusively infected with MAP Type II. However, when beef cattle and deer were both present at farm level, they harboured similar subtypes. This study indicates that cross-species transmission of MAP occurs on New Zealand farms although close contact between species appears to be required, as in the case of sheep and beef cattle which are commonly grazed together in New Zealand. Copyright © 2014 Elsevier B.V. All rights reserved.

Epstein-Barr virus-positive gastric cancer: a distinct molecular subtype of the disease?

PubMed

Jácome, Alexandre Andrade Dos Anjos; Lima, Enaldo Melo de; Kazzi, Ana Izabela; Chaves, Gabriela Freitas; Mendonça, Diego Cavalheiro de; Maciel, Marina Mara; Santos, José Sebastião Dos

2016-04-01

Approximately 90% of the world population is infected by Epstein-Barr virus (EBV). Usually, it infects B lymphocytes, predisposing them to malignant transformation. Infection of epithelial cells occurs rarely, and it is estimated that about to 10% of gastric cancer patients harbor EBV in their malignant cells. Given that gastric cancer is the third leading cause of cancer-related mortality worldwide, with a global annual incidence of over 950,000 cases, EBV-positive gastric cancer is the largest group of EBV-associated malignancies. Based on gene expression profile studies, gastric cancer was recently categorized into four subtypes; EBV-positive, microsatellite unstable, genomically stable and chromosomal instability. Together with previous studies, this report provided a more detailed molecular characterization of gastric cancer, demonstrating that EBV-positive gastric cancer is a distinct molecular subtype of the disease, with unique genetic and epigenetic abnormalities, reflected in a specific phenotype. The recognition of characteristic molecular alterations in gastric cancer allows the identification of molecular pathways involved in cell proliferation and survival, with the potential to identify therapeutic targets. These findings highlight the enormous heterogeneity of gastric cancer, and the complex interplay between genetic and epigenetic alterations in the disease, and provide a roadmap to implementation of genome-guided personalized therapy in gastric cancer. The present review discusses the initial studies describing EBV-positive gastric cancer as a distinct clinical entity, presents recently described genetic and epigenetic alterations, and considers potential therapeutic insights derived from the recognition of this new molecular subtype of gastric adenocarcinoma.

Neuronal cell fate specification by the molecular convergence of different spatio-temporal cues on a common initiator terminal selector gene

PubMed Central

Stratmann, Johannes

2017-01-01

The extensive genetic regulatory flows underlying specification of different neuronal subtypes are not well understood at the molecular level. The Nplp1 neuropeptide neurons in the developing Drosophila nerve cord belong to two sub-classes; Tv1 and dAp neurons, generated by two distinct progenitors. Nplp1 neurons are specified by spatial cues; the Hox homeotic network and GATA factor grn, and temporal cues; the hb -> Kr -> Pdm -> cas -> grh temporal cascade. These spatio-temporal cues combine into two distinct codes; one for Tv1 and one for dAp neurons that activate a common terminal selector feedforward cascade of col -> ap/eya -> dimm -> Nplp1. Here, we molecularly decode the specification of Nplp1 neurons, and find that the cis-regulatory organization of col functions as an integratory node for the different spatio-temporal combinatorial codes. These findings may provide a logical framework for addressing spatio-temporal control of neuronal sub-type specification in other systems. PMID:28414802

Inter- and Intra-subtype genotypic differences that differentiate Mycobacterium avium subspecies paratuberculosis strains

PubMed Central

2012-01-01

Background Mycobacterium avium subspecies paratuberculosis (Map) is the aetiological agent of Johne’s disease or paratuberculosis and is included within the Mycobacterium avium complex (MAC). Map strains are of two major types often referred to as ‘Sheep’ or ‘S-type’ and ‘Cattle’ or ‘C-type’. With the advent of more discriminatory typing techniques it has been possible to further classify the S-type strains into two groups referred to as Type I and Type III. This study was undertaken to genotype a large panel of S-type small ruminant isolates from different hosts and geographical origins and to compare them with a large panel of well documented C-type isolates to assess the genetic diversity of these strain types. Methods used included Mycobacterial Interspersed Repetitive Units - Variable-Number Tandem Repeat analysis (MIRU-VNTR), analysis of Large Sequence Polymorphisms by PCR (LSP analysis), Single Nucleotide Polymorphism (SNP) analysis of gyr genes, Pulsed-Field Gel Electrophoresis (PFGE) and Restriction Fragment Length Polymorphism analysis coupled with hybridization to IS900 (IS900-RFLP) analysis. Results The presence of LSPA4 and absence of LSPA20 was confirmed in all 24 Map S-type strains analysed. SNPs within the gyr genes divided the S-type strains into types I and III. Twenty four PFGE multiplex profiles and eleven different IS900-RFLP profiles were identified among the S-type isolates, some of them not previously published. Both PFGE and IS900-RFLP segregated the S-type strains into types I and III and the results concurred with those of the gyr SNP analysis. Nine MIRU-VNTR genotypes were identified in these isolates. MIRU-VNTR analysis differentiated Map strains from other members of Mycobacterium avium Complex, and Map S-type from C-type but not type I from III. Pigmented Map isolates were found of type I or III. Conclusion This is the largest panel of S-type strains investigated to date. The S-type strains could be further divided into two subtypes, I and III by some of the typing techniques (IS900-RFLP, PFGE and SNP analysis of the gyr genes). MIRU-VNTR did not divide the strains into the subtypes I and III but did detect genetic differences between isolates within each of the subtypes. Pigmentation is not exclusively associated with type I strains. PMID:23164429

Comparison of Three Different Hepatitis C Virus Genotyping Methods: 5'NCR PCR-RFLP, Core Type-Specific PCR, and NS5b Sequencing in a Tertiary Care Hospital in South India.

PubMed

Daniel, Hubert D-J; David, Joel; Raghuraman, Sukanya; Gnanamony, Manu; Chandy, George M; Sridharan, Gopalan; Abraham, Priya

2017-05-01

Based on genetic heterogeneity, hepatitis C virus (HCV) is classified into seven major genotypes and 64 subtypes. In spite of the sequence heterogeneity, all genotypes share an identical complement of colinear genes within the large open reading frame. The genetic interrelationships between these genes are consistent among genotypes. Due to this property, complete sequencing of the HCV genome is not required. HCV genotypes along with subtypes are critical for planning antiviral therapy. Certain genotypes are also associated with higher progression to liver cirrhosis. In this study, 100 blood samples were collected from individuals who came for routine HCV genotype identification. These samples were used for the comparison of two different genotyping methods (5'NCR PCR-RFLP and HCV core type-specific PCR) with NS5b sequencing. Of the 100 samples genotyped using 5'NCR PCR-RFLP and HCV core type-specific PCR, 90% (κ = 0.913, P < 0.00) and 96% (κ = 0.794, P < 0.00) correlated with NS5b sequencing, respectively. Sixty percent and 75% of discordant samples by 5'NCR PCR-RFLP and HCV core type-specific PCR, respectively, belonged to genotype 6. All the HCV genotype 1 subtypes were classified accurately by both the methods. This study shows that the 5'NCR-based PCR-RFLP and the HCV core type-specific PCR-based assays correctly identified HCV genotypes except genotype 6 from this region. Direct sequencing of the HCV core region was able to identify all the genotype 6 from this region and serves as an alternative to NS5b sequencing. © 2016 Wiley Periodicals, Inc.

Genomic and epigenomic heterogeneity in molecular subtypes of gastric cancer.

PubMed

Lim, Byungho; Kim, Jong-Hwan; Kim, Mirang; Kim, Seon-Young

2016-01-21

Gastric cancer is a complex disease that is affected by multiple genetic and environmental factors. For the precise diagnosis and effective treatment of gastric cancer, the heterogeneity of the disease must be simplified; one way to achieve this is by dividing the disease into subgroups. Toward this effort, recent advances in high-throughput sequencing technology have revealed four molecular subtypes of gastric cancer, which are classified as Epstein-Barr virus-positive, microsatellite instability, genomically stable, and chromosomal instability subtypes. We anticipate that this molecular subtyping will help to extend our knowledge for basic research purposes and will be valuable for clinical use. Here, we review the genomic and epigenomic heterogeneity of the four molecular subtypes of gastric cancer. We also describe a mutational meta-analysis and a reanalysis of DNA methylation that were performed using previously reported gastric cancer datasets.

Virological Surveillance of Influenza A Subtypes Isolated in 2014 from Clinical Outbreaks in Canadian Swine

PubMed Central

Grgić, Helena; Gallant, Jackie; Poljak, Zvonimir

2017-01-01

Influenza A viruses (IAVs) are respiratory pathogens associated with an acute respiratory disease that occurs year-round in swine production. It is currently one of the most important pathogens in swine populations, with the potential to infect other host species including humans. Ongoing research indicates that the three major subtypes of IAV—H1N1, H1N2, and H3N2—continue to expand in their genetic and antigenic diversity. In this study, we conducted a comprehensive genomic analysis of 16 IAVs isolated from different clinical outbreaks in Alberta, Manitoba, Ontario, and Saskatchewan in 2014. We also examined the genetic basis for probable antigenic differences among sequenced viruses. On the basis of phylogenetic analysis, all 13 Canadian H3N2 viruses belonged to cluster IV, eight H3N2 viruses were part of the IV-C cluster, and one virus belonged to the IV-B and one to the IV-D cluster. Based on standards used in this study, three H3N2 viruses could not be clearly classified into any currently established group within cluster IV (A to F). Three H1N2 viruses were part of the H1α cluster. PMID:28335552

Brain Cancer Stem Cells in Adults and Children: Cell Biology and Therapeutic Implications.

PubMed

Abou-Antoun, Tamara J; Hale, James S; Lathia, Justin D; Dombrowski, Stephen M

2017-04-01

Brain tumors represent some of the most malignant cancers in both children and adults. Current treatment options target the majority of tumor cells but do not adequately target self-renewing cancer stem cells (CSCs). CSCs have been reported to resist the most aggressive radiation and chemotherapies, and give rise to recurrent, treatment-resistant secondary malignancies. With advancing technologies, we now have a better understanding of the genetic, epigenetic and molecular signatures and microenvironmental influences which are useful in distinguishing between distinctly different tumor subtypes. As a result, efforts are now underway to identify and target CSCs within various tumor subtypes based on this foundation. This review discusses progress in CSC biology as it relates to targeted therapies which may be uniquely different between pediatric and adult brain tumors. Studies to date suggest that pediatric brain tumors may benefit more from genetic and epigenetic targeted therapies, while combination treatments aimed specifically at multiple molecular pathways may be more effective in treating adult brain tumors which seem to have a greater propensity towards microenvironmental interactions. Ultimately, CSC targeting approaches in combination with current clinical therapies have the potential to be more effective owing to their ability to compromise CSCs maintenance and the mechanisms which underlie their highly aggressive and deadly nature.

Autoimmune mechanisms in myasthenia gravis.

PubMed

Cavalcante, Paola; Bernasconi, Pia; Mantegazza, Renato

2012-10-01

This article reviews recent findings on factors and mechanisms implicated in the pathogenesis of myasthenia gravis and briefly summarizes data on therapies acting at various stages of the autoimmune process. Data published over the last year promise to improve understanding of pathogenic mechanisms underlying myasthenia gravis. Animal studies have at last shown that antimuscle-specific kinase (MuSK) autoantibodies, like antiacetylcholine receptor (AChR) autoantibodies, are myasthenogenic. A new autoantigen, the low-density lipoprotein receptor-related protein 4 (LRP4), has been identified in variable proportions of otherwise seronegative patients. Anti-LRP4 antibodies may define a new myasthenia gravis subtype, supporting the concept that myasthenia gravis is not a single disease entity, and that different subtypes can differ in aetiology. Genetic and environmental factors are implicated in myasthenia gravis. The finding of persisting viral infection in the thymus of AChR-myasthenia gravis patients, combined with data on chronic inflammation, suggest that pathogens may favour intrathymic AChR-specific autosensitization and maintenance of autoimmunity in genetically susceptible individuals. Defective immunoregulatory mechanisms, involving pathogenic Th17 and regulatory T cells, contribute to tolerance loss and perpetuation of the autoimmune response in myasthenia gravis patients. The recent identification of mechanisms initiating and perpetuating autoimmunity in myasthenia gravis may stimulate the development of more effective therapies.

Apparent founder effect during the early years of the San Francisco HIV type 1 epidemic (1978-1979).

PubMed

Foley, B; Pan, H; Buchbinder, S; Delwart, E L

2000-10-10

HIV-1 envelope sequence variants were RT-PCR amplified from serum samples cryopreserved in San Francisco in 1978-1979. The HIV-1 subtype B env V3-V5 sequences from four homosexual men clustered phylogenetically, with a median nucleotide distance of 2.8%, reflecting a recent common origin. These early U.S. HIV-1 env variants mapped close to the phylogenetic root of the subtype B tree while env variants collected in the United States throughout the 1980s and 1990s showed, on average, increasing genetic diversity and divergence from the subtype B consensus sequence. These results indicate that the majority of HIV-1 currently circulating in the United States may be descended from an initial introduction and rapid spread during the mid- to late 1970s of subtype B viruses with limited variability (i.e., a founder effect). As expected from the starburst-shaped phylogeny of HIV-1 subtype B, contemporary U.S. strains were, on average, more closely related at the nucleic acid and amino acid levels to the earlier 1978-1979 env variants than to each other. The growing levels of HIV-1 genetic diversity, one of multiple obstacles in designing a protective vaccine, may therefore be mitigated by using epidemic founding variants as antigenic strains for protection against contemporary strains.

Lower genetic variability of HIV-1 and antiretroviral drug resistance in pregnant women from the state of Pará, Brazil.

PubMed

Machado, Luiz Fernando Almeida; Costa, Iran Barros; Folha, Maria Nazaré; da Luz, Anderson Levy Bessa; Vallinoto, Antonio Carlos Rosário; Ishak, Ricardo; Ishak, Marluisa Oliveira Guimarães

2017-04-12

The present study aimed to describe the genetic diversity of HIV-1, as well as the resistance profile of the viruses identified in HIV-1 infected pregnant women under antiretroviral therapy in the state of Pará, Northern Brazil. Blood samples were collected from 45 HIV-1 infected pregnant to determine the virus subtypes according to the HIV-1 protease (PR) gene and part of the HIV-1 reverse transcriptase (RT) gene by sequencing the nucleotides of these regions. Drug resistance mutations and susceptibility to antiretroviral drugs were analyzed by the Stanford HIV Drug Resistance Database. Out of 45 samples, only 34 could be amplified for PR and 30 for RT. Regarding the PR gene, subtypes B (97.1%) and C (2.9%) were identified; for the RT gene, subtypes B (90.0%), F (6.7%), and C (3.3%) were detected. Resistance to protease inhibitors (PI) was identified in 5.8% of the pregnant, and mutations conferring resistance to nucleoside reverse transcriptase inhibitors were found in 3.3%, while mutations conferring resistance to non-nucleoside reverse transcriptase inhibitors were found in 3.3%. These results showed a low frequency of strains resistant to antiretroviral drugs, the prevalence of subtypes B and F, and the persistent low transmission of subtype C in pregnant of the state of Pará, Brazil.

Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing.

PubMed

Carlson, Jenna C; Taub, Margaret A; Feingold, Eleanor; Beaty, Terri H; Murray, Jeffrey C; Marazita, Mary L; Leslie, Elizabeth J

2017-07-17

Orofacial clefts (OFCs), including nonsyndromic cleft lip with or without cleft palate (NSCL/P), are common birth defects. NSCL/P is highly heterogeneous with multiple phenotypic presentations. Two common subtypes of NSCL/P are cleft lip (CL) and cleft lip with cleft palate (CLP) which have different population prevalence. Similarly, NSCL/P can be divided into bilateral and unilateral clefts, with unilateral being the most common. Individuals with unilateral NSCL/P are more likely to be affected on the left side of the upper lip, but right side affection also occurs. Moreover, NSCL/P is twice as common in males as in females. The goal of this study is to discover genetic variants that have different effects in case subgroups. We conducted both common variant and rare variant analyses in 1034 individuals of Asian ancestry with NSCL/P, examining four sources of heterogeneity within CL/P: cleft type, sex, laterality, and side. We identified several regions associated with subtype differentiation: cleft type differences in 8q24 (p = 1.00 × 10 -4 ), laterality differences in IRF6, a gene previously implicated with wound healing (p = 2.166 × 10 -4 ), sex differences and side of unilateral CL differences in FGFR2 (p = 3.00 × 10 -4 ; p = 6.00 × 10 -4 ), and sex differences in VAX1 (p < 1.00 × 10 -4 ) among others. Many of the regions associated with phenotypic modification were either adjacent to or overlapping functional elements based on ENCODE chromatin marks and published craniofacial enhancers. We have identified multiple common and rare variants as potential phenotypic modifiers of NSCL/P, and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs. Birth Defects Research 109:1030-1038, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Panic disorder respiratory subtype: psychopathology, laboratory challenge tests, and response to treatment.

PubMed

Freire, Rafael C; Perna, Giampaolo; Nardi, Antonio E

2010-01-01

Our objective is to summarize the new findings concerning the respiratory subtype (RS) of panic disorder (PD) since its first description. Two searches were made in the Institute for Scientific Information Web of Science: with the keywords "panic disorder" and "respiratory symptoms," and all articles that cited Briggs and colleagues' 1993 article "Subtyping of Panic Disorder by Symptom Profile" (Br J Psychiatry 1993;163:201-9). Altogether, 133 articles were reviewed. We describe and discuss RS epidemiology, genetics, psychopathology, demographic features, clinical features, correlations with the respiratory system, traumatic suffocation history, provocative tests, and nocturnal panic. Compared to patients with the nonrespiratory subtype (non-RS), the RS patients had higher familial history of PD, lower comorbidity with depression, longer duration of illness, lower neuroticism scores, and higher scores in severity scales, such as the Panic and Agoraphobia Scale, Panic-Agoraphobia Spectrum scale and the Clinical Global Impression scale. Tests to induce panic attacks, such as those with CO(2), hyperventilation, and caffeine, produce panic attacks in a higher proportion of RS patients than non-RS patients. Differences in the subtypes' improvement with the pharmacologic treatment were found. There are also some controversial findings regarding the RS, including the age of onset of PD, and alcohol and tobacco use in RS patients. Some characteristics, such as the increased sensitivity to CO(2) and the higher familial history of PD, clearly distinguish the RS from the non-RS. Nevertheless, there are also controversial findings. More studies are needed to determine the validity of the RS subtype.

Second Malignancy Risks After Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: Differences by Lymphoma Subtype

PubMed Central

Morton, Lindsay M.; Curtis, Rochelle E.; Linet, Martha S.; Bluhm, Elizabeth C.; Tucker, Margaret A.; Caporaso, Neil; Ries, Lynn A.G.; Fraumeni, Joseph F.

2010-01-01

Purpose Previous studies have shown increased risks of second malignancies after non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, no earlier investigation has quantified differences in risk of new malignancy by lymphoma subtype. Patients and Methods We evaluated second cancer and leukemia risks among 43,145 1-year survivors of CLL/small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL) from 11 Surveillance, Epidemiology, and End Results (SEER) population-based registries during 1992 to 2006. Results Among patients without HIV/AIDS–related lymphoma, lung cancer risks were significantly elevated after CLL/SLL and FL but not after DLBCL (standardized incidence ratio [SIR], CLL/SLL = 1.42, FL = 1.28, DLBCL = 1.00; Poisson regression P for difference among subtypes, PDiff = .001). A similar pattern was observed for risk of cutaneous melanoma (SIR: CLL/SLL = 1.92, FL = 1.60, DLBCL = 1.06; PDiff = .004). Acute nonlymphocytic leukemia risks were significantly elevated after FL and DLBCL, particularly among patients receiving initial chemotherapy, but not after CLL/SLL (SIR: CLL/SLL = 1.13, FL = 5.96, DLBCL = 4.96; PDiff < .001). Patients with HIV/AIDS–related lymphoma (n = 932) were predominantly diagnosed with DLBCL and had significantly and substantially elevated risks for second anal cancer (SIR = 120.50) and Kaposi's sarcoma (SIR = 138.90). Conclusion Our findings suggest that differing immunologic alterations, treatments (eg, alkylating agent chemotherapy), genetic susceptibilities, and other risk factors (eg, viral infections, tobacco use) among lymphoma subtypes contribute to the patterns of second malignancy risk. Elucidating these patterns may provide etiologic clues to lymphoma as well as to the second malignancies. PMID:20940199

Genetic Risk for Conduct Disorder Symptom Subtypes in an ADHD Sample: Specificity to Aggressive Symptoms

ERIC Educational Resources Information Center

Monuteaux, Michael C.; Biederman, Joseph; Doyle, Alysa E.; Mick, Eric; Faraone, Stephen V.

2009-01-01

Four hundred forty-four subjects aged 6-55 years were evaluated to examine the role of COMT and SLC6A4 genes in the risk for conduct disorder and its symptomatic subtypes in the context of attention deficit hyperactivity disorder. No significant association is found between these genes and the risk for conduct disorder.

Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey.

PubMed

Butler, Merlin G; Manzardo, Ann M; Heinemann, Janalee; Loker, Carolyn; Loker, James

2017-06-01

Prader-Willi syndrome (PWS) is a rare, complex, neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans and leads to a shortened life expectancy. This report summarizes the primary causes of death and evaluates mortality trends in a large cohort of individuals with PWS. The US Prader-Willi Syndrome Association (PWSA (USA)) syndrome-specific database of death reports was collected through a cursory bereavement program for PWSA (USA) families using a brief survey created in 1999. Causes of death were descriptively characterized and statistically examined using Cox proportional hazards. A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015, with mean age of 29.5 ± 16 years (2 months-67 years); 70% occurred in adulthood. Respiratory failure was the most common cause, accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries and cardiopulmonary factors compared to females. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype. These findings highlight the heightened vulnerability to obesity and hyperphagia-related mortality in PWS. Future research is needed to address critical vulnerabilities such as gender and genetic subtype in the cause of death in PWS.Genet Med advance online publication 17 November 2016.

Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial.

PubMed

Aung, Kyaw L; Fischer, Sandra E; Denroche, Robert E; Jang, Gun-Ho; Dodd, Anna; Creighton, Sean; Southwood, Bernadette; Liang, Sheng-Ben; Chadwick, Dianne; Zhang, Amy; O'Kane, Grainne M; Albaba, Hamzeh; Moura, Shari; Grant, Robert C; Miller, Jessica K; Mbabaali, Faridah; Pasternack, Danielle; Lungu, Ilinca M; Bartlett, John M S; Ghai, Sangeet; Lemire, Mathieu; Holter, Spring; Connor, Ashton A; Moffitt, Richard A; Yeh, Jen Jen; Timms, Lee; Krzyzanowski, Paul M; Dhani, Neesha; Hedley, David; Notta, Faiyaz; Wilson, Julie M; Moore, Malcolm J; Gallinger, Steven; Knox, Jennifer J

2018-03-15

Purpose: To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection. Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Results: Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype ( P = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients. Conclusions: Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. Clin Cancer Res; 24(6); 1344-54. ©2017 AACR . ©2017 American Association for Cancer Research.

Evidence of at Least Two Introductions of HIV-1 in the Amerindian Warao Population from Venezuela

PubMed Central

Rangel, Héctor R.; Maes, Mailis; Villalba, Julian; Sulbarán, Yoneira; de Waard, Jacobus H.; Bello, Gonzalo; Pujol, Flor H.

2012-01-01

Background The Venezuelan Amerindians were, until recently, free of human immunodeficiency virus (HIV) infection. However, in 2007, HIV-1 infection was detected for the first time in the Warao Amerindian population living in the Eastern part of Venezuela, in the delta of the Orinoco river. The aim of this study was to analyze the genetic diversity of the HIV-1 circulating in this population. Methodology/Principal Findings The pol genomic region was sequenced for 16 HIV-1 isolates and for some of them, sequences from env, vif and nef genomic regions were obtained. All HIV-1 isolates were classified as subtype B, with exception of one that was classified as subtype C. The 15 subtype B isolates exhibited a high degree of genetic similarity and formed a highly supported monophyletic cluster in each genomic region analyzed. Evolutionary analyses of the pol genomic region indicated that the date of the most recent common ancestor of the Waraos subtype B clade dates back to the late 1990s. Conclusions/Significance At least two independent introductions of HIV-1 have occurred in the Warao Amerindians from Venezuela. The HIV-1 subtype B was successfully established and got disseminated in the community, while no evidence of local dissemination of the HIV-1 subtype C was detected in this study. These results warrant further surveys to evaluate the burden of this disease, which can be particularly devastating in this Amerindian population, with a high prevalence of tuberculosis, hepatitis B, among other infectious diseases, and with limited access to primary health care. PMID:22808212

Peripheral Neuropathy in Spinocerebellar Ataxia Type 1, 2, 3, and 6.

PubMed

Linnemann, Christoph; Tezenas du Montcel, Sophie; Rakowicz, Maryla; Schmitz-Hübsch, Tanja; Szymanski, Sandra; Berciano, Jose; van de Warrenburg, Bart P; Pedersen, Karine; Depondt, Chantal; Rola, Rafal; Klockgether, Thomas; García, Antonio; Mutlu, Gurkan; Schöls, Ludger

2016-04-01

Spinocerebellar ataxias (SCAs) are characterized by autosomal dominantly inherited progressive ataxia but are clinically heterogeneous due to variable involvement of non-cerebellar parts of the nervous system. Non-cerebellar symptoms contribute significantly to the burden of SCAs, may guide the clinician to the underlying genetic subtype, and might be useful markers to monitor disease. Peripheral neuropathy is frequently observed in SCA, but subtype-specific features and subclinical manifestations have rarely been evaluated. We performed a multicenter nerve conduction study with 162 patients with genetically confirmed SCA1, SCA2, SCA3, and SCA6. The study proved peripheral nerves to be involved in the neurodegenerative process in 82 % of SCA1, 63 % of SCA2, 55 % of SCA3, and 22 % of SCA6 patients. Most patients of all subtypes revealed affection of both sensory and motor fibers. Neuropathy was most frequently of mixed type with axonal and demyelinating characteristics in all SCA subtypes. However, nerve conduction velocities of SCA1 patients were slower compared to other genotypes. SCA6 patients revealed less axonal damage than patients with other subtypes. No influence of CAG repeat length or biometric determinants on peripheral neuropathy could be identified in SCA1, SCA3, and SCA6. In SCA2, earlier onset and more severe ataxia were associated with peripheral neuropathy. We proved peripheral neuropathy to be a frequent site of the neurodegenerative process in all common SCA subtypes. Since damage to peripheral nerves is readily assessable by electrophysiological means, nerve conduction studies should be performed in a longitudinal approach to assess these parameters as potential progression markers.

Development of a clinical diagnostic matrix for characterizing inherited epidermolysis bullosa.

PubMed

Yenamandra, V K; Moss, C; Sreenivas, V; Khan, M; Sivasubbu, S; Sharma, V K; Sethuraman, G

2017-06-01

Accurately diagnosing the subtype of epidermolysis bullosa (EB) is critical for management and genetic counselling. Modern laboratory techniques are largely inaccessible in developing countries, where the diagnosis remains clinical and often inaccurate. To develop a simple clinical diagnostic tool to aid in the diagnosis and subtyping of EB. We developed a matrix indicating presence or absence of a set of distinctive clinical features (as rows) for the nine most prevalent EB subtypes (as columns). To test an individual patient, presence or absence of these features was compared with the findings expected in each of the nine subtypes to see which corresponded best. If two or more diagnoses scored equally, the diagnosis with the greatest number of specific features was selected. The matrix was tested using findings from 74 genetically characterized patients with EB aged > 6 months by an investigator blinded to molecular diagnosis. For concordance, matrix diagnoses were compared with molecular diagnoses. Overall, concordance between the matrix and molecular diagnoses for the four major types of EB was 91·9%, with a kappa coefficient of 0·88 [95% confidence interval (CI) 0·81-0·95; P < 0·001]. The matrix achieved a 75·7% agreement in classifying EB into its nine subtypes, with a kappa coefficient of 0·73 (95% CI 0·69-0·77; P < 0·001). The matrix appears to be simple, valid and useful in predicting the type and subtype of EB. An electronic version will facilitate further testing. © 2016 British Association of Dermatologists.

The Genetic Diversity and Evolution of HIV-1 Subtype B Epidemic in Puerto Rico.

PubMed

López, Pablo; Rivera-Amill, Vanessa; Rodríguez, Nayra; Vargas, Freddie; Yamamura, Yasuhiro

2015-12-23

HIV-1 epidemics in Caribbean countries, including Puerto Rico, have been reported to be almost exclusively associated with the subtype B virus (HIV-1B). However, while HIV infections associated with other clades have been only sporadically reported, no organized data exist to accurately assess the prevalence of non-subtype B HIV-1 infection. We analyzed the nucleotide sequence data of the HIV pol gene associated with HIV isolates from Puerto Rican patients. The sequences (n = 945) were obtained from our "HIV Genotyping" test file, which has been generated over a period of 14 years (2001-2014). REGA subtyping tool found the following subtypes: B (90%), B-like (3%), B/D recombinant (6%), and D/B recombinant (0.6%). Though there were fewer cases, the following subtypes were also found (in the given proportions): A1B (0.3%), BF1 (0.2%), subtype A (01-AE) (0.1%), subtype A (A2) (0.1%), subtype F (12BF) (0.1%), CRF-39 BF-like (0.1%), and others (0.1%). Some of the recombinants were identified as early as 2001. Although the HIV epidemic in Puerto Rico is primarily associated with HIV-1B virus, our analysis uncovered the presence of other subtypes. There was no indication of subtype C, which has been predominantly associated with heterosexual transmission in other parts of the world.

Sex linked versus autosomal inbreeding coefficient in close consanguineous marriages in the Basque country and Castile (Spain): genetic implications.

PubMed

Calderón, R; Morales, B; Peña, J A; Delgado, J

1995-10-01

Pedigree structures of 161 uncle/niece-aunt/nephew and 4420 first cousin consanguineous marriages registered during the 19th and 20th centuries in two large and very different Spanish regions have been analysed and their genetic consequences evaluated. The frequencies of the different pedigree subtypes within each degree of relationship were quite similar in both populations despite significant heterogeneity in inbreeding patterns. The mean X-linked inbreeding coefficient (Fx) for each type of cousin mating was calculated and compared to that expected for autosomal genes (F). The effect of genealogical structure on the Fx/F ratio was compared to different cultural populations worldwide. Preferentiality and avoidance of close consanguinity along with specific types of pedigrees are discussed on the basis of premarital migration and sociocultural rules still deeply rooted in certain human groups. By admitting that the observed Fx coefficient is usually higher than F in most human populations some remarks have been made in terms of population genetic risk.

Automated subtyping of HIV-1 genetic sequences for clinical and surveillance purposes: performance evaluation of the new REGA version 3 and seven other tools.

PubMed

Pineda-Peña, Andrea-Clemencia; Faria, Nuno Rodrigues; Imbrechts, Stijn; Libin, Pieter; Abecasis, Ana Barroso; Deforche, Koen; Gómez-López, Arley; Camacho, Ricardo J; de Oliveira, Tulio; Vandamme, Anne-Mieke

2013-10-01

To investigate differences in pathogenesis, diagnosis and resistance pathways between HIV-1 subtypes, an accurate subtyping tool for large datasets is needed. We aimed to evaluate the performance of automated subtyping tools to classify the different subtypes and circulating recombinant forms using pol, the most sequenced region in clinical practice. We also present the upgraded version 3 of the Rega HIV subtyping tool (REGAv3). HIV-1 pol sequences (PR+RT) for 4674 patients retrieved from the Portuguese HIV Drug Resistance Database, and 1872 pol sequences trimmed from full-length genomes retrieved from the Los Alamos database were classified with statistical-based tools such as COMET, jpHMM and STAR; similarity-based tools such as NCBI and Stanford; and phylogenetic-based tools such as REGA version 2 (REGAv2), REGAv3, and SCUEAL. The performance of these tools, for pol, and for PR and RT separately, was compared in terms of reproducibility, sensitivity and specificity with respect to the gold standard which was manual phylogenetic analysis of the pol region. The sensitivity and specificity for subtypes B and C was more than 96% for seven tools, but was variable for other subtypes such as A, D, F and G. With regard to the most common circulating recombinant forms (CRFs), the sensitivity and specificity for CRF01_AE was ~99% with statistical-based tools, with phylogenetic-based tools and with Stanford, one of the similarity based tools. CRF02_AG was correctly identified for more than 96% by COMET, REGAv3, Stanford and STAR. All the tools reached a specificity of more than 97% for most of the subtypes and the two main CRFs (CRF01_AE and CRF02_AG). Other CRFs were identified only by COMET, REGAv2, REGAv3, and SCUEAL and with variable sensitivity. When analyzing sequences for PR and RT separately, the performance for PR was generally lower and variable between the tools. Similarity and statistical-based tools were 100% reproducible, but this was lower for phylogenetic-based tools such as REGA (~99%) and SCUEAL (~96%). REGAv3 had an improved performance for subtype B and CRF02_AG compared to REGAv2 and is now able to also identify all epidemiologically relevant CRFs. In general the best performing tools, in alphabetical order, were COMET, jpHMM, REGAv3, and SCUEAL when analyzing pure subtypes in the pol region, and COMET and REGAv3 when analyzing most of the CRFs. Based on this study, we recommend to confirm subtyping with 2 well performing tools, and be cautious with the interpretation of short sequences. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Genetic characterisation of novel, highly pathogenic avian influenza (HPAI) H5N6 viruses isolated in birds, South Korea, November 2016

PubMed Central

Si, Young-Jae; Lee, In Won; Kim, Eun-Ha; Kim, Young-Il; Kwon, Hyeok-Il; Park, Su-Jin; Nguyen, Hiep Dinh; Kim, Se Mi; Kwon, Jin-Jung; Choi, Won-Suk; Beak, Yun Hee; Song, Min-Suk; Kim, Chul-Joong; Webby, Richard J.; Choi, Young-Ki

2017-01-01

A novel genotype of H5N6 influenza viruses was isolated from migratory birds in South Korea during November 2016. Domestic outbreaks of this virus were associated with die-offs of wild birds near reported poultry cases in Chungbuk province, central South Korea. Genetic analysis and animal studies demonstrated that the Korean H5N6 viruses are highly pathogenic avian influenza (HPAI) viruses and that these viruses are novel reassortants of at least three different subtypes (H5N6, H4N2 and H1N1). PMID:28079520

NS3 protease polymorphisms and genetic barrier to drug resistance of distinct hepatitis C virus genotypes from worldwide treatment-naïve subjects.

PubMed

Vidal, L L; Soares, M A; Santos, A F

2016-11-01

Hepatitis C virus (HCV) NS3 protease inhibitors have been primarily designed against genotype 1, the one with the lowest response to dual therapy. However, less evidence of their efficacy on non-1 genotypes is available, and any such information is mostly concentrated on genotypes 2-4. This study evaluated HCV protease resistance profiles in the major six HCV genotypes and identified genetic barrier (GB) profiles to each available protease inhibitor across HCV strains from different locations worldwide. We obtained 15 099 HCV sequences from treatment-naïve subjects retrieved at the Los Alamos HCV Sequence Database. The wild-type codons of different HCV genotypes were used to analyse the smallest number of nucleotide substitution steps required for changing that codon to the closest one associated with drug resistance. The 36L and 175L RAVs were found as genetic signatures of genotypes 2-5, while the 80K RAV was found in all genotype 5 sequences. Genotypes 4 and 6 showed a higher GB to RAV mutations conferring resistance to telaprevir, while genotypes 2-5 presented baseline resistance to that drug, carrying the 36L mutation. Genotype 4 had a higher GB to simeprevir resistance, requiring three substitutions to acquire the 155K mutation. Subtype 1b showed a higher GB than subtype 1a to resistance for most PIs, with RAVs at codons 36 and 155. Geographic disparities were also found in frequencies of certain RAVs in genotypes 2 and 3. Under a scenario of unprecedented evolution of anti-HCV direct-acting agents, the genetic composition of the circulating HCV sequences should be evaluated worldwide to choose the most appropriate/feasible therapeutic schemes with the highest genetic barriers to resistance. © 2016 John Wiley & Sons Ltd.

Novel reassortant H9N2 viruses in pigeons and evidence for antigenic diversity of H9N2 viruses isolated from quails in Egypt.

PubMed

Kandeil, Ahmed; El-Shesheny, Rabeh; Maatouq, Asmaa; Moatasim, Yassmin; Cai, Zhipeng; McKenzie, Pamela; Webby, Richard; Kayali, Ghazi; Ali, Mohamed A

2017-04-01

The endemicity of avian influenza viruses (AIVs) among Egyptian poultry represents a public health risk. Co-circulation of low pathogenic AIV H9N2 subtype with highly pathogenic AIV H5N1 subtype in Egyptian farms provides a possibility to generate novel reassortant viruses. Here, the genetic characteristics of surface glycoproteins of 59 Egyptian H9N2 viruses, isolated between 2013 and 2015, were analysed. To elucidate the potential of genetic reassortment, 10 H9N2 isolates were selected based on different avian hosts (chickens, ducks, pigeons and quails) and phylogenetic analyses of their full genome sequences were conducted. Additionally, we performed antigenic analysis to further investigate the antigenic evolution of H9N2 viruses isolated during 2011-2015. Different viral characteristics including receptor-binding affinity and drug resistance of representative Egyptian H9N2 viruses were further investigated. The surface glycoproteins of current Egyptian H9N2 viruses were closely related to viruses of the G1-like lineage isolated from Egypt. Several genetic markers that enhance virulence in poultry and transmission to humans were detected. Analysis of the full genome of 10 H9N2 isolates indicated that two pigeon isolates inherited five internal genes from Eurasian AIVs circulating in wild birds. Antigenic conservation of different Egyptian H9N2 isolates from chickens, pigeons and ducks was observed, whereas quail isolates showed antigenic drift. The Egyptian H9N2 viruses preferentially bound to the human-like receptor rather than to the avian-like receptor. Our results suggest that the endemic H9N2 viruses in Egypt contain elements that may favour avian-to-human transmission and thus represent a public health risk.

Divergent structural brain abnormalities between different genetic subtypes of children with Prader-Willi syndrome.

PubMed

Lukoshe, Akvile; White, Tonya; Schmidt, Marcus N; van der Lugt, Aad; Hokken-Koelega, Anita C

2013-10-22

Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with symptoms that indicate not only hypothalamic, but also a global, central nervous system (CNS) dysfunction. However, little is known about developmental differences in brain structure in children with PWS. Thus, our aim was to investigate global brain morphology in children with PWS, including the comparison between different genetic subtypes of PWS. In addition, we performed exploratory cortical and subcortical focal analyses. High resolution structural magnetic resonance images were acquired in 20 children with genetically confirmed PWS (11 children carrying a deletion (DEL), 9 children with maternal uniparental disomy (mUPD)), and compared with 11 age- and gender-matched typically developing siblings as controls. Brain morphology measures were obtained using the FreeSurfer software suite. Both children with DEL and mUPD showed smaller brainstem volume, and a trend towards smaller cortical surface area and white matter volume. Children with mUPD had enlarged lateral ventricles and larger cortical cerebrospinal fluid (CSF) volume. Further, a trend towards increased cortical thickness was found in children with mUPD. Children with DEL had a smaller cerebellum, and smaller cortical and subcortical grey matter volumes. Focal analyses revealed smaller white matter volumes in left superior and bilateral inferior frontal gyri, right cingulate cortex, and bilateral precuneus areas associated with the default mode network (DMN) in children with mUPD. Children with PWS show signs of impaired brain growth. Those with mUPD show signs of early brain atrophy. In contrast, children with DEL show signs of fundamentally arrested, although not deviant brain development and presented few signs of cortical atrophy. Our results of global brain measurements suggest divergent neurodevelopmental patterns in children with DEL and mUPD.

Divergent structural brain abnormalities between different genetic subtypes of children with Prader–Willi syndrome

PubMed Central

2013-01-01

Background Prader–Willi syndrome (PWS) is a complex neurogenetic disorder with symptoms that indicate not only hypothalamic, but also a global, central nervous system (CNS) dysfunction. However, little is known about developmental differences in brain structure in children with PWS. Thus, our aim was to investigate global brain morphology in children with PWS, including the comparison between different genetic subtypes of PWS. In addition, we performed exploratory cortical and subcortical focal analyses. Methods High resolution structural magnetic resonance images were acquired in 20 children with genetically confirmed PWS (11 children carrying a deletion (DEL), 9 children with maternal uniparental disomy (mUPD)), and compared with 11 age- and gender-matched typically developing siblings as controls. Brain morphology measures were obtained using the FreeSurfer software suite. Results Both children with DEL and mUPD showed smaller brainstem volume, and a trend towards smaller cortical surface area and white matter volume. Children with mUPD had enlarged lateral ventricles and larger cortical cerebrospinal fluid (CSF) volume. Further, a trend towards increased cortical thickness was found in children with mUPD. Children with DEL had a smaller cerebellum, and smaller cortical and subcortical grey matter volumes. Focal analyses revealed smaller white matter volumes in left superior and bilateral inferior frontal gyri, right cingulate cortex, and bilateral precuneus areas associated with the default mode network (DMN) in children with mUPD. Conclusions Children with PWS show signs of impaired brain growth. Those with mUPD show signs of early brain atrophy. In contrast, children with DEL show signs of fundamentally arrested, although not deviant brain development and presented few signs of cortical atrophy. Our results of global brain measurements suggest divergent neurodevelopmental patterns in children with DEL and mUPD. PMID:24144356

Genetic susceptibility to bilateral tinnitus in a Swedish twin cohort.

PubMed

Maas, Iris Lianne; Brüggemann, Petra; Requena, Teresa; Bulla, Jan; Edvall, Niklas K; Hjelmborg, Jacob V B; Szczepek, Agnieszka J; Canlon, Barbara; Mazurek, Birgit; Lopez-Escamez, Jose A; Cederroth, Christopher R

2017-09-01

Genetic contributions to tinnitus have been difficult to determine due to the heterogeneity of the condition and its broad etiology. Here, we evaluated the genetic and nongenetic influences on self-reported tinnitus from the Swedish Twin Registry (STR). Cross-sectional data from the STR was obtained. Casewise concordance rates (the risk of one twin being affected given that his/her twin partner has tinnitus) were compared for monozygotic (MZ) and dizygotic (DZ) twin pairs (N = 10,464 concordant and discordant twin pairs) and heritability coefficients (the proportion of the total variance attributable to genetic factors) were calculated using biometrical model fitting procedures. Stratification of tinnitus cases into subtypes according to laterality (unilateral versus bilateral) revealed that heritability of bilateral tinnitus was 0.56; however, it was 0.27 for unilateral tinnitus. Heritability was greater in men (0.68) than in women (0.41). However, when female pairs younger than 40 years of age were selected, heritability of 0.62 was achieved with negligible effects of shared environment. Unlike unilateral tinnitus, bilateral tinnitus is influenced by genetic factors and might constitute a genetic subtype. Overall, our study provides the initial evidence for a tinnitus phenotype with a genetic influence.Genet Med advance online publication 23 March 2017.

Subtyping of STEC by MLVA in Argentina

PubMed Central

Bustamante, Ana V.; Sanso, Andrea M.; Parma, Alberto E.; Lucchesi, Paula M. A.

2012-01-01

Shiga toxin-producing Escherichia coli (STEC) causes serious human illness such as hemolytic uremic syndrome (HUS). Argentina has the world’s highest rate of this syndrome, which is the leading cause of acute renal failure among children. E. coli O157:H7 is the most common cause of HUS, but a substantial and growing proportion of this illness is caused by infection due to non-O157 strains. Multiple-locus variable-number tandem repeat analysis (MLVA) has become an established technique to subtype STEC. This review will address the use of routine STEC subtyping by MLVA in order to type this group of isolates and to get insight into the genetic diversity of native STEC. With regard to these objectives we modified and adapted two MLVA protocols, one exclusive for O157 and the other, a generic E. coli assay. A total of 202 STEC isolates, from different sources and corresponding to 20 serotypes, have been MLVA genotyped in our laboratory. In our experience, MLVA constitutes a very sensitive tool and enables us to perform an efficient STEC subtyping. The diversity found in many serotypes may be useful for future epidemiological studies of STEC clonality, applied to O157 as well as to non-O157 isolates. PMID:22919698

[An overview on swine influenza viruses].

PubMed

Yang, Shuai; Zhu, Wen-Fei; Shu, Yue-Long

2013-05-01

Swine influenza viruses (SIVs) are respiratory pathogens of pigs. They cause both economic bur den in livestock-dependent industries and serious global public health concerns in humans. Because of their dual susceptibility to human and avian influenza viruses, pigs are recognized as intermediate hosts for genetic reassortment and interspecies transmission. Subtypes H1N1, H1N2, and H3N2 circulate in swine populations around the world, with varied origin and genetic characteristics among different continents and regions. In this review, the role of pigs in evolution of influenza A viruses, the genetic evolution of SIVs and interspecies transmission of SIVs are described. Considering the possibility that pigs might produce novel influenza viruses causing more outbreaks and pandemics, routine epidemiological surveillance of influenza viruses in pig populations is highly recommended.

Cell type of origin as well as genetic alterations contribute to breast cancer phenotypes

PubMed Central

West, William W.; Qiu, Fang; Band, Hamid; Band, Vimla

2015-01-01

Breast cancer is classified into different subtypes that are associated with different patient survival outcomes, underscoring the importance of understanding the role of precursor cell and genetic alterations in determining tumor subtypes. In this study, we evaluated the oncogenic phenotype of two distinct mammary stem/progenitor cell types designated as K5+/K19− or K5+/K19+ upon introduction of identical combinations of oncogenes-mutant H-Ras (mRas) and mutant p53 (mp53), together with either wild-type ErbB2(wtErbB2) or wild-type EGFR (wtEGFR). We examined their tumor forming and metastasis potential, using both in-vitro and in-vivo assays. Both the combinations efficiently transformed K5+/K19− or K5+/K19+ cells. Xenograft tumors formed by these cells were histologically heterogeneous, with variable proportions of luminal, basal-like and claudin-low type components depending on the cell types and oncogene combinations. Notably, K5+/K19− cells transformed with mRas/mp53/wtEGFR combination had a significantly longer latency for primary tumor development than other cell lines but more lung metastasis incidence than same cells expressing mRas/mp53/wtErbB2. K5+/K19+ cells exhibit shorter overall tumor latency, and high metastatic potential than K5+/K19− cells, suggesting that these K19+ progenitors are more susceptible to oncogenesis and metastasis. Our results suggest that both genetic alterations and cell type of origin contribute to oncogenic phenotype of breast tumors. PMID:25940703

An Investigation of Executive Function Abilities in Adults with Praderwilli Syndrome

ERIC Educational Resources Information Center

Walley, R. M.; Donaldson, M. D. C.

2005-01-01

Background: PraderWilli syndrome (PWS) is a genetic disorder caused by the absence of expression of maternally imprinted genes on the long arm of chromosome 15 (15q 11-13). There are two main genetic sub-types: (1) deletion, caused by the absence of paternally derived genetic material; and (2) uniparental disomy (UPD), where two copies of…

Human genetics as a tool to identify progranulin regulators.

PubMed

Nicholson, Alexandra M; Finch, NiCole A; Rademakers, Rosa

2011-11-01

Frontotemporal lobar degeneration (FTLD) is a common neurodegenerative disorder that predominantly affects individuals under the age of 65. It is known that the most common pathological subtype is FTLD with TAR DNA-binding protein 43 inclusions (FTLD-TDP). FTLD has a strong genetic component with about 50% of cases having a positive family history. Mutations identified in the progranulin gene (GRN) have been shown to cause FTLD-TDP as a result of progranulin haploinsufficiency. These findings suggest a progranulin-dependent mechanism in this pathological FTLD subtype. Thus, identifying regulators of progranulin levels is essential for new therapies and treatments for FTLD and related disorders. In this review, we discuss the role of genetic studies in identifying progranulin regulators, beginning with the discovery of pathogenic GRN mutations and additional GRN risk variants. We also cover more recent genetic advances, including the detection of variants in the transmembrane protein 106 B gene that increase FTLD-TDP risk presumably by modulating progranulin levels and the identification of a potential progranulin receptor, sortilin. This review highlights the importance of genetic studies in the context of FTLD and further emphasizes the need for future genetic and cell biology research to continue the effort in finding a cure for progranulin-related diseases.

CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.

PubMed

Candido, Juliana B; Morton, Jennifer P; Bailey, Peter; Campbell, Andrew D; Karim, Saadia A; Jamieson, Thomas; Lapienyte, Laura; Gopinathan, Aarthi; Clark, William; McGhee, Ewan J; Wang, Jun; Escorcio-Correia, Monica; Zollinger, Raphael; Roshani, Rozita; Drew, Lisa; Rishi, Loveena; Arkell, Rebecca; Evans, T R Jeffry; Nixon, Colin; Jodrell, Duncan I; Wilkinson, Robert W; Biankin, Andrew V; Barry, Simon T; Balkwill, Frances R; Sansom, Owen J

2018-05-01

Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Family History of Cancer in Benign Brain Tumor Subtypes Versus Gliomas

PubMed Central

Ostrom, Quinn T.; McCulloh, Christopher; Chen, Yanwen; Devine, Karen; Wolinsky, Yingli; Davitkov, Perica; Robbins, Sarah; Cherukuri, Rajesh; Patel, Ashokkumar; Gupta, Rajnish; Cohen, Mark; Barrios, Jaime Vengoechea; Brewer, Cathy; Schilero, Cathy; Smolenski, Kathy; McGraw, Mary; Denk, Barbara; Naska, Theresa; Laube, Frances; Steele, Ruth; Greene, Dale; Kastl, Alison; Bell, Susan; Aziz, Dina; Chiocca, E. A.; McPherson, Christopher; Warnick, Ronald; Barnett, Gene H.; Sloan, Andrew E.; Barnholtz-Sloan, Jill S.

2012-01-01

Purpose: Family history is associated with gliomas, but this association has not been established for benign brain tumors. Using information from newly diagnosed primary brain tumor patients, we describe patterns of family cancer histories in patients with benign brain tumors and compare those to patients with gliomas. Methods: Newly diagnosed primary brain tumor patients were identified as part of the Ohio Brain Tumor Study. Each patient was asked to participate in a telephone interview about personal medical history, family history of cancer, and other exposures. Information was available from 33 acoustic neuroma (65%), 78 meningioma (65%), 49 pituitary adenoma (73.1%), and 152 glioma patients (58.2%). The association between family history of cancer and each subtype was compared with gliomas using unconditional logistic regression models generating odds ratios (ORs) and 95% confidence intervals. Results: There was no significant difference in family history of cancer between patients with glioma and benign subtypes. Conclusion: The results suggest that benign brain tumor may have an association with family history of cancer. More studies are warranted to disentangle the potential genetic and/or environmental causes for these diseases. PMID:22649779

Evolution of a reassortant North American gull influenza virus lineage: drift, shift and stability

USGS Publications Warehouse

Hall, Jeffrey S.; TeSlaa, Joshua L.; Nashold, Sean W.; Halpin, Rebecca A.; Stockwell, Timothy; Wentworth, David E.; Dugan, Vivien; Ip, Hon S.

2013-01-01

Background: The role of gulls in the ecology of avian influenza (AI) is different than that of waterfowl. Different constellations of subtypes circulate within the two groups of birds and AI viruses isolated from North American gulls frequently possess reassortant genomes with genetic elements from both North America and Eurasian lineages. A 2008 isolate from a Newfoundland Great Black-backed Gull contained a mix of North American waterfowl, North American gull and Eurasian lineage genes. Methods: We isolated, sequenced and phylogenetically compared avian influenza viruses from 2009 Canadian wild birds. Results: We analyzed six 2009 virus isolates from Canada and found the same phylogenetic lineage had persisted over a larger geographic area, with an expanded host range that included dabbling and diving ducks as well as gulls. All of the 2009 virus isolates contained an internal protein coding set of genes of the same Eurasian lineage genes except PB1 that was from a North American lineage, and these genes continued to evolve by genetic drift. We show evidence that the 2008 Great Black-backed Gull virus was derived from this lineage with a reassortment of a North American PA gene into the more stable core set of internal protein coding genes that has circulated in avian populations for at least 2 years. From this core, the surface glycoprotein genes have switched several times creating H13N6, H13N2, and H16N3 subtypes. These gene segments were from North American lineages except for the H16 and N3 vRNAs. Conclusions: This process appears similar to genetic shifts seen with swine influenza where a stable "triple reassortant internal gene" core has circulated in swine populations with genetic shifts occurring with hemaggluttinin and neuraminidase proteins getting periodically switched. Thus gulls may serve as genetic mixing vessels for different lineages of avian influenza, similar to the role of swine with regards to human influenza. These findings illustrate the need for continued surveillance in gull and waterfowl populations, both on the Pacific and especially Atlantic coasts of North America, to document virus intercontinental movement and the role of gull species in the evolution and epidemiology of AI.

[Medulloblastoma. Pathology].

PubMed

Siegfried, A; Delisle, M-B

2018-04-24

Medulloblastomas, embryonal neuroepithelial tumors developed in the cerebellum or brain stem, are mainly observed in childhood. The treatment of WHO-Grade IV tumors depends on stratifications that are usually based on postoperative data, histopathological subtype, tumor extension and presence of MYC or NMYC amplifications. Recently, molecular biology studies, based on new technologies (i.e. sequencing, transcriptomic, methylomic) have introduced genetic subtypes integrated into the latest WHO-2016 neuropathological classification. According to this classification, the three genetic groups WNT, SHH, with or without mutated TP53 gene, and non-WNT/non-SHH, comprising subgroups 3 and 4, are recalled in this review. The contribution of immunohistochemistry to define these groups is specified. The four histopathological groups are detailed in comparison to the WHO-2007 classification and the molecular data: classic medulloblastoma, desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity, and large cell/anaplastic medulloblastoma. The groups defined on genetic and histopathological grounds are not strictly concordant. Depending on the age of the patients, their correlations are different, as well as their role in the management and prognosis of these tumors. Other embryonal tumors, for which new classifications are in progress and gliomas may be confused with a medulloblastoma and the elements of the differential diagnosis of these entities are discussed. This evolution in classification fully justifies ongoing structuring procedures such as histopathological review (RENOCLIP) and the organization of molecular biology platforms. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Genetically encoding a light switch in an ionotropic glutamate receptor reveals subunit-specific interfaces.

PubMed

Zhu, Shujia; Riou, Morgane; Yao, C Andrea; Carvalho, Stéphanie; Rodriguez, Pamela C; Bensaude, Olivier; Paoletti, Pierre; Ye, Shixin

2014-04-22

Reprogramming receptors to artificially respond to light has strong potential for molecular studies and interrogation of biological functions. Here, we design a light-controlled ionotropic glutamate receptor by genetically encoding a photoreactive unnatural amino acid (UAA). The photo-cross-linker p-azido-L-phenylalanine (AzF) was encoded in NMDA receptors (NMDARs), a class of glutamate-gated ion channels that play key roles in neuronal development and plasticity. AzF incorporation in the obligatory GluN1 subunit at the GluN1/GluN2B N-terminal domain (NTD) upper lobe dimer interface leads to an irreversible allosteric inhibition of channel activity upon UV illumination. In contrast, when pairing the UAA-containing GluN1 subunit with the GluN2A subunit, light-dependent inactivation is completely absent. By combining electrophysiological and biochemical analyses, we identify subunit-specific structural determinants at the GluN1/GluN2 NTD dimer interfaces that critically dictate UV-controlled inactivation. Our work reveals that the two major NMDAR subtypes differ in their ectodomain-subunit interactions, in particular their electrostatic contacts, resulting in GluN1 NTD coupling more tightly to the GluN2B NTD than to the GluN2A NTD. It also paves the way for engineering light-sensitive ligand-gated ion channels with subtype specificity through the genetic code expansion.

Pseudoxanthoma elasticum: similar autosomal recessive subtype in Belgian and Afrikaner families.

PubMed

De Paepe, A; Viljoen, D; Matton, M; Beighton, P; Lenaerts, V; Vossaert, K; De Bie, S; Voet, D; De Laey, J J; Kint, A

1991-01-01

A multidisciplinary survey of the clinical and genetic characteristics of 26 Belgian and 32 Afrikaner families with biopsy-proven pseudoxanthoma elasticum (PXE) was undertaken. The major PXE phenotype emerging from this study is very similar in both patient groups and is characterized by severe ophthalmologic manifestations with variable, mild cutaneous and vascular symptoms. In the families with more than one affected relative, segregation analysis is compatible with autosomal recessive inheritance in both groups. It is suggested that the PXE phenotype of these Belgian and Afrikaner patients is distinct from the other recognized PXE subtypes. The phenotypic resemblance in both patient groups raises the question whether a similar genetic mechanism is involved.

Genetically Diverse Low Pathogenicity Avian Influenza A Virus Subtypes Co-Circulate among Poultry in Bangladesh

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerloff, Nancy A.; Khan, Salah Uddin; Zanders, Natosha

Influenza virus surveillance, poultry outbreak investigations and genomic sequencing were assessed to understand the ecology and evolution of low pathogenicity avian influenza (LPAI) A viruses in Bangladesh from 2007 to 2013. We analyzed 506 avian specimens collected from poultry in live bird markets and backyard flocks to identify influenza A viruses. Virus isolation-positive specimens (n = 50) were subtyped and their coding-complete genomes were sequenced. The most frequently identified subtypes among LPAI isolates were H9N2, H11N3, H4N6, and H1N1. Less frequently detected subtypes included H1N3, H2N4, H3N2, H3N6, H3N8, H4N2, H5N2, H6N1, H6N7, and H7N9. Gene sequences were compared tomore » publicly available sequences using phylogenetic inference approaches. Among the 14 subtypes identified, the majority of viral gene segments were most closely related to poultry or wild bird viruses commonly found in Southeast Asia, Europe, and/or northern Africa. LPAI subtypes were distributed over several geographic locations in Bangladesh, and surface and internal protein gene segments clustered phylogenetically with a diverse number of viral subtypes suggesting extensive reassortment among these LPAI viruses. H9N2 subtype viruses differed from other LPAI subtypes because genes from these viruses consistently clustered together, indicating this subtype is enzootic in Bangladesh. The H9N2 strains identified in Bangladesh were phylogenetically and antigenically related to previous human-derived H9N2 viruses detected in Bangladesh representing a potential source for human infection. In contrast, the circulating LPAI H5N2 and H7N9 viruses were both phylogenetically and antigenically unrelated to H5 viruses identified previously in humans in Bangladesh and H7N9 strains isolated from humans in China. In Bangladesh, domestic poultry sold in live bird markets carried a wide range of LPAI virus subtypes and a high diversity of genotypes. Here these findings, combined with the seven year timeframe of sampling, indicate a continuous circulation of these viruses in the country.« less

Genetically Diverse Low Pathogenicity Avian Influenza A Virus Subtypes Co-Circulate among Poultry in Bangladesh

DOE PAGES

Gerloff, Nancy A.; Khan, Salah Uddin; Zanders, Natosha; ...

2016-03-24

Influenza virus surveillance, poultry outbreak investigations and genomic sequencing were assessed to understand the ecology and evolution of low pathogenicity avian influenza (LPAI) A viruses in Bangladesh from 2007 to 2013. We analyzed 506 avian specimens collected from poultry in live bird markets and backyard flocks to identify influenza A viruses. Virus isolation-positive specimens (n = 50) were subtyped and their coding-complete genomes were sequenced. The most frequently identified subtypes among LPAI isolates were H9N2, H11N3, H4N6, and H1N1. Less frequently detected subtypes included H1N3, H2N4, H3N2, H3N6, H3N8, H4N2, H5N2, H6N1, H6N7, and H7N9. Gene sequences were compared tomore » publicly available sequences using phylogenetic inference approaches. Among the 14 subtypes identified, the majority of viral gene segments were most closely related to poultry or wild bird viruses commonly found in Southeast Asia, Europe, and/or northern Africa. LPAI subtypes were distributed over several geographic locations in Bangladesh, and surface and internal protein gene segments clustered phylogenetically with a diverse number of viral subtypes suggesting extensive reassortment among these LPAI viruses. H9N2 subtype viruses differed from other LPAI subtypes because genes from these viruses consistently clustered together, indicating this subtype is enzootic in Bangladesh. The H9N2 strains identified in Bangladesh were phylogenetically and antigenically related to previous human-derived H9N2 viruses detected in Bangladesh representing a potential source for human infection. In contrast, the circulating LPAI H5N2 and H7N9 viruses were both phylogenetically and antigenically unrelated to H5 viruses identified previously in humans in Bangladesh and H7N9 strains isolated from humans in China. In Bangladesh, domestic poultry sold in live bird markets carried a wide range of LPAI virus subtypes and a high diversity of genotypes. Here these findings, combined with the seven year timeframe of sampling, indicate a continuous circulation of these viruses in the country.« less

Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants.

PubMed

Abrahams, M-R; Anderson, J A; Giorgi, E E; Seoighe, C; Mlisana, K; Ping, L-H; Athreya, G S; Treurnicht, F K; Keele, B F; Wood, N; Salazar-Gonzalez, J F; Bhattacharya, T; Chu, H; Hoffman, I; Galvin, S; Mapanje, C; Kazembe, P; Thebus, R; Fiscus, S; Hide, W; Cohen, M S; Karim, S Abdool; Haynes, B F; Shaw, G M; Hahn, B H; Korber, B T; Swanstrom, R; Williamson, C

2009-04-01

Identifying the specific genetic characteristics of successfully transmitted variants may prove central to the development of effective vaccine and microbicide interventions. Although human immunodeficiency virus transmission is associated with a population bottleneck, the extent to which different factors influence the diversity of transmitted viruses is unclear. We estimate here the number of transmitted variants in 69 heterosexual men and women with primary subtype C infections. From 1,505 env sequences obtained using a single genome amplification approach we show that 78% of infections involved single variant transmission and 22% involved multiple variant transmissions (median of 3). We found evidence for mutations selected for cytotoxic-T-lymphocyte or antibody escape and a high prevalence of recombination in individuals infected with multiple variants representing another potential escape pathway in these individuals. In a combined analysis of 171 subtype B and C transmission events, we found that infection with more than one variant does not follow a Poisson distribution, indicating that transmission of individual virions cannot be seen as independent events, each occurring with low probability. While most transmissions resulted from a single infectious unit, multiple variant transmissions represent a significant fraction of transmission events, suggesting that there may be important mechanistic differences between these groups that are not yet understood.

Distinct Molecular Features of Different Macroscopic Subtypes of Colorectal Neoplasms

PubMed Central

Konda, Kenichi; Konishi, Kazuo; Yamochi, Toshiko; Ito, Yoichi M.; Nozawa, Hisako; Tojo, Masayuki; Shinmura, Kensuke; Kogo, Mari; Katagiri, Atsushi; Kubota, Yutaro; Muramoto, Takashi; Yano, Yuichiro; Kobayashi, Yoshiya; Kihara, Toshihiro; Tagawa, Teppei; Makino, Reiko; Takimoto, Masafumi; Imawari, Michio; Yoshida, Hitoshi

2014-01-01

Background Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs). Methods We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance. Results S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41). Conclusion We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis. PMID:25093594

Population genetics of Cryptosporidium meleagridis in humans and birds: evidence for cross-species transmission.

PubMed

Wang, Yuanfei; Yang, Wenli; Cama, Vitaliano; Wang, Lin; Cabrera, Lilia; Ortega, Ynes; Bern, Caryn; Feng, Yaoyu; Gilman, Robert; Xiao, Lihua

2014-07-01

Population genetic studies have been used to understand the transmission of pathogens in humans and animals, especially the role of zoonotic infections and evolution and dispersal of virulent subtypes. In this study, we analysed the genetic diversity and population structure of Cryptosporidium meleagridis, the only known Cryptosporidium species that infects both avian and mammalian hosts and is responsible for approximately 10% of human cryptosporidiosis in some areas. A total of 62 C. meleagridis specimens from children, AIDS patients, and birds in Lima, Peru were characterised by sequence analysis of the ssrRNA gene and five minisatellite, microsatellite and polymorphic markers in chromosome 6, including the 60 kDa glycoprotein (gp60), 47 kDa glycoprotein (CP47), a serine repeat antigen (MSC6-5), retinitis pigmentosa GTPase regulator (RPGR) and thrombospondin protein 8 (TSP8). The multilocus sequence analysis identified concurrent infections with Cryptosporidium hominis in four AIDS patients and three children. Unique subtypes of C. meleagridis ranged from eight at the gp60 locus (gene diversity -Hd=0.651), three at the RPGR (Hd=0.556), three at the MSC6-5 locus (Hd=0.242), two at TSP8 (Hd=0.198), to one at CP47 (monomorphic), much lower than that of C. hominis in the same area. Intragenic linkage disequilibrium was strong and complete at all gene loci. Intergenic linkage disequilibrium was highly significant (P<0.001) for all pairs of polymorphic loci. Two major groups of subtypes were seen, with most subtypes belonging to group 1. Within group 1, there was no clear population segregation, and two of the 14 multilocus subtypes of C. meleagridis were found in both AIDS patients and birds. We believe that these results provide the first evidence of a clonal population structure of C. meleagridis and the likely occurrence of cross-species transmission of C. meleagridis between birds and humans. Published by Elsevier Ltd.

Dynamic HIV-1 genetic recombination and genotypic drug resistance among treatment-experienced adults in northern Ghana.

PubMed

Nii-Trebi, Nicholas Israel; Brandful, James Ashun Mensah; Ibe, Shiro; Sugiura, Wataru; Barnor, Jacob Samson; Bampoh, Patrick Owiredu; Yamaoka, Shoji; Matano, Tetsuro; Yoshimura, Kazuhisa; Ishikawa, Koichi; Ampofo, William Kwabena

2017-11-01

There have been hardly any reports on the human immunodeficiency virus type 1 (HIV-1) drug-resistance profile from northern Ghana since antiretroviral therapy (ART) was introduced over a decade ago. This study investigated prevailing HIV-1 subtypes and examined the occurrence of drug resistance in ART-experienced patients in Tamale, the capital of the Northern Region of Ghana. A cross-sectional study was carried out on HIV-infected adult patients receiving first-line ART. HIV viral load (VL) and CD4 + T-cell counts were measured. The pol gene sequences were analysed for genotypic resistance by an in-house HIV-1 drug-resistance test; the prevailing HIV-1 subtypes were analysed in detail.Results/Key findings. A total of 33 subjects were studied. Participants comprised 11 males (33.3 %) and 22 (66.7 %) females, with a median age of 34.5 years [interquartile range (IQR) 30.0-40.3]. The median duration on ART was 12 months (IQR 8.0-24). Of the 24 subjects successfully genotyped, 10 (41.7 %) viruses possessed at least one mutation conferring resistance to nucleoside or non-nucleoside reverse-transcriptase inhibitors (NRTIs/NNRTIs). Two-class drug resistance to NRTI and NNRTI was mostly detected (25 %, 6/24). The most frequent mutations were lamivudine-resistance M184V and efavirenz/nevirapine-resistance K103N. HIV-1 subtype CRF02_AG was predominant (79.2 %). Other HIV-1 subtypes detected were G (8.3 %), A3 (4.2 %) and importantly two (8.3 %) unique HIV-1 recombinant forms with CRF02_AG/A3 mosaic. HIV-1 shows high genetic diversity and on-going viral genetic recombination in the study region. Nearly 42 % of the patients studied harboured a drug-resistant virus. The study underscores the need for continued surveillance of HIV-1 subtype diversity; and of drug-resistance patterns to guide selection of second-line regimens in northern Ghana.

Genetic Diversity of Venezuelan Alphaviruses and Circulation of a Venezuelan Equine Encephalitis Virus Subtype IAB Strain During an Interepizootic Period

PubMed Central

Medina, Gladys; Garzaro, Domingo J.; Barrios, Miguel; Auguste, Albert J.; Weaver, Scott C.; Pujol, Flor H.

2015-01-01

Several species of alphaviruses have been previously described in the Americas, some of which are associated with encephalitis and others are associated with arthralgia. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV) are endemic to Venezuela, with the former being responsible for major outbreaks of severe and often fatal disease in animals and humans. The aim of this study was to analyze the genetic diversity of Venezuelan alphaviruses isolated during two decades (1973–1999) of surveillance in northern Venezuela. Phylogenetic analysis indicated the circulation of a VEEV subtype IAB strain 8 years after the last reported outbreak. Thirteen strains within two subclades of South American lineage III of EEEV were also found in Venezuela. Considerable genetic variability was observed among Venezuelan Una virus strains, which were widely distributed among the clades. The first Venezuelan Mayaro sequence was also characterized. PMID:25940191

A national study of the molecular epidemiology of HIV-1 in Australia 2005-2012.

PubMed

Castley, Alison; Sawleshwarkar, Shailendra; Varma, Rick; Herring, Belinda; Thapa, Kiran; Dwyer, Dominic; Chibo, Doris; Nguyen, Nam; Hawke, Karen; Ratcliff, Rodney; Garsia, Roger; Kelleher, Anthony; Nolan, David

2017-01-01

Rates of new HIV-1 diagnoses are increasing in Australia, with evidence of an increasing proportion of non-B HIV-1 subtypes reflecting a growing impact of migration and travel. The present study aims to define HIV-1 subtype diversity patterns and investigate possible HIV-1 transmission networks within Australia. The Australian Molecular Epidemiology Network (AMEN) HIV collaborating sites in Western Australia, South Australia, Victoria, Queensland and western Sydney (New South Wales), provided baseline HIV-1 partial pol sequence, age and gender information for 4,873 patients who had genotypes performed during 2005-2012. HIV-1 phylogenetic analyses utilised MEGA V6, with a stringent classification of transmission pairs or clusters (bootstrap ≥98%, genetic distance ≤1.5% from at least one other sequence in the cluster). HIV-1 subtype B represented 74.5% of the 4,873 sequences (WA 59%, SA 68.4%, w-Syd 73.8%, Vic 75.6%, Qld 82.1%), with similar proportion of transmission pairs and clusters found in the B and non-B cohorts (23% vs 24.5% of sequences, p = 0.3). Significantly more subtype B clusters were comprised of ≥3 sequences compared with non-B clusters (45.0% vs 24.0%, p = 0.021) and significantly more subtype B pairs and clusters were male-only (88% compared to 53% CRF01_AE and 17% subtype C clusters). Factors associated with being in a cluster of any size included; being sequenced in a more recent time period (p<0.001), being younger (p<0.001), being male (p = 0.023) and having a B subtype (p = 0.02). Being in a larger cluster (>3) was associated with being sequenced in a more recent time period (p = 0.05) and being male (p = 0.008). This nationwide HIV-1 study of 4,873 patient sequences highlights the increased diversity of HIV-1 subtypes within the Australian epidemic, as well as differences in transmission networks associated with these HIV-1 subtypes. These findings provide epidemiological insights not readily available using standard surveillance methods and can inform the development of effective public health strategies in the current paradigm of HIV prevention in Australia.

Genomic organization, sequence divergence, and recombination of feline immunodeficiency virus from lions in the wild

PubMed Central

Pecon-Slattery, Jill; McCracken, Carrie L; Troyer, Jennifer L; VandeWoude, Sue; Roelke, Melody; Sondgeroth, Kerry; Winterbach, Christiaan; Winterbach, Hanlie; O'Brien, Stephen J

2008-01-01

Background Feline immunodeficiency virus (FIV) naturally infects multiple species of cat and is related to human immunodeficiency virus in humans. FIV infection causes AIDS-like disease and mortality in the domestic cat (Felis catus) and serves as a natural model for HIV infection in humans. In African lions (Panthera leo) and other exotic felid species, disease etiology introduced by FIV infection are less clear, but recent studies indicate that FIV causes moderate to severe CD4 depletion. Results In this study, comparative genomic methods are used to evaluate the full proviral genome of two geographically distinct FIV subtypes isolated from free-ranging lions. Genome organization of FIVPle subtype B (9891 bp) from lions in the Serengeti National Park in Tanzania and FIVPle subtype E (9899 bp) isolated from lions in the Okavango Delta in Botswana, both resemble FIV genome sequence from puma, Pallas cat and domestic cat across 5' LTR, gag, pol, vif, orfA, env, rev and 3'LTR regions. Comparative analyses of available full-length FIV consisting of subtypes A, B and C from FIVFca, Pallas cat FIVOma and two puma FIVPco subtypes A and B recapitulate the species-specific monophyly of FIV marked by high levels of genetic diversity both within and between species. Across all FIVPle gene regions except env, lion subtypes B and E are monophyletic, and marginally more similar to Pallas cat FIVOma than to other FIV. Sequence analyses indicate the SU and TM regions of env vary substantially between subtypes, with FIVPle subtype E more related to domestic cat FIVFca than to FIVPle subtype B and FIVOma likely reflecting recombination between strains in the wild. Conclusion This study demonstrates the necessity of whole-genome analysis to complement population/gene-based studies, which are of limited utility in uncovering complex events such as recombination that may lead to functional differences in virulence and pathogenicity. These full-length lion lentiviruses are integral to the advancement of comparative genomics of human pathogens, as well as emerging disease in wild populations of endangered species. PMID:18251995

Navigating Microbiological Food Safety in the Era of Whole-Genome Sequencing

PubMed Central

Nasheri, Neda; Petronella, Nicholas; Pagotto, Franco

2016-01-01

SUMMARY The epidemiological investigation of a foodborne outbreak, including identification of related cases, source attribution, and development of intervention strategies, relies heavily on the ability to subtype the etiological agent at a high enough resolution to differentiate related from nonrelated cases. Historically, several different molecular subtyping methods have been used for this purpose; however, emerging techniques, such as single nucleotide polymorphism (SNP)-based techniques, that use whole-genome sequencing (WGS) offer a resolution that was previously not possible. With WGS, unlike traditional subtyping methods that lack complete information, data can be used to elucidate phylogenetic relationships and disease-causing lineages can be tracked and monitored over time. The subtyping resolution and evolutionary context provided by WGS data allow investigators to connect related illnesses that would be missed by traditional techniques. The added advantage of data generated by WGS is that these data can also be used for secondary analyses, such as virulence gene detection, antibiotic resistance gene profiling, synteny comparisons, mobile genetic element identification, and geographic attribution. In addition, several software packages are now available to generate in silico results for traditional molecular subtyping methods from the whole-genome sequence, allowing for efficient comparison with historical databases. Metagenomic approaches using next-generation sequencing have also been successful in the detection of nonculturable foodborne pathogens. This review addresses state-of-the-art techniques in microbial WGS and analysis and then discusses how this technology can be used to help support food safety investigations. Retrospective outbreak investigations using WGS are presented to provide organism-specific examples of the benefits, and challenges, associated with WGS in comparison to traditional molecular subtyping techniques. PMID:27559074

Molecular Diagnostic and Prognostic Subtyping of Gliomas in Tunisian Population.

PubMed

Trabelsi, Saoussen; Chabchoub, Imen; Ksira, Iadh; Karmeni, Nadhir; Mama, Nadia; Kanoun, Samia; Burford, Anna; Jury, Alexa; Mackay, Alan; Popov, Sergey; Bouaouina, Noureddine; Ben Ahmed, Slim; Mokni, Moncef; Tlili, Kalthoum; Krifa, Hedi; Yacoubi, Mohamed Tahar; Jones, Chris; Saad, Ali; H'mida Ben Brahim, Dorra

2017-05-01

It has become increasingly evident that morphologically similar gliomas may have distinct clinical phenotypes arising from diverse genetic signatures. To date, glial tumours from the Tunisian population have not been investigated. To address this, we correlated the clinico-pathology with molecular data of 110 gliomas by a combination of HM450K array, MLPA and TMA-IHC. PTEN loss and EGFR amplification were distributed in different glioma histological groups. However, 1p19q co-deletion and KIAA1549:BRAF fusion were, respectively, restricted to Oligodendroglioma and Pilocytic Astrocytoma. CDKN2A loss and EGFR overexpression were more common within high-grade gliomas. Furthermore, survival statistical correlations led us to identify Glioblastoma (GB) prognosis subtypes. In fact, significant lower overall survival (OS) was detected within GB that overexpressed EGFR and Cox2. In addition, IDH1R132H mutation seemed to provide a markedly survival advantage. Interestingly, the association of IDHR132H mutation and EGFR normal status, as well as the association of differentiation markers, defined GB subtypes with good prognosis. By contrast, poor survival GB subtypes were defined by the combination of PTEN loss with PDGFRa expression and/or EGFR amplification. Additionally, GB presenting p53-negative staining associated with CDKN2A loss or p21 positivity represented a subtype with short survival. Thus, distinct molecular subtypes with individualised prognosis were identified. Interestingly, we found a unique histone mutation in a poor survival young adult GB case. This tumour exceptionally associated the H3F3A G34R mutation and MYCN amplification as well as 1p36 loss and 10q loss. Furthermore, by exhibiting a remarkable methylation profile, it emphasised the oncogenic power of G34R mutation connecting gliomagenesis and chromatin regulation.

Causes of Death in Prader-Willi Syndrome: Prader-Willi Syndrome Association (USA) 40-Year Mortality Survey

PubMed Central

Butler, Merlin G.; Manzardo, Ann M.; Heinemann, Janalee; Loker, Carolyn; Loker, James

2016-01-01

Background Prader-Willi syndrome (PWS) is a rare complex neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans leading to a shortened life expectancy. This report summarizes the primary causes of death and evaluates mortality trends in a large cohort of individuals with PWS. Methods PWSA (USA) mortality syndrome-specific database of death reports was collected through a cursory bereavement program for PWSA(USA) families using a brief survey created in 1999. Causes of death were descriptively characterized and statistically examined using Cox Proportional Hazards. Results A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015 with mean age of 29.5 ± 16 years (2mo–67yrs), 70% occurring in adulthood. Respiratory failure was the most common cause accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries compared to females and cardiopulmonary factors. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype. Conclusions These findings highlight the heightened vulnerability towards obesity and hyperphagia-related mortality in PWS. Future research is needed to address critical vulnerabilities such as gender and genetic subtype in the cause of death in PWS. PMID:27854358

Ischemic Stroke Is Associated with the ABO Locus: The EuroCLOT Study

PubMed Central

Williams, Frances M K; Carter, Angela M; Hysi, Pirro G; Surdulescu, Gabriela; Hodgkiss, Dylan; Soranzo, Nicole; Traylor, Matthew; Bevan, Steve; Dichgans, Martin; Rothwell, Peter M W; Sudlow, Cathie; Farrall, Martin; Silander, Kaisa; Kaunisto, Mari; Wagner, Peter; Saarela, Olli; Kuulasmaa, Kari; Virtamo, Jarmo; Salomaa, Veikko; Amouyel, Philippe; Arveiler, Dominique; Ferrieres, Jean; Wiklund, Per-Gunnar; Arfan Ikram, M; Hofman, Albert; Boncoraglio, Giorgio B; Parati, Eugenio A; Helgadottir, Anna; Gretarsdottir, Solveig; Thorsteinsdottir, Unnur; Thorleifsson, Gudmar; Stefansson, Kari; Seshadri, Sudha; DeStefano, Anita; Gschwendtner, Andreas; Psaty, Bruce; Longstreth, Will; Mitchell, Braxton D; Cheng, Yu-Ching; Clarke, Robert; Ferrario, Marco; Bis, Joshua C; Levi, Christopher; Attia, John; Holliday, Elizabeth G; Scott, Rodney J; Fornage, Myriam; Sharma, Pankaj; Furie, Karen L; Rosand, Jonathan; Nalls, Mike; Meschia, James; Mosely, Thomas H; Evans, Alun; Palotie, Aarno; Markus, Hugh S; Grant, Peter J; Spector, Tim D

2013-01-01

Objective End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype. Methods Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3). Results Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10–8) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10–186), rs10665 with FVII (p = 2.4 × 10–47), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10–57) and factor VIII (p = 1.2 × 10–36). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88–0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). Interpretation ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype. Ann Neurol 2013 PMID:23381943

Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity.

PubMed

Almendro, Vanessa; Cheng, Yu-Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege G; Helland, Aslaug; Rye, Inga H; Borresen-Dale, Anne-Lise; Maruyama, Reo; van Oudenaarden, Alexander; Dowsett, Mitchell; Jones, Robin L; Reis-Filho, Jorge; Gascon, Pere; Gönen, Mithat; Michor, Franziska; Polyak, Kornelia

2014-02-13

Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and posttreatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of cellular diversity for genetic and phenotypic features

PubMed Central

Almendro, Vanessa; Cheng, Yu-Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege G.; Helland, Åslaug; Rye, Inga H.; Borresen-Dale, Anne-Lise; Maruyama, Reo; van Oudenaarden, Alexander; Dowsett, Mitchell; Jones, Robin L.; Reis-Filho, Jorge; Gascon, Pere; Gönen, Mithat; Michor, Franziska; Polyak, Kornelia

2014-01-01

SUMMARY Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor subtype-specific and it did not change during treatment in tumors with partial or no response. However, lower pre-treatment genetic diversity was significantly associated with complete pathologic response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution. PMID:24462293

Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

DOE PAGES

Almendro, Vanessa; Cheng, Yu -Kang; Randles, Amanda; ...

2014-02-01

Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatialmore » distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.« less

[Acute lymphoblastic leukemia of T progenitors: from biology to clinics].

PubMed

Genescà, Eulàlia; Ribera, Jordi; Ribera, Josep-Maria

2015-03-09

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and the main cause of morbidity among childhood blood disorders. There are 2 subtypes according to the affected lymphoid progenitor: B-ALL and T-ALL. The T-ALL is the less common and, although historically was associated with poor prognosis in both adults and children, at present, treatment outcomes do not differ significantly between the 2 types of ALL. The T-ALL subtype is the most complex and heterogeneous at the genetic level and currently the one with less new therapeutic alternatives available. This trend is changing thanks to the remarkable progress upon understanding its biology. This review summarizes the most recent and important biological findings in T-ALL and their possible therapeutic implications. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Genetic characterization of avian influenza subtype H4N6 and H4N9 from live bird market, Thailand

USDA-ARS?s Scientific Manuscript database

A one year active surveillance program for influenza A viruses among avian species in a live-bird market (LBM) in Bangkok, Thailand was conducted in 2009. Out of 970 samples collected, influenza A virus subtypes H4N6 (n=2) and H4N9 (n=1), were isolated from healthy Muscovy ducks. All three viruses w...

Evidence for genetic variation of Eurasian avian influenza viruses, subtype H15: The first report of an H15N7 virus

USDA-ARS?s Scientific Manuscript database

Since the first detection of H15 avian influenza viruses (AIVs) in Australia in 1979, only seven H15 strains have been reported. A new H15 AIV was detected in Ukraine in 2010, carrying the unique HA-NA subtype combination H15N7. This virus replicated efficiently in chicken eggs, and antisera against...

Agreement between TOAST and CCS ischemic stroke classification: the NINDS SiGN study.

PubMed

McArdle, Patrick F; Kittner, Steven J; Ay, Hakan; Brown, Robert D; Meschia, James F; Rundek, Tatjana; Wassertheil-Smoller, Sylvia; Woo, Daniel; Andsberg, Gunnar; Biffi, Alessandro; Brenner, David A; Cole, John W; Corriveau, Roderick; de Bakker, Paul I W; Delavaran, Hossein; Dichgans, Martin; Grewal, Raji P; Gwinn, Katrina; Huq, Mohammed; Jern, Christina; Jimenez-Conde, Jordi; Jood, Katarina; Kaplan, Robert C; Katschnig, Petra; Katsnelson, Michael; Labovitz, Daniel L; Lemmens, Robin; Li, Linxin; Lindgren, Arne; Markus, Hugh S; Peddareddygari, Leema R; Pedersén, Annie; Pera, Joanna; Redfors, Petra; Roquer, Jaume; Rosand, Jonathan; Rost, Natalia S; Rothwell, Peter M; Sacco, Ralph L; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie; Thijs, Vincent; Tiedt, Steffen; Valenti, Raffaella; Worrall, Bradford B

2014-10-28

The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58). Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner. © 2014 American Academy of Neurology.

Cholangiocarcinoma — evolving concepts and therapeutic strategies

PubMed Central

Rizvi, Sumera; Khan, Shahid A.; Hallemeier, Christopher L.; Kelley, Robin K.; Gores, Gregory J.

2018-01-01

Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma. PMID:28994423

The impact of HIV-1 genetic diversity on the efficacy of a combinatorial RNAi-based gene therapy.

PubMed

Herrera-Carrillo, E; Berkhout, B

2015-06-01

A hurdle for human immunodeficiency virus (HIV-1) therapy is the genomic diversity of circulating viruses and the possibility that drug-resistant virus variants are selected. Although RNA interference (RNAi) is a powerful tool to stably inhibit HIV-1 replication by the expression of antiviral short hairpin RNAs (shRNAs) in transduced T cells, this approach is also vulnerable to pre-existing genetic variation and the development of viral resistance through mutation. To prevent viral escape, we proposed to combine multiple shRNAs against important regions of the HIV-1 RNA genome, which should ideally be conserved in all HIV-1 subtypes. The vulnerability of RNAi therapy to viral escape has been studied for a single subtype B strain, but it is unclear whether the antiviral shRNAs can inhibit diverse virus isolates and subtypes, including drug-resistant variants that could be present in treated patients. To determine the breadth of the RNAi gene therapy approach, we studied the susceptibility of HIV-1 subtypes A-E and drug-resistant variants. In addition, we monitored the evolution of HIV-1 escape variants. We demonstrate that the combinatorial RNAi therapy is highly effective against most isolates, supporting the future testing of this gene therapy in appropriate in vivo models.

In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics.

PubMed

Weiss, Karin; Kruszka, Paul; Guillen Sacoto, Maria J; Addissie, Yonit A; Hadley, Donald W; Hadsall, Casey K; Stokes, Bethany; Hu, Ping; Roessler, Erich; Solomon, Beth; Wiggs, Edythe; Thurm, Audrey; Hufnagel, Robert B; Zein, Wadih M; Hahn, Jin S; Stashinko, Elaine; Levey, Eric; Baldwin, Debbie; Clegg, Nancy J; Delgado, Mauricio R; Muenke, Maximilian

2018-01-01

PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.MethodsParticipants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.ConclusionIndividuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort.

Genetic characterization of influenza A viruses circulating in pigs and isolated in north-east Spain during the period 2006-2007.

PubMed

Baratelli, Massimiliano; Córdoba, Lorena; Pérez, Lester J; Maldonado, Jaime; Fraile, Lorenzo; Núñez, José I; Montoya, Maria

2014-04-01

Swine influenza virus is one of the most important pathogens involved in the swine respiratory disease complex. Recent serological surveys showed a high prevalence of swine influenza strains belonging to the H1N1, H1N2 and H3N2 subtypes circulating in pigs in Spain. However, little is known about their genome sequence. Five swine influenza strains were isolated from some unrelated outbreaks occurred during 2006-2007, and their complete genome sequences were determined. Phylogenetic analysis revealed that they belonged to the lineages "Avian-Like" H1N1, "Human-Like" H3N2, and "Human-Like" H1N2, showing tight relationships with early or contemporary strains described in Europe. Notably, one virus of the H1N2 subtype showed genetic and antigenic divergence with the European contemporary strains or vaccinal strains of the same subtype, suggesting that some local and divergent clusters of the virus may pass unnoticed in routinary subtyping. Finally, analysis on the entire pattern of genome segments suggested that a second reassortment event could have influenced the evolution of that divergent H1N2 strain. Copyright © 2013 Elsevier Ltd. All rights reserved.

Diversity of human immunodeficiency virus type 1 subtypes in Kagera and Kilimanjaro regions, Tanzania.

PubMed

Nyombi, Balthazar M; Kristiansen, Knut I; Bjune, Gunnar; Müller, Fredrik; Holm-Hansen, Carol

2008-06-01

A strategy to prevent the spread of HIV-1 worldwide is complicated by the high genetic diversity of the virus. To gain a better understanding of the HIV-1 genetic diversity in Tanzania, a molecular epidemiological investigation was conducted in Kagera and Kilimanjaro regions. While several studies have addressed HIV-1 subtypes in Tanzania, this is the first study to describe the virus subtypes circulating in Kagera. The Kagera region is the epicenter of the HIV-1 epidemic in Africa, and it was therefore of interest to compare the prevalence of HIV subtypes in this region and Kilimanjaro. Blood samples were obtained from 246 HIV-1-infected pregnant women attending antenatal clinics. Plasma HIV-1 RNA was extracted, amplified, and sequenced in the env C2V3 and/or pol regions from 209 samples. Based on the analysis of env C2V3 and pol sequences, 47.4% had concordant subtypes, 19.1% were discordant indicating recombination, and for 33.5% sequences were obtained for only one region. The distribution HIV-1 subtypes based on the phylogenetic analysis of paired env C2V3/ pol sequences in Kagera region was A/A (27.8%), C/C (29.6%), D/D (16.7%), and unique recombinant forms (25.9%), and in Kilimanjaro region was A/A (32.9%), C/C (25.9%), D/D (10.6%), CRF10_CD (1.2%), and unique recombinant forms (29.4%). The env C2V3 subsubtype A2 and env C2V3/pol CRF10_CD were also observed indicating that these recombinants are circulating in Tanzania. The high diversity of HIV-1 subtypes and the high prevalence of recombinants demonstrated in this study necessitate expanded and continuous monitoring of the epidemic in Tanzania. The trend may have implications for current national control strategies against the HIV-1 epidemic.

Genetic analysis of human and swine influenza A viruses isolated in Northern Italy during 2010-2015.

PubMed

Chiapponi, C; Ebranati, E; Pariani, E; Faccini, S; Luppi, A; Baioni, L; Manfredi, R; Carta, V; Merenda, M; Affanni, P; Colucci, M E; Veronesi, L; Zehender, G; Foni, E

2018-02-01

Influenza A virus (IAV) infection in swine plays an important role in the ecology of influenza viruses. The emergence of new IAVs comes through different mechanisms, with the genetic reassortment of genes between influenza viruses, also originating from different species, being common. We performed a genetic analysis on 179 IAV isolates from humans (n. 75) and pigs (n. 104) collected in Northern Italy between 2010 and 2015, to monitor the genetic exchange between human and swine IAVs. No cases of human infection with swine strains were noticed, but direct infections of swine with H1N1pdm09 strains were detected. Moreover, we pointed out a continuous circulation of H1N1pdm09 strains in swine populations evidenced by the introduction of internal genes of this subtype. These events contribute to generating new viral variants-possibly endowed with pandemic potential-and emphasize the importance of continuous surveillance at both animal and human level. © 2017 The Authors. Zoonoses and Public Health published by Blackwell Verlag GmbH.

Evolving Diversity of Hepatitis C Viruses in Yunnan Honghe, China

PubMed Central

Yang, Lanhui; Jiang, Chenyan; Hu, Song; Diao, Qiongni; Li, Jia; Si, Wei; Chen, Mei; Zhao, Richard Y.

2016-01-01

The Chinese Honghe Autonomous Prefecture (Honghe) in Yunnan Province is a unique ethnic area because it is inhabited by more than ten different minority ethnic groups. Geographically, Honghe directly shares a border with Vietnam. The objective of this study was to investigate genetic diversity and distribution of the Hepatitis C virus (HCV) in Honghe. Ninety nine subjects who were infected with HCV or HCV/HIV (Human Immunodeficiency Virus Type 1) were recruited into this study. HCV genotypes and subtypes were determined based on the sequences of the core/envelope 1 (C/E1) and the nonstructural protein 5B (NS5B) genomic regions. The viral diversity and origins of dissemination were examined by phylogenetic analyses. Three HCV genotypes (1, 3 and 6) with six subtypes (1b, 3b, 3a, 6a, 6n and 6v) were identified. The most predominant form was genotype 3 (54.6%) followed by 6 (34.3%), and 1 (9.1%). The HCV subtype 3b appeared to be the most frequent form (38.4%) followed by 6n (20.2%) and 3a (16.2%). Statistical analyses suggested a possible rise of the genotype 6a in Honghe among intravenous drug users with HCV/HIV co-infections. Further phylogenetic analyses suggested that similar HCV-6a viruses might have been circulating in the Honghe area for more than a decade, which likely originated from Vietnam or vice versa. Two HCV samples with single HCV infection (SC34 and SC45) were isolated that could represent new recombinant variants. Although the genetic prevalence of HCV in Honghe is in general agreement with that of Southwest China and Yunnan Province, the diversity of HCV genotypes and subtypes in Honghe is somewhat unique and evolving. Information presented here should provide useful information for future health surveillance and prevention of HCV infection in this area. PMID:26999127

Genetic characterisation of novel, highly pathogenic avian influenza (HPAI) H5N6 viruses isolated in birds, South Korea, November 2016.

PubMed

Si, Young-Jae; Lee, In Won; Kim, Eun-Ha; Kim, Young-Il; Kwon, Hyeok-Il; Park, Su-Jin; Nguyen, Hiep Dinh; Kim, Se Mi; Kwon, Jin-Jung; Choi, Won-Suk; Beak, Yun Hee; Song, Min-Suk; Kim, Chul-Joong; Webby, Richard J; Choi, Young-Ki

2017-01-05

A novel genotype of H5N6 influenza viruses was isolated from migratory birds in South Korea during November 2016. Domestic outbreaks of this virus were associated with die-offs of wild birds near reported poultry cases in Chungbuk province, central South Korea. Genetic analysis and animal studies demonstrated that the Korean H5N6 viruses are highly pathogenic avian influenza (HPAI) viruses and that these viruses are novel reassortants of at least three different subtypes (H5N6, H4N2 and H1N1). This article is copyright of The Authors, 2017.

Waardenburg syndrome--a case report.

PubMed

Bansal, Yuvika; Jain, Parul; Goyal, Gaurav; Singh, Malvika; Mishra, Chittranjan

2013-02-01

Waardenburg syndrome is a rare genetic disorder characterized by varying degree of deafness associated with pigmentary anomaly and defects of neural crest cell derived structures. Four subtypes (I-IV) with variable penetrance and gene expression of different clinical features have been described. We report a patient showing constellation of complete heterochromia, dystopia canthorum, white forelock, and synophrys. Other affected family relatives with heterochromia have been depicted in pedigree. Copyright © 2012 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome.

PubMed

Whittington, J; Holland, A; Webb, T; Butler, J; Clarke, D; Boer, H

2004-02-01

Prader-Willi syndrome (PWS) is characterized by extreme floppiness at birth, impaired sexual development, short stature, severe over-eating, characteristic physical features and learning disabilities (LD). Impaired social cognition, literal mindedness and cognitive inflexibility are also present. The syndrome has two main genetic subtypes that both result in the failure of expression of maternally imprinted genes on chromosome 15 at the locus q11-13. Through multiple sources, we attempted to identify all people with PWS living in one health region in the UK. Additional people with PWS identified in other regions were also recruited to augment the study sample. A comparison group of people with LD as a result of aetiologies other than PWS was also identified. All people from these three groups, over age three, who gave their consent, were assessed using tests of ability and attainment. In addition, their main carers were interviewed using a semistructured interview. Blood samples for genetic diagnosis were obtained from all consenting participants. The IQ distribution of the population sample was approximately normal with a mean IQ 40 points below that of the general population. There were systematic differences between the two main genetic subtypes. Those with disomies differed in cognitive profiles from both those with deletions and the comparison LD group (the latter two groups were very similar) in terms of better verbal abilities and impaired coding ability. Some people with PWS deletions had strong visuospatial skills. We propose that the normal distribution of IQ, shifted downwards relative to that of the general population, is the result of a global effect on IQ of the PWS gene(s), and that the different cognitive profile seen in those with chromosome 15 maternal disomies is a specific effect of a gene, or genes, on chromosome 15 which is differentially either expressed or not expressed in those with disomies relative to those with deletions. One hypothesis is that these subtle cognitive differences are a manifestation of the genetic influences of gender-specific imprinted genes on cerebral lateralization. This requires further investigation.

Genetic susceptibility loci for subtypes of breast cancer in an African American population

PubMed Central

Palmer, Julie R.; Ruiz-Narvaez, Edward A.; Rotimi, Charles N.; Cupples, L. Adrienne; Cozier, Yvette C.; Adams-Campbell, Lucile L.; Rosenberg, Lynn

2012-01-01

Background Most genome-wide association scans (GWAS) have been carried out in European ancestry populations; no risk variants for breast cancer have been identified solely from African ancestry GWAS data. Few GWAS hits have replicated in African ancestry populations. Methods In a nested case-control study of breast cancer in the Black Women’s Health Study (1,199 cases/1,948 controls), we evaluated index SNPs in 21 loci from GWAS of European or Asian ancestry populations, overall, in subtypes defined by estrogen (ER) and progesterone (PR) receptor status (ER+/PR+, n=336; ER−/PR−, n=229), and in triple-negative breast cancer (TNBC, N=81). To evaluate the contribution of genetic factors to population differences in breast cancer subtype, we also examined global percent African ancestry. Results Index SNPs in five loci were replicated, including three associated with ER−/PR− breast cancer (TERT rs10069690 in 5p15.33, rs704010 in 10q22.3, and rs8170 in 19p13.11): per allele odds ratios were 1.29 (95% confidence interval (CI) 1.04–1.59), p=0.02, 1.52 (95% CI 1.12–2.08), p=0.01, and 1.30 (95% CI 1.01–1.68), p=0.04, respectively. Stronger associations were observed for TNBC. Furthermore, cases in the highest quintile of percent African ancestry were three times more likely to have TNBC than ER+/PR+ cancer. Conclusions These findings provide the first confirmation of the TNBC SNP rs8170 in an African ancestry population, and independent confirmation of the TERT ER− SNP. Further, the risk of developing ER− breast cancer, particularly TNBC, increased with increasing proportion of global African ancestry. Impact The findings demonstrate the importance of genetic factors in the disproportionately high occurrence of TNBC in African American women. PMID:23136140

[Genetic evolution and substitution frequency of avian influenza virus HA gene in chicken H9N2 subtype in China in the last 20 years].

PubMed

Meng, Fang; Xu, Huaiying; Zhang, Wei; Huang, Dihai; Zhang, Zaihui; Liu, Xia; Chang, Weishan; Qin, Zhuoming

2016-01-04

Low pathogenic avian influenza (LPAI) H9N2 subtype virus has been prevalent in domestic poultry in China over two decades. This study was to determine the genetic evolution trend of H9N2 avian influenza virus (AIV) under immune pressure of vaccine. H9 HA sequences of 40 isolates from the present study and 136 pandemic strains and 7 classical strains from China downloaded from GenBank, were genetically analyzed to determine evolution, molecular characteristic, and mutation frequency. Phylogenetic trees analysis suggested that H9N2 subtypes AIV could be clustered into 5 distinct lineages: G1-like, BJ94-like, Y280-like, S2-like and Americans lineages. Most H9N2 isolates in 2005-2014 belonged to S2-like sub-genotype, suggesting that this genotype was the dominate isolates in China. Further more, comparison based on the amino acid sequence showed that different lineages have their distinct characteristics, and significant accumulations of amino acid variation were also found. In addition, in comparison with reference Ck/BJ/1/1994 HA gene, average annual substitution rates of H9N2 pandemic strain nucleotide and amino acid were 5.73 x 10⁻³ and 4.25 x 10⁻³ from 1994 to 2014, respectively. Substitution rate during 2011-2014 were 6.35 x 10⁻³ and 5.32 x 10⁻³, higher than that during the period of 2006-2010 (5.22 x 10⁻³ and 3.70 x 10⁻³) and even much higher than that during the 1999-2005 (0.74 x 10⁻³ and 0.50 x 10⁻³), when the vaccines were initially applied in the field. Overall, these data indicate that the mismatch between H9N2 vaccine strains and pandemic strains drives the virus to quickly mutate.

Parental psychopathology in families of children with attention-deficit/hyperactivity disorder and exposed to maternal smoking during pregnancy.

PubMed

Sengupta, Sarojini M; Fortier, Marie-Ève; Thakur, Geeta A; Bhat, Venkat; Grizenko, Natalie; Joober, Ridha

2015-02-01

Both genetic and environmental factors have been implicated in the etiology of attention-deficit/hyperactivity disorder (ADHD). We had previously suggested that exposure to maternal smoking during pregnancy (MSDP) may be a valid basis for delineating a distinct subtype of ADHD, where children exposed to MSDP present with a more severe clinical picture. Here, we examine the psychopathology of parents in this group, to better understand the etiology of ADHD. Using the Family Interview for Genetic Studies in a sample of 514 families of children with ADHD, we collected data pertaining to lifetime parental psychopathology. Families were stratified based on maternal smoking during the complete gestational period. The frequency of different disorders was compared using the χ2 statistic. In the group where mothers smoked during pregnancy, both parents were significantly more likely to have antisocial personality disorder, and problems with alcohol and drug abuse. Mothers had a significantly higher frequency of major depressive disorder (MDD), while fathers showed a trend for both MDD and bipolar disorder. Based on the pattern of psychopathology in parents of children exposed to MSDP, as well as earlier reports of the severe clinical, behavioral, and cognitive phenotype in these children, combined with the large body of epidemiological evidence, we propose that these children present a distinct subtype of ADHD with comorbid conduct disorder. Furthermore, we propose that MSDP may be a proxy measure to help delineate this subtype. © 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.

Cancer type-dependent genetic interactions between cancer driver alterations indicate plasticity of epistasis across cell types

PubMed Central

Park, Solip; Lehner, Ben

2015-01-01

Cancers, like many diseases, are normally caused by combinations of genetic alterations rather than by changes affecting single genes. It is well established that the genetic alterations that drive cancer often interact epistatically, having greater or weaker consequences in combination than expected from their individual effects. In a stringent statistical analysis of data from > 3,000 tumors, we find that the co-occurrence and mutual exclusivity relationships between cancer driver alterations change quite extensively in different types of cancer. This cannot be accounted for by variation in tumor heterogeneity or unrecognized cancer subtypes. Rather, it suggests that how genomic alterations interact cooperatively or partially redundantly to driver cancer changes in different types of cancers. This re-wiring of epistasis across cell types is likely to be a basic feature of genetic architecture, with important implications for understanding the evolution of multicellularity and human genetic diseases. In addition, if this plasticity of epistasis across cell types is also true for synthetic lethal interactions, a synthetic lethal strategy to kill cancer cells may frequently work in one type of cancer but prove ineffective in another. PMID:26227665

Subtypes in clinical burnout patients enrolled in an employee rehabilitation program: differences in burnout profiles, depression, and recovery/resources-stress balance.

PubMed

Bauernhofer, Kathrin; Bassa, Daniela; Canazei, Markus; Jiménez, Paulino; Paechter, Manuela; Papousek, Ilona; Fink, Andreas; Weiss, Elisabeth M

2018-01-17

Burnout is generally perceived a unified disorder with homogeneous symptomatology across people (exhaustion, cynicism, and reduced professional efficacy). However, increasing evidence points to intra-individual patterns of burnout symptoms in non-clinical samples such as students, athletes, healthy, and burned-out employees. Different burnout subtypes might therefore exist. Yet, burnout subtypes based on burnout profiles have hardly been explored in clinical patients, and the samples investigated in previous studies were rather heterogeneous including patients with various physical, psychological, and social limitations, symptoms, and disabilities. Therefore, the aim of this study is to explore burnout subtypes based on burnout profiles in clinically diagnosed burnout patients enrolled in an employee rehabilitation program, and to investigate whether the subtypes differ in depression, recovery/resources-stress balance, and sociodemographic characteristics. One hundred three patients (66 women, 37 men) with a clinical burnout diagnosis, who were enrolled in a 5 week employee rehabilitation program in two specialized psychosomatic clinics in Austria, completed a series of questionnaires including the Maslach Burnout Inventory - General Survey (MBI-GS), the Beck Depression Inventory, and the Recovery-Stress-Questionnaire for Work. Cluster analyses with the three MBI-GS subscales as clustering variables were used to identify the burnout subtypes. Subsequent multivariate/univariate analysis of variance and Pearson chi-square tests were performed to investigate differences in depression, recovery/resources-stress balance, and sociodemographic characteristics. Three different burnout subtypes were discovered: the exhausted subtype, the exhausted/cynical subtype, and the burned-out subtype. The burned-out subtype and the exhausted/cynical subtype showed both more severe depression symptoms and a worse recovery/resources-stress balance than the exhausted subtype. Furthermore, the burned-out subtype was more depressed than the exhausted/cynical subtype, but no difference was observed between these two subtypes with regard to perceived stress, recovery, and resources. Sociodemographic characteristics were not associated with the subtypes. The present study indicates that there are different subtypes in clinical burnout patients (exhausted, exhausted/cynical, and burned-out), which might represent patients at different developmental stages in the burnout cycle. Future studies need to replicate the current findings, investigate the stability of the symptom patterns, and examine the efficacy of rehabilitation interventions in different subtypes.

Human JCV Infections as a Bio-Anthropological Marker of the Formation of Brazilian Amazonian Populations

PubMed Central

Cayres-Vallinoto, Izaura M. V.; Vallinoto, Antonio C. R.; Azevedo, Vânia N.; Machado, Luis Fernando Almeida; Ishak, Marluísa de Oliveira Guimarães; Ishak, Ricardo

2012-01-01

JC polyomavirus (JCV) is a member of the Polyomaviridae family. It presents a tropism to kidney cells, and the infection occurs in a variety of human population groups of different ethnic background. The present study investigated the prevalence of JCV infection among human populations from the Brazilian Amazon region, and describes the molecular and phylogenetic features of the virus. Urine samples from two urban groups of Belém (healthy subjects), one Brazilian Afro-descendant “quilombo” from the Rio Trombetas region, and native Indians from the Wai-Wai, Urubu-Kaapor, Tembé, Assurini, Arara do Laranjal, Aukre, Parakanã, Surui and Munduruku villages were investigated for the presence of the virus by amplifying VP1 (230 bp) and IG (610 bp) regions using a polymerase chain reaction. Nucleotide sequences (440 nucleotides, nt) from 48 samples were submitted to phylogenetic analysis. The results confirmed the occurrence of types A (subtype EU), B (subtypes Af-2, African and MY, Asiatic) and C (subtype Af-1) among healthy subjects; type B, subtypes Af-2 and MY, among the Afro-Brazilians; and type B, subtype MY, within the Surui Indians. An unexpected result was the detection of another polyomavirus, the BKV, among Afro-descendants. The present study shows, for the first time, the occurrence of JC and BK polyomaviruses infecting humans from the Brazilian Amazon region. The results show a large genetic variability of strains circulating in the region, infecting a large group of individuals. The presence of European, Asiatic and African subtypes associated to the ethnic origin of the population samples investigated herein, highlights the idea that JCV is a fairly good marker for studying the early migration of human populations, reflecting their early and late history. Furthermore, the identification of the specific mutations associated to the virus subtypes, suggests that these mutations have occurred after the entrance of the virus in the Amazon region of Brazil. PMID:23071582

Genetic Characterization of a Panel of Diverse HIV-1 Isolates at Seven International Sites

PubMed Central

Chen, Yue; Sanchez, Ana M.; Sabino, Ester; Hunt, Gillian; Ledwaba, Johanna; Hackett, John; Swanson, Priscilla; Hewlett, Indira; Ragupathy, Viswanath; Vikram Vemula, Sai; Zeng, Peibin; Tee, Kok-Keng; Chow, Wei Zhen; Ji, Hezhao; Sandstrom, Paul; Denny, Thomas N.; Busch, Michael P.; Gao, Feng

2016-01-01

HIV-1 subtypes and drug resistance are routinely tested by many international surveillance groups. However, results from different sites often vary. A systematic comparison of results from multiple sites is needed to determine whether a standardized protocol is required for consistent and accurate data analysis. A panel of well-characterized HIV-1 isolates (N = 50) from the External Quality Assurance Program Oversight Laboratory (EQAPOL) was assembled for evaluation at seven international sites. This virus panel included seven subtypes, six circulating recombinant forms (CRFs), nine unique recombinant forms (URFs) and three group O viruses. Seven viruses contained 10 major drug resistance mutations (DRMs). HIV-1 isolates were prepared at a concentration of 107 copies/ml and compiled into blinded panels. Subtypes and DRMs were determined with partial or full pol gene sequences by conventional Sanger sequencing and/or Next Generation Sequencing (NGS). Subtype and DRM results were reported and decoded for comparison with full-length genome sequences generated by EQAPOL. The partial pol gene was amplified by RT-PCR and sequenced for 89.4%-100% of group M viruses at six sites. Subtyping results of majority of the viruses (83%-97.9%) were correctly determined for the partial pol sequences. All 10 major DRMs in seven isolates were detected at these six sites. The complete pol gene sequence was also obtained by NGS at one site. However, this method missed six group M viruses and sequences contained host chromosome fragments. Three group O viruses were only characterized with additional group O-specific RT-PCR primers employed by one site. These results indicate that PCR protocols and subtyping tools should be standardized to efficiently amplify diverse viruses and more consistently assign virus genotypes, which is critical for accurate global subtype and drug resistance surveillance. Targeted NGS analysis of partial pol sequences can serve as an alternative approach, especially for detection of low-abundance DRMs. PMID:27314585

Genetic Characterization of a Panel of Diverse HIV-1 Isolates at Seven International Sites.

PubMed

Hora, Bhavna; Keating, Sheila M; Chen, Yue; Sanchez, Ana M; Sabino, Ester; Hunt, Gillian; Ledwaba, Johanna; Hackett, John; Swanson, Priscilla; Hewlett, Indira; Ragupathy, Viswanath; Vikram Vemula, Sai; Zeng, Peibin; Tee, Kok-Keng; Chow, Wei Zhen; Ji, Hezhao; Sandstrom, Paul; Denny, Thomas N; Busch, Michael P; Gao, Feng

2016-01-01

HIV-1 subtypes and drug resistance are routinely tested by many international surveillance groups. However, results from different sites often vary. A systematic comparison of results from multiple sites is needed to determine whether a standardized protocol is required for consistent and accurate data analysis. A panel of well-characterized HIV-1 isolates (N = 50) from the External Quality Assurance Program Oversight Laboratory (EQAPOL) was assembled for evaluation at seven international sites. This virus panel included seven subtypes, six circulating recombinant forms (CRFs), nine unique recombinant forms (URFs) and three group O viruses. Seven viruses contained 10 major drug resistance mutations (DRMs). HIV-1 isolates were prepared at a concentration of 107 copies/ml and compiled into blinded panels. Subtypes and DRMs were determined with partial or full pol gene sequences by conventional Sanger sequencing and/or Next Generation Sequencing (NGS). Subtype and DRM results were reported and decoded for comparison with full-length genome sequences generated by EQAPOL. The partial pol gene was amplified by RT-PCR and sequenced for 89.4%-100% of group M viruses at six sites. Subtyping results of majority of the viruses (83%-97.9%) were correctly determined for the partial pol sequences. All 10 major DRMs in seven isolates were detected at these six sites. The complete pol gene sequence was also obtained by NGS at one site. However, this method missed six group M viruses and sequences contained host chromosome fragments. Three group O viruses were only characterized with additional group O-specific RT-PCR primers employed by one site. These results indicate that PCR protocols and subtyping tools should be standardized to efficiently amplify diverse viruses and more consistently assign virus genotypes, which is critical for accurate global subtype and drug resistance surveillance. Targeted NGS analysis of partial pol sequences can serve as an alternative approach, especially for detection of low-abundance DRMs.

A study of vaccine-induced immune pressure on breakthrough infections in the Phambili phase 2b HIV-1 vaccine efficacy trial

PubMed Central

Rolland, M.; Magaret, C.A.; Rademeyer, C.; Fiore-Gartland, A.; Edlefsen, P.T.; DeCamp, A.; Ahmed, H.; Ngandu, N.; Larsen, B.B.; Frahm, N.; Marais, J.; Thebus, R.; Geraghty, D.; Hural, J.; Corey, L.; Kublin, J.; Gray, G.; McElrath, M.J.; Mullins, J.I.; Gilbert, P.B.; Williamson, C.

2016-01-01

Introduction The Merck Adenovirus-5 Gag/Pol/Nef HIV-1 subtype-B vaccine evaluated in predominately subtype B epidemic regions (Step Study), while not preventing infection, exerted vaccine-induced immune pressure on HIV-1 breakthrough infections. Here we investigated if the same vaccine exerted immune pressure when tested in the Phambili Phase 2b study in a subtype C epidemic. Materials and methods A sieve analysis, which compares breakthrough viruses from placebo and vaccine arms, was performed on 277 near full-length genomes generated from 23 vaccine and 20 placebo recipients. Vaccine coverage was estimated by computing the percentage of 9-mers that were exact matches to the vaccine insert. Results There was significantly greater protein distances from the vaccine immunogen sequence in Gag (p = 0.045) and Nef (p = 0.021) in viruses infecting vaccine recipients compared to placebo recipients. Twenty-seven putative sites of vaccine-induced pressure were identified (p < 0.05) in Gag (n = 10), Pol (n = 7) and Nef (n = 10), although they did not remain significant after adjustment for multiple comparisons. We found the epitope sieve effect in Step was driven by HLA A*02:01; an allele which was found in low frequency in Phambili participants compared to Step participants. Furthermore, the coverage of the vaccine against subtype C Phambili viruses was 31%, 46% and 14% for Gag, Pol and Nef, respectively, compared to subtype B Step virus coverage of 56%, 61% and 26%, respectively. Discussion This study presents evidence of sieve effects in Gag and Nef; however could not confirm effects on specific amino acid sites. We propose that this weaker signal of vaccine immune pressure detected in the Phambili study compared to the Step study may have been influenced by differences in host genetics (HLA allele frequency) and reduced impact of vaccine-induced immune responses due to mismatch between the viral subtype in the vaccine and infecting subtypes. PMID:27756485

[Influenza virus epidemiology and ecology, with special reference to bird species associated with water. Literature review and observations].

PubMed

van Tongeren, H A; Voous, K H

1987-12-01

Only a limited number of A-subtypes of influenza virus so far caused disease in human subjects, pigs and horses; this occurred in more or less defined areas which occasionally showed epidemic aggravations, becoming apparent as rapidly spreading epidemics or otherwise in even the form of pandemics. However this number of antigenic subtypes was found to be fairly constant and host-specific. Earlier studies were done in domesticated fowl and birds, though particularly in water birds in recent years, and numerous subtypes were detected, only a small number of these subtypes also being found to occur in man, pigs and horses. It became increasingly apparent that particularly mallards, but also other water birds play an extremely important role in the maintenance as well as in the distribution and circulation of these orthomyxoviruses in nature. These infections in water birds were not merely caused by a single subtype but occasionally by two or more antigenically different subtypes. This could be conducive to the appearance of recombinants as a result of genetic rearrangement in the cells lining the alimentary tracts of birds. Occasionally, subtypes observed in man were also found to occur in birds, which gave rise to the question of the extent to which birds are the origin or sources of infections of human epidemics caused by these subtypes. This also holds good for the subtypes in pigs. In addition to a number of oecological and ornithological considerations, reference was also made to systematic facts and routes along which further investigations on the presence of influenza viruses in the world of birds could be taken up, particular attention being paid to migratory birds. As birds of passage pass over and find their way into isolated areas as well as human population centres, these birds play a role which is yet unknown both in the distribution and in the overwintering of influenza viruses. Conditions in which wild and domesticated (water) birds, pigs, horses and man form a chain of close contact, and the areas in which new influenza viruses pathogenic for man are most likely to appear. Studies on the transgression of these barriers of species by subtypes of influenza virus still are entirely separate matter. The fact that a multidisciplinary approach is essential admits of no discussion.

[Detection and Analysis of Human Parainfluenza Virus Infection in Hospitalized Adults with Acute Respiratory Tract Infections].

PubMed

Li, Xing-Qiao; Liu, Xue-Wei; Zhou, Tao; Pei, Xiao-Fang

2017-11-01

To investigate the prevalence and gene characteristics of different groups of human parainfluenza virus (HPIV) infection in hospitalized adults with acute respiratory tract infections (ARI). RT-PCR was used to detect HPIV hemagglutinin (HA) DNA,which was extracted from sputum samples of 1 039 adult patients with ARI from March,2014 to June,2016. The HA gene amplified from randomly selected positive samples were sequenced to analyze the homology and variation. 10.6% (110/1 039) of these samples were positive for HPIV,including 8 cases of HPIV-1,22 cases of HPIV-2,46 cases of HPIV-3 and 34 cases of HPIV-4. Detectable rate varied among different groups of HPIV according to seasons of the year and ages of patients. No significant differences were found between the positive samples and the reference sequences. Compared with different reference strains of different regions,the genetic distance of nucleotide is the smallest between the strains tested in this study and the reference strains of other provinces and cities in China. In Chengdu region,HPIV virus is highly detected in ARI,all subtypes were detected with HPIV-3 being the main subtype.

Targetable genetic features of primary testicular and primary central nervous system lymphomas

PubMed Central

Chapuy, Bjoern; Roemer, Margaretha G. M.; Stewart, Chip; Tan, Yuxiang; Abo, Ryan P.; Zhang, Liye; Dunford, Andrew J.; Meredith, David M.; Thorner, Aaron R.; Jordanova, Ekaterina S.; Liu, Gang; Feuerhake, Friedrich; Ducar, Matthew D.; Illerhaus, Gerald; Gusenleitner, Daniel; Linden, Erica A.; Sun, Heather H.; Homer, Heather; Aono, Miyuki; Pinkus, Geraldine S.; Ligon, Azra H.; Ligon, Keith L.; Ferry, Judith A.; Freeman, Gordon J.; van Hummelen, Paul; Golub, Todd R.; Getz, Gad; Rodig, Scott J.; de Jong, Daphne; Monti, Stefano

2016-01-01

Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL. PMID:26702065

Genetic Diversity and Distribution of Blastocystis Subtype 3 in Human Populations, with Special Reference to a Rural Population in Central Mexico

PubMed Central

Serrano-Vázquez, Angélica; Pérez-Juárez, Horacio; Poot-Hernández, Augusto C.; González, Enrique; Hernández, Eric; Nieves-Ramírez, Miriam E.; Magaña, Ulises; Eguiarte, Luis E.; Piñero, Daniel

2018-01-01

Blastocystis subtype 3 (ST3) is a parasitic protist found in the digestive tract of symptomatic and asymptomatic humans around the world. While this parasite exhibits a high prevalence in the human population, its true geographic distribution and global genetic diversity are still unknown. This gap in knowledge limits the understanding of the spread mechanisms, epidemiology, and impact that this parasite has on human populations. Herein, we provided new data on the geographical distribution and genetic diversity of Blastocystis ST3 from a rural human population in Mexico. To do so, we collected and targeted the SSU-rDNA region in fecal samples from this population and further compared its genetic diversity and structure with that previously observed in populations of Blastocystis ST3 from other regions of the planet. Our analyses reveled that diversity of Blastocystis ST3 showed a high haplotype diversity and genetic structure to the world level; however, they were low in the Morelos population. The haplotype network revealed a common widespread haplotype from which the others were generated recently. Finally, our results suggested a recent expansion of the diversity of Blastocystis ST3 worldwide. PMID:29744356

Genetic Diversity and Distribution of Blastocystis Subtype 3 in Human Populations, with Special Reference to a Rural Population in Central Mexico.

PubMed

Rojas-Velázquez, Liliana; Morán, Patricia; Serrano-Vázquez, Angélica; Fernández, Leonardo D; Pérez-Juárez, Horacio; Poot-Hernández, Augusto C; Portillo, Tobías; González, Enrique; Hernández, Eric; Partida-Rodríguez, Oswaldo; Nieves-Ramírez, Miriam E; Magaña, Ulises; Torres, Javier; Eguiarte, Luis E; Piñero, Daniel; Ximénez, Cecilia

2018-01-01

Blastocystis subtype 3 (ST3) is a parasitic protist found in the digestive tract of symptomatic and asymptomatic humans around the world. While this parasite exhibits a high prevalence in the human population, its true geographic distribution and global genetic diversity are still unknown. This gap in knowledge limits the understanding of the spread mechanisms, epidemiology, and impact that this parasite has on human populations. Herein, we provided new data on the geographical distribution and genetic diversity of Blastocystis ST3 from a rural human population in Mexico. To do so, we collected and targeted the SSU-rDNA region in fecal samples from this population and further compared its genetic diversity and structure with that previously observed in populations of Blastocystis ST3 from other regions of the planet. Our analyses reveled that diversity of Blastocystis ST3 showed a high haplotype diversity and genetic structure to the world level; however, they were low in the Morelos population. The haplotype network revealed a common widespread haplotype from which the others were generated recently. Finally, our results suggested a recent expansion of the diversity of Blastocystis ST3 worldwide.

Whole-genome sequencing in a pair of monozygotic twins with discordant cleft lip and palate subtypes.

PubMed

Takahashi, Masahiro; Hosomichi, Kazuyoshi; Yamaguchi, Tetsutaro; Nagahama, Ryo; Yoshida, Hiroshi; Maki, Koutaro; Marazita, Mary L; Weinberg, Seth M; Tajima, Atsushi

2018-06-06

Orofacial clefts (OFCs) are common and aetiologically complex birth defects. This study explored potential genetic differences in a pair of Japanese monozygotic (MZ) twins with different forms of OFC using whole-genome sequencing. One co-twin (MZ-1) presented with non-syndromic bilateral cleft lip and palate; the other co-twin (MZ-2) had non-syndromic bilateral cleft lip and unilateral left-sided cleft alveolus. Neither parent had an OFC. Craniofacial morphologic features and potential genetic differences were compared using standard cephalometry and whole-genome sequencing, respectively. Morphologically, MZ-1 had a smaller vertical mandibular height, compared to MZ-2. However, no discordant genetic differences were detected. Moreover, both twins and their parents harboured rare candidate gene variants (GRHL3; TPM1) considered to be associated with OFCs. The observed differences between MZ-1 and MZ-2 in craniofacial morphology assessed by cephalograms might be directly attributable to the effects of the OFC on growth and/or differences in surgical history, given the lack of any differences in genetic background. However, comparisons of discordant MZ twins should continue to identify novel candidates that might control OFC or that might partly explain the missing heritability for this common birth defect, in addition to understanding craniofacial growth and development. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Differentiating disease subtypes by using pathway patterns constructed from gene expressions and protein networks.

PubMed

Hung, Fei-Hung; Chiu, Hung-Wen

2015-01-01

Gene expression profiles differ in different diseases. Even if diseases are at the same stage, such diseases exhibit different gene expressions, not to mention the different subtypes at a single lesion site. Distinguishing different disease subtypes at a single lesion site is difficult. In early cases, subtypes were initially distinguished by doctors. Subsequently, further differences were found through pathological experiments. For example, a brain tumor can be classified according to its origin, its cell-type origin, or the tumor site. Because of the advancements in bioinformatics and the techniques for accumulating gene expressions, researchers can use gene expression data to classify disease subtypes. Because the operation of a biopathway is closely related to the disease mechanism, the application of gene expression profiles for clustering disease subtypes is insufficient. In this study, we collected gene expression data of healthy and four myelodysplastic syndrome subtypes and applied a method that integrated protein-protein interaction and gene expression data to identify different patterns of disease subtypes. We hope it is efficient for the classification of disease subtypes in adventure.

High-throughput genotyping assay for the large-scale genetic characterization of Cryptosporidium parasites from human and bovine samples.

PubMed

Abal-Fabeiro, J L; Maside, X; Llovo, J; Bello, X; Torres, M; Treviño, M; Moldes, L; Muñoz, A; Carracedo, A; Bartolomé, C

2014-04-01

The epidemiological study of human cryptosporidiosis requires the characterization of species and subtypes involved in human disease in large sample collections. Molecular genotyping is costly and time-consuming, making the implementation of low-cost, highly efficient technologies increasingly necessary. Here, we designed a protocol based on MALDI-TOF mass spectrometry for the high-throughput genotyping of a panel of 55 single nucleotide variants (SNVs) selected as markers for the identification of common gp60 subtypes of four Cryptosporidium species that infect humans. The method was applied to a panel of 608 human and 63 bovine isolates and the results were compared with control samples typed by Sanger sequencing. The method allowed the identification of species in 610 specimens (90·9%) and gp60 subtype in 605 (90·2%). It displayed excellent performance, with sensitivity and specificity values of 87·3 and 98·0%, respectively. Up to nine genotypes from four different Cryptosporidium species (C. hominis, C. parvum, C. meleagridis and C. felis) were detected in humans; the most common ones were C. hominis subtype Ib, and C. parvum IIa (61·3 and 28·3%, respectively). 96·5% of the bovine samples were typed as IIa. The method performs as well as the widely used Sanger sequencing and is more cost-effective and less time consuming.

Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial.

PubMed

Erdem-Eraslan, Lale; van den Bent, Martin J; Hoogstrate, Youri; Naz-Khan, Hina; Stubbs, Andrew; van der Spek, Peter; Böttcher, René; Gao, Ya; de Wit, Maurice; Taal, Walter; Oosterkamp, Hendrika M; Walenkamp, Annemiek; Beerepoot, Laurens V; Hanse, Monique C J; Buter, Jan; Honkoop, Aafke H; van der Holt, Bronno; Vernhout, René M; Sillevis Smitt, Peter A E; Kros, Johan M; French, Pim J

2016-02-01

The results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva), a humanized monoclonal antibody against circulating VEGF-A, when added to CCNU chemotherapy in patients with recurrent glioblastoma (GBM). In this study, we performed gene expression profiling (DASL and RNA-seq) of formalin-fixed, paraffin-embedded tumor material from participants of the BELOB trial to identify patients with recurrent GBM who benefitted most from beva+CCNU treatment. We demonstrate that tumors assigned to the IGS-18 or "classical" subtype and treated with beva+CCNU showed a significant benefit in progression-free survival and a trend toward benefit in overall survival, whereas other subtypes did not exhibit such benefit. In particular, expression of FMO4 and OSBPL3 was associated with treatment response. Importantly, the improved outcome in the beva+CCNU treatment arm was not explained by an uneven distribution of prognostically favorable subtypes as all molecular glioma subtypes were evenly distributed along the different study arms. The RNA-seq analysis also highlighted genetic alterations, including mutations, gene fusions, and copy number changes, within this well-defined cohort of tumors that may serve as useful predictive or prognostic biomarkers of patient outcome. Further validation of the identified molecular markers may enable the future stratification of recurrent GBM patients into appropriate treatment regimens. ©2016 American Association for Cancer Research.

Association of MTHFR C677T Genotype With Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype

PubMed Central

Traylor, Matthew; Adib-Samii, Poneh; Thijs, Vincent; Sudlow, Cathie; Rothwell, Peter M.; Boncoraglio, Giorgio; Dichgans, Martin; Meschia, James; Maguire, Jane; Levi, Christopher; Rost, Natalia S.; Rosand, Jonathan; Hassan, Ahamad; Bevan, Steve; Markus, Hugh S.

2016-01-01

Background and Purpose— Elevated plasma homocysteine levels are associated with stroke. However, this might be a reflection of bias or confounding because trials have failed to demonstrate an effect from homocysteine lowering in stroke patients, although a possible benefit has been suggested in lacunar stroke. Genetic studies could potentially overcome these issues because genetic variants are inherited randomly and are fixed at conception. Therefore, we tested the homocysteine levels–associated genetic variant MTHFR C677T for association with magnetic resonance imaging–confirmed lacunar stroke and compared this with associations with large artery and cardioembolic stroke subtypes. Methods— We included 1359 magnetic resonance imaging–confirmed lacunar stroke cases, 1824 large artery stroke cases, 1970 cardioembolic stroke cases, and 14 448 controls, all of European ancestry. Furthermore, we studied 3670 ischemic stroke patients in whom white matter hyperintensities volume was measured. We tested MTHFR C677T for association with stroke subtypes and white matter hyperintensities volume. Because of the established association of homocysteine with hypertension, we additionally stratified for hypertension status. Results— MTHFR C677T was associated with lacunar stroke (P=0.0003) and white matter hyperintensity volume (P=0.04), but not with the other stroke subtypes. Stratifying the lacunar stroke cases for hypertension status confirmed this association in hypertensive individuals (P=0.0002), but not in normotensive individuals (P=0.30). Conclusions— MTHFR C677T was associated with magnetic resonance imaging–confirmed lacunar stroke, but not large artery or cardioembolic stroke. The association may act through increased susceptibility to, or interaction with, high blood pressure. This heterogeneity of association might explain the lack of effect of lowering homocysteine in secondary prevention trials which included all strokes. PMID:26839351

Genetic Characterization and Comparison of Clostridium botulinum Isolates from Botulism Cases in Japan between 2006 and 2011

PubMed Central

Sekizuka, Tsuyoshi; Yamamoto, Akihiko; Iwaki, Masaaki; Komiya, Takako; Hatakeyama, Takashi; Nakajima, Hiroshi; Takahashi, Motohide; Kuroda, Makoto; Shibayama, Keigo

2014-01-01

Genetic characterization was performed for 10 group I Clostridium botulinum strains isolated from botulism cases in Japan between 2006 and 2011. Of these, 1 was type A, 2 were type B, and 7 were type A(B) {carrying a silent bont/B [bont/(B)] gene} serotype strains, based on botulinum neurotoxin (BoNT) production. The type A strain harbored the subtype A1 BoNT gene (bont/A1), which is associated with the ha gene cluster. The type B strains carried bont/B5 or bont/B6 subtype genes. The type A(B) strains carried bont/A1 identical to that of type A(B) strain NCTC2916. However, bont/(B) genes in these strains showed single-nucleotide polymorphisms (SNPs) among strains. SNPs at 2 nucleotide positions of bont/(B) enabled classification of the type A(B) strains into 3 groups. Pulsed-field gel electrophoresis (PFGE) and multiple-locus variable-number tandem-repeat analysis (MLVA) also provided consistent separation results. In addition, the type A(B) strains were separated into 2 lineages based on their plasmid profiles. One lineage carried a small plasmid (5.9 kb), and another harbored 21-kb plasmids. To obtain more detailed genetic information about the 10 strains, we sequenced their genomes and compared them with 13 group I C. botulinum genomes in a database using whole-genome SNP analysis. This analysis provided high-resolution strain discrimination and enabled us to generate a refined phylogenetic tree that provides effective traceability of botulism cases, as well as bioterrorism materials. In the phylogenetic tree, the subtype B6 strains, Okayama2011 and Osaka05, were distantly separated from the other strains, indicating genomic divergence of subtype B6 strains among group I strains. PMID:25192986

HUMAN GENETICS AS A TOOL TO IDENTIFY PROGRANULIN REGULATORS

PubMed Central

Nicholson, Alexandra M.; Finch, NiCole A.; Rademakers, Rosa

2012-01-01

Frontotemporal lobar degeneration (FTLD) is a common neurodegenerative disorder that predominantly affects individuals under the age of 65. It is known that the most common pathological subtype is FTLD with TAR DNA-binding protein 43 inclusions (FTLD-TDP). FTLD has a strong genetic component with about 50% of cases having a positive family history. Mutations identified in the progranulin gene (GRN) have been shown to cause FTLD-TDP as a result of progranulin haploinsufficiency. These findings suggest a progranulin-dependent mechanism in this pathological FTLD subtype. Thus, identifying regulators of progranulin levels is essential for new therapies and treatments for FTLD and related disorders. In this review, we discuss the role of genetic studies in identifying progranulin regulators, beginning with the discovery of pathogenic GRN mutations and additional GRN risk variants. We also cover more recent genetic advances, including the detection of variants in the transmembrane protein 106 B gene that increase FTLD-TDP risk presumably by modulating progranulin levels and the identification of a potential progranulin receptor, sortilin. This review highlights the importance of genetic studies in the context of FTLD and further emphasizes the need for future genetic and cell biology research to continue the effort in finding a cure for progranulin-related diseases. PMID:21626010

Advances in the molecular diagnosis of diffuse large B-cell lymphoma in the era of precision medicine.

PubMed

Araf, Shamzah; Korfi, Koorosh; Rahim, Tahrima; Davies, Andrew; Fitzgibbon, Jude

2016-10-01

The adoption of high-throughput technologies has led to a transformation in our ability to classify diffuse large B-cell lymphoma (DLBCL) into unique molecular subtypes. In parallel, the expansion of agents targeting key genetic and gene expression signatures has led to an unprecedented opportunity to personalize cancer therapies, paving the way for precision medicine. Areas covered: This review summarizes the key molecular subtypes of DLBCL and outlines the novel technology platforms in development to discriminate clinically relevant subtypes. Expert commentary: The application of emerging diagnostic tests into routine clinical practise is gaining momentum following the demonstration of subtype specific activity by novel agents. Co-ordinated efforts are required to ensure that these state of the art technologies provide reliable and clinically meaningful results accessible to the wider haematology community.

Genetic variability of HEV isolates: inconsistencies of current classification.

PubMed

Oliveira-Filho, Edmilson F; König, Matthias; Thiel, Heinz-Jürgen

2013-07-26

Many HEV and HEV-like sequences have been reported during the last years, including isolates which may represent a number of potential new genera, new genotypes or new subtypes within the family Hepeviridae. Using the most common classification system, difficulties in the establishment of subtypes have been reported. Moreover the relevance of subtype classification for epidemiology can be questioned. In this study we have performed phylogenetic analyses based on whole capsid gene and complete HEV genomic sequences in order to evaluate the current classification of HEV at genotype and subtype levels. The results of our analyses modify the current taxonomy of genotype 3 and refine the established system for typing of HEV. In addition we suggest a classification for hepeviruses recently isolated from bats, ferrets, rats and wild boar. Copyright © 2013 Elsevier B.V. All rights reserved.

Memory Effects of Benzodiazepines: Memory Stages and Types Versus Binding-Site Subtypes

PubMed Central

Savić, Miroslav M.; Obradović, Dragan I.; Ugrešić, Nenad D.; Bokonjić, Dubravko R.

2005-01-01

Benzodiazepines are well established as inhibitory modulators of memory processing. This effect is especially prominent when applied before the acquisition phase of a memory task. This minireview concentrates on the putative subtype selectivity of the acquisition-impairing action of benzodiazepines. Namely, recent genetic studies and standard behavioral tests employing subtype-selective ligands pointed to the predominant involvement of two subtypes of benzodiazepine binding sites in memory modulation. Explicit memory learning seems to be affected through the GABAA receptors containing the α1 and α1 subunits, whereas the effects on procedural memory can be mainly mediated by the α1 subunit. The pervading involvement of the α1 subunit in memory modulation is not at all unexpected because this subunit is the major subtype, present in 60% of all GABAA receptors. On the other hand, the role of α5 subunits, mainly expressed in the hippocampus, in modulating distinct forms of memory gives promise of selective pharmacological coping with certain memory deficit states. PMID:16444900

Apoptosis of Limb Innervating Motor Neurons and Erosion of Motor Pool Identity Upon Lineage Specific Dicer Inactivation

PubMed Central

Chen, Jun-An; Wichterle, Hynek

2012-01-01

Diversification of mammalian spinal motor neurons into hundreds of subtypes is critical for the maintenance of body posture and coordination of complex movements. Motor neuron differentiation is controlled by extrinsic signals that regulate intrinsic genetic programs specifying and consolidating motor neuron subtype identity. While transcription factors have been recognized as principal regulators of the intrinsic program, the role of posttranscriptional regulations has not been systematically tested. MicroRNAs produced by Dicer mediated cleavage of RNA hairpins contribute to gene regulation by posttranscriptional silencing. Here we used Olig2-cre conditional deletion of Dicer gene in motor neuron progenitors to examine effects of miRNA biogenesis disruption on postmitotic spinal motor neurons. We report that despite the initial increase in the number of motor neuron progenitors, disruption of Dicer function results in a loss of many limb- and sympathetic ganglia-innervating spinal motor neurons. Furthermore, it leads to defects in motor pool identity specification. Thus, our results indicate that miRNAs are an integral part of the genetic program controlling motor neuron survival and acquisition of subtype specific properties. PMID:22629237

Cell of Origin and Cancer Stem Cells in Tumor Suppressor Mouse Models of Glioblastoma.

PubMed

Alcantara Llaguno, Sheila R; Xie, Xuanhua; Parada, Luis F

2016-01-01

The cellular origins and the mechanisms of progression, maintenance of tumorigenicity, and therapeutic resistance are central questions in the glioblastoma multiforme (GBM) field. Using tumor suppressor mouse models, our group recently reported two independent populations of adult GBM-initiating central nervous system progenitors. We found different functional and molecular subtypes depending on the tumor-initiating cell lineage, indicating that the cell of origin is a driver of GBM subtype diversity. Using an in vivo model, we also showed that GBM cancer stem cells (CSCs) or glioma stem cells (GSCs) contribute to resistance to chemotherapeutic agents and that genetic ablation of GSCs leads to a delay in tumor progression. These studies are consistent with the cell of origin and CSCs as critical regulators of the pathogenesis of GBM. © 2016 Alcantara Llaguno et al; Published by Cold Spring Harbor Laboratory Press.

Recent human-to-poultry host jump, adaptation, and pandemic spread of Staphylococcus aureus.

PubMed

Lowder, Bethan V; Guinane, Caitriona M; Ben Zakour, Nouri L; Weinert, Lucy A; Conway-Morris, Andrew; Cartwright, Robyn A; Simpson, A John; Rambaut, Andrew; Nübel, Ulrich; Fitzgerald, J Ross

2009-11-17

The impact of globalization on the emergence and spread of pathogens is an important veterinary and public health issue. Staphylococcus aureus is a notorious human pathogen associated with serious nosocomial and community-acquired infections. In addition, S. aureus is a major cause of animal diseases including skeletal infections of poultry, which are a large economic burden on the global broiler chicken industry. Here, we provide evidence that the majority of S. aureus isolates from broiler chickens are the descendants of a single human-to-poultry host jump that occurred approximately 38 years ago (range, 30 to 63 years ago) by a subtype of the worldwide human ST5 clonal lineage unique to Poland. In contrast to human subtypes of the ST5 radiation, which demonstrate strong geographic clustering, the poultry ST5 clade was distributed in different continents, consistent with wide dissemination via the global poultry industry distribution network. The poultry ST5 clade has undergone genetic diversification from its human progenitor strain by acquisition of novel mobile genetic elements from an avian-specific accessory gene pool, and by the inactivation of several proteins important for human disease pathogenesis. These genetic events have resulted in enhanced resistance to killing by chicken heterophils, reflecting avian host-adaptive evolution. Taken together, we have determined the evolutionary history of a major new animal pathogen that has undergone rapid avian host adaptation and intercontinental dissemination. These data provide a new paradigm for the impact of human activities on the emergence of animal pathogens.

Activity of Tachykinin1-Expressing Pet1 Raphe Neurons Modulates the Respiratory Chemoreflex

PubMed Central

Corcoran, Andrea E.; Brust, Rachael D.; Chang, YoonJeung; Nattie, Eugene E.

2017-01-01

Homeostatic control of breathing, heart rate, and body temperature relies on circuits within the brainstem modulated by the neurotransmitter serotonin (5-HT). Mounting evidence points to specialized neuronal subtypes within the serotonergic neuronal system, borne out in functional studies, for the modulation of distinct facets of homeostasis. Such functional differences, read out at the organismal level, are likely subserved by differences among 5-HT neuron subtypes at the cellular and molecular levels, including differences in the capacity to coexpress other neurotransmitters such as glutamate, GABA, thyrotropin releasing hormone, and substance P encoded by the Tachykinin-1 (Tac1) gene. Here, we characterize in mice a 5-HT neuron subtype identified by expression of Tac1 and the serotonergic transcription factor gene Pet1, referred to as the Tac1-Pet1 neuron subtype. Transgenic cell labeling showed Tac1-Pet1 soma resident largely in the caudal medulla. Chemogenetic [clozapine-N-oxide (CNO)-hM4Di] perturbation of Tac1-Pet1 neuron activity blunted the ventilatory response of the respiratory CO2 chemoreflex, which normally augments ventilation in response to hypercapnic acidosis to restore normal pH and PCO2. Tac1-Pet1 axonal boutons were found localized to brainstem areas implicated in respiratory modulation, with highest density in motor regions. These findings demonstrate that the activity of a Pet1 neuron subtype with the potential to release both 5-HT and substance P is necessary for normal respiratory dynamics, perhaps via motor outputs that engage muscles of respiration and maintain airway patency. These Tac1-Pet1 neurons may act downstream of Egr2-Pet1 serotonergic neurons, which were previously established in respiratory chemoreception, but do not innervate respiratory motor nuclei. SIGNIFICANCE STATEMENT Serotonin (5-HT) neurons modulate physiological processes and behaviors as diverse as body temperature, respiration, aggression, and mood. Using genetic tools, we characterize a 5-HT neuron subtype defined by expression of Tachykinin1 and Pet1 (Tac1-Pet1 neurons), mapping soma localization to the caudal medulla primarily and axonal projections to brainstem motor nuclei most prominently, and, when silenced, observed blunting of the ventilatory response to inhaled CO2. Tac1-Pet1 neurons thus appear distinct from and contrast previously described Egr2-Pet1 neurons, which project primarily to chemosensory integration centers and are themselves chemosensitive. PMID:28073937

Evaluation of a low density DNA microarray for small B-cell non-Hodgkin lymphoma differential diagnosis.

PubMed

Gillet, Jean-Pierre; Molina, Thierry Jo; Jamart, Jacques; Gaulard, Philippe; Leroy, Karen; Briere, Josette; Theate, Ivan; Thieblemont, Catherine; Bosly, Andre; Herin, Michel; Hamels, Jacques; Remacle, Jose

2009-03-01

Lymphomas are classified according to the World Health Organisation (WHO) classification which defines subtypes on the basis of clinical, morphological, immunophenotypic, molecular and cytogenetic criteria. Differential diagnosis of the subtypes is sometimes difficult, especially for small B-cell lymphoma (SBCL). Standardisation of molecular genetic assays using multiple gene expression analysis by microarrays could be a useful complement to the current diagnosis. The aim of the present study was to develop a low density DNA microarray for the analysis of 107 genes associated with B-cell non-Hodgkin lymphoma and to evaluate its performance in the diagnosis of SBCL. A predictive tool based on Fisher discriminant analysis using a training set of 40 patients including four different subtypes (follicular lymphoma n = 15, mantle cell lymphoma n = 7, B-cell chronic lymphocytic leukemia n = 6 and splenic marginal zone lymphoma n = 12) was designed. A short additional preliminary analysis to gauge the accuracy of this signature was then performed on an external set of nine patients. Using this model, eight of nine of those samples were classified successfully. This pilot study demonstrates that such a microarray tool may be a promising diagnostic approach for small B-cell non-Hodgkin lymphoma.

Transgenic mice reveal unexpected diversity of On-Off direction selective retinal ganglion cell subtypes and brain structures involved in motion processing

PubMed Central

Rivlin-Etzion, Michal; Zhou, Kaili; Wei, Wei; Elstrott, Justin; Nguyen, Phong L.; Barres, Ben; Huberman, Andrew D.; Feller, Marla B.

2011-01-01

On-Off direction selective retinal ganglion cells (DSGCs) encode the axis of visual motion. They respond strongly to an object moving in a preferred direction and weakly to an object moving in the opposite, ‘null’, direction. Historically, On-Off DSGCs were classified into 4 subtypes according to their directional preference (anterior, posterior, superior or inferior). Here, we compare two genetically identified populations of On-Off DSGCs: DRD4-DSGCs and TRHR-DSGCs. We find that although both populations are tuned for posterior motion, they can be distinguished by a variety of physiological and anatomical criteria. First, the directional tuning of TRHR-DSGCs is broader than that of DRD4-DSGCs. Second, whereas both populations project similarly to the dorsal lateral geniculate nucleus, they project differently to the ventral lateral geniculate nucleus and the superior colliculus. Moreover, TRHR-DSGCs, but not DRD4-DSGCs, also project to the zona incerta, a thalamic area not previously known to receive direction-tuned visual information. Our findings reveal unexpected diversity among mouse On-Off DSGC subtypes that uniquely process and convey image motion to the brain. PMID:21677160

Anxiety and Depression: Mouse Genetics and Pharmacological Approaches to the Role of GABAA Receptor Subtypes

PubMed Central

Smith, Kiersten S.; Rudolph, Uwe

2012-01-01

GABAA receptors mediate fast synaptic inhibitory neurotransmission throughout the central nervous system. Recent work indicates a role for GABAA receptors in physiologically modulating anxiety and depression levels. In this review, we summarize research that led to the identification of the essential role of GABAA receptors in counteracting trait anxiety and depression-related behaviors, and research aimed at identifying individual GABAA receptor subtypes involved in physiological and pharmacological modulation of emotions. PMID:21810433

A taxonomy of bacterial microcompartment loci constructed by a novel scoring method

DOE PAGES

Axen, Seth D.; Erbilgin, Onur; Kerfeld, Cheryl A.; ...

2014-10-23

Bacterial microcompartments (BMCs) are proteinaceous organelles involved in both autotrophic and heterotrophic metabolism. All BMCs share homologous shell proteins but differ in their complement of enzymes; these are typically encoded adjacent to shell protein genes in genetic loci, or operons. To enable the identification and prediction of functional (sub)types of BMCs, we developed LoClass, an algorithm that finds putative BMC loci and inventories, weights, and compares their constituent pfam domains to construct a locus similarity network and predict locus (sub)types. In addition to using LoClass to analyze sequences in the Non-redundant Protein Database, we compared predicted BMC loci found inmore » seven candidate bacterial phyla (six from single-cell genomic studies) to the LoClass taxonomy. Together, these analyses resulted in the identification of 23 different types of BMCs encoded in 30 distinct locus (sub)types found in 23 bacterial phyla. These include the two carboxysome types and a divergent set of metabolosomes, BMCs that share a common catalytic core and process distinct substrates via specific signature enzymes. Furthermore, many Candidate BMCs were found that lack one or more core metabolosome components, including one that is predicted to represent an entirely new paradigm for BMC-associated metabolism, joining the carboxysome and metabolosome. By placing these results in a phylogenetic context, we provide a framework for understanding the horizontal transfer of these loci, a starting point for studies aimed at understanding the evolution of BMCs. This comprehensive taxonomy of BMC loci, based on their constituent protein domains, foregrounds the functional diversity of BMCs and provides a reference for interpreting the role of BMC gene clusters encoded in isolate, single cell, and metagenomic data. Many loci encode ancillary functions such as transporters or genes for cofactor assembly; this expanded vocabulary of BMC-related functions should be useful for design of genetic modules for introducing BMCs in bioengineering applications.« less

HCV Genotyping from NGS Short Reads and Its Application in Genotype Detection from HCV Mixed Infected Plasma

PubMed Central

Qiu, Ping; Stevens, Richard; Wei, Bo; Lahser, Fred; Howe, Anita Y. M.; Klappenbach, Joel A.; Marton, Matthew J.

2015-01-01

Genotyping of hepatitis C virus (HCV) plays an important role in the treatment of HCV. As new genotype-specific treatment options become available, it has become increasingly important to have accurate HCV genotype and subtype information to ensure that the most appropriate treatment regimen is selected. Most current genotyping methods are unable to detect mixed genotypes from two or more HCV infections. Next generation sequencing (NGS) allows for rapid and low cost mass sequencing of viral genomes and provides an opportunity to probe the viral population from a single host. In this paper, the possibility of using short NGS reads for direct HCV genotyping without genome assembly was evaluated. We surveyed the publicly-available genetic content of three HCV drug target regions (NS3, NS5A, NS5B) in terms of whether these genes contained genotype-specific regions that could predict genotype. Six genotypes and 38 subtypes were included in this study. An automated phylogenetic analysis based HCV genotyping method was implemented and used to assess different HCV target gene regions. Candidate regions of 250-bp each were found for all three genes that have enough genetic information to predict HCV genotypes/subtypes. Validation using public datasets shows 100% genotyping accuracy. To test whether these 250-bp regions were sufficient to identify mixed genotypes, we developed a random primer-based method to sequence HCV plasma samples containing mixtures of two HCV genotypes in different ratios. We were able to determine the genotypes without ambiguity and to quantify the ratio of the abundances of the mixed genotypes in the samples. These data provide a proof-of-concept that this random primed, NGS-based short-read genotyping approach does not need prior information about the viral population and is capable of detecting mixed viral infection. PMID:25830316

A Taxonomy of Bacterial Microcompartment Loci Constructed by a Novel Scoring Method

PubMed Central

Kerfeld, Cheryl A.

2014-01-01

Bacterial microcompartments (BMCs) are proteinaceous organelles involved in both autotrophic and heterotrophic metabolism. All BMCs share homologous shell proteins but differ in their complement of enzymes; these are typically encoded adjacent to shell protein genes in genetic loci, or operons. To enable the identification and prediction of functional (sub)types of BMCs, we developed LoClass, an algorithm that finds putative BMC loci and inventories, weights, and compares their constituent pfam domains to construct a locus similarity network and predict locus (sub)types. In addition to using LoClass to analyze sequences in the Non-redundant Protein Database, we compared predicted BMC loci found in seven candidate bacterial phyla (six from single-cell genomic studies) to the LoClass taxonomy. Together, these analyses resulted in the identification of 23 different types of BMCs encoded in 30 distinct locus (sub)types found in 23 bacterial phyla. These include the two carboxysome types and a divergent set of metabolosomes, BMCs that share a common catalytic core and process distinct substrates via specific signature enzymes. Furthermore, many Candidate BMCs were found that lack one or more core metabolosome components, including one that is predicted to represent an entirely new paradigm for BMC-associated metabolism, joining the carboxysome and metabolosome. By placing these results in a phylogenetic context, we provide a framework for understanding the horizontal transfer of these loci, a starting point for studies aimed at understanding the evolution of BMCs. This comprehensive taxonomy of BMC loci, based on their constituent protein domains, foregrounds the functional diversity of BMCs and provides a reference for interpreting the role of BMC gene clusters encoded in isolate, single cell, and metagenomic data. Many loci encode ancillary functions such as transporters or genes for cofactor assembly; this expanded vocabulary of BMC-related functions should be useful for design of genetic modules for introducing BMCs in bioengineering applications. PMID:25340524

Multi-locus analysis of Giardia duodenalis from nonhuman primates kept in zoos in China: geographical segregation and host-adaptation of assemblage B isolates.

PubMed

Karim, Md Robiul; Wang, Rongjun; Yu, Fuchang; Li, Tongyi; Dong, Haiju; Li, Dezhong; Zhang, Longxian; Li, Junqiang; Jian, Fuchun; Zhang, Sumei; Rume, Farzana Islam; Ning, Changshen; Xiao, Lihua

2015-03-01

Only a few studies based on single locus characterization have been conducted on the molecular epidemiology of Giardia duodenalis in nonhuman primates (NHPs). The present study was conducted to examine the occurrence and genotype identity of G. duodenalis in NHPs based on multi-locus analysis of the small-subunit ribosomal RNA (SSU rRNA), triose phosphate isomerase (tpi), glutamate dehydrogenase (gdh), and beta-giardin (bg) genes. Fecal specimens were collected from 496 animals of 36 NHP species kept in seven zoos in China and screened for G. duodenalis by tpi-based PCR. G. duodenalis was detected in 92 (18.6%) specimens from 18 NHP species, belonging to assemblage A (n=4) and B (n=88). In positive NHP species, the infection rates ranged from 4.8% to 100%. In tpi sequence analysis, the assemblage A included subtypes A1, A2 and one novel subtype. Multi-locus analysis of the tpi, gdh, and bg genes detected 11 (8 known and 3 new), 6 (3 known and 3 new) and 9 (2 known and 7 new) subtypes in 88, 47 and 35 isolates in assemblage B, respectively. Thirty-two assemblage B isolates with data at all three loci yielded 15 multi-locus genotypes (MLGs), including 2 known and 13 new MLGs. Phylogenetic analysis of concatenated sequences of assemblage B showed that MLGs found here were genetically different from those of humans, NHPs, rabbit and guinea pig in Italy and Sweden. It further indicated that assemblage B isolates in ring-tailed lemurs and squirrel monkeys might be genetically different from those in other NHPs. These data suggest that NHPs are mainly infected with G. duodenalis assemblage B and there might be geographical segregation and host-adaptation in assemblage B in NHPs. Copyright © 2014 Elsevier B.V. All rights reserved.

Laboratory, clinical and therapeutic features of respiratory panic disorder subtype.

PubMed

Zugliani, Morena M; Freire, Rafael C; Perna, Giampaolo; Crippa, Jose A; Nardi, Antonio E

2015-01-01

It is our aim to elaborate on the new developments in regard to the respiratory subtype (RS) of panic disorder (PD) since it was first described. We will present psychopathological features, diagnostic criteria, genetic and physiopathological hypotheses, as well as therapeutic and prognostic characteristics. Two searches were performed in the Thomson Reuters Web of Knowledge (http://wokinfo.com/): 1 - search terms: "panic disorder" AND ("respiratory symptom" OR "respiratory symptoms" OR "respiratory subtype" OR "respiratory panic" OR "cardiorespiratory"); 2 - all articles citing Briggs and colleagues' 1993 article "Subtyping of Panic Disorder by Symptom Profile" (Br J Psychiatry 1993;163: 201-9). Only those articles involving human subjects and written English were included. In comparison with patients of the non-respiratory subtype (NRS), RS patients showed greater familial history of PD, and higher comorbidity rates for anxiety disorders and depressive disorders. These patients were also more sensitive to CO2, hyperventilation and caffeine. Certain characteristics, such as heightened sensitivity to CO2 and the higher incidence of a family history of PD, clearly distinguished the Respiratory Subtype patients from the Non-Respiratory. Nonetheless, some studies failed to demonstrate differential responses to pharmacological treatment and CBT across the subtypes. RS patients seem to respond faster than NRS to pharmacological treatment with antidepressants and benzodiazepines, but more studies are needed to confirm this finding.

Quantitating the Multiplicity of Infection with Human Immunodeficiency Virus Type 1 Subtype C Reveals a Non-Poisson Distribution of Transmitted Variants▿ †

PubMed Central

Abrahams, M.-R.; Anderson, J. A.; Giorgi, E. E.; Seoighe, C.; Mlisana, K.; Ping, L.-H.; Athreya, G. S.; Treurnicht, F. K.; Keele, B. F.; Wood, N.; Salazar-Gonzalez, J. F.; Bhattacharya, T.; Chu, H.; Hoffman, I.; Galvin, S.; Mapanje, C.; Kazembe, P.; Thebus, R.; Fiscus, S.; Hide, W.; Cohen, M. S.; Karim, S. Abdool; Haynes, B. F.; Shaw, G. M.; Hahn, B. H.; Korber, B. T.; Swanstrom, R.; Williamson, C.

2009-01-01

Identifying the specific genetic characteristics of successfully transmitted variants may prove central to the development of effective vaccine and microbicide interventions. Although human immunodeficiency virus transmission is associated with a population bottleneck, the extent to which different factors influence the diversity of transmitted viruses is unclear. We estimate here the number of transmitted variants in 69 heterosexual men and women with primary subtype C infections. From 1,505 env sequences obtained using a single genome amplification approach we show that 78% of infections involved single variant transmission and 22% involved multiple variant transmissions (median of 3). We found evidence for mutations selected for cytotoxic-T-lymphocyte or antibody escape and a high prevalence of recombination in individuals infected with multiple variants representing another potential escape pathway in these individuals. In a combined analysis of 171 subtype B and C transmission events, we found that infection with more than one variant does not follow a Poisson distribution, indicating that transmission of individual virions cannot be seen as independent events, each occurring with low probability. While most transmissions resulted from a single infectious unit, multiple variant transmissions represent a significant fraction of transmission events, suggesting that there may be important mechanistic differences between these groups that are not yet understood. PMID:19193811

Sex Differences in Stroke Severity, Symptoms, and Deficits After First-Ever Ischemic Stroke

PubMed Central

Barrett, Kevin M.; Brott, Thomas G.; Brown, Robert D.; Frankel, Michael R.; Worrall, Bradford B.; Silliman, Scott L.; Case, L. Douglas; Rich, Stephen S.; Meschia, James F.

2007-01-01

Objective The purpose of the study was to assess whether there were sex differences in stroke severity, infarct characteristics, symptoms, or the symptoms-deficit relationship at the time of acute stroke presentation. Methods In a prospective study of 505 patients with first-ever ischemic stroke (the Ischemic Stroke Genetics Study), stroke subtype was centrally adjudicated and infarcts were characterized by imaging. Deficits were assessed by National Institutes of Health Stroke Scale and stroke symptoms were assessed using a structured interview. Kappa statistics were generated to assess agreement between the National Institutes of Health Stroke Scale and the structured interview, and a χ2 test was used to assess agreement between the National Institutes of Health Stroke Scale and the structured interview by sex. Results Two hundred seventy-six patients (55%) were men and 229 (45%) were women. Ages ranged from 19 to 94 years (median, 65 years). The mean (±SD) National Institutes of Health Stroke Scale score of 3.8 (±4.5) for men and 4.3 (±5.2) for women was similar (P=.15). No sex difference was observed for the symptoms of numbness, visual deficits, or language. Weakness occurred in a greater proportion of women (69%) than men (59%) (P=.03). Stroke subtype did not differ significantly between sexes (P=.79). Infarct size and location were similar for each sex. The association between symptoms and neurologic deficits did not differ by sex. Conclusions We found no sex difference in stroke severity, stroke subtype, or infarct size and location in patients with incident ischemic stroke. A greater proportion of women presented with weakness; however, similar proportions of men and women presented with other traditional stroke symptoms. PMID:17689390

In Pursuit of Neurophenotypes: The Consequences of Having Autism and a Big Brain

PubMed Central

Amaral, David G.; Li, Deana; Libero, Lauren; Solomon, Marjorie; Van de Water, Judy; Mastergeorge, Ann; Naigles, Letitia; Rogers, Sally; Nordahl, Christine Wu

2017-01-01

A consensus has emerged that despite common core features, autism spectrum disorder (ASD) has multiple etiologies and various genetic and biological characteristics. The fact that there are likely to be subtypes of ASD has complicated attempts to develop effective therapies. The UC Davis MIND Institute Autism Phenome Project is a longitudinal, multidisciplinary analysis of children with autism and age-matched typically developing controls; nearly 400 families are participating in this study. The overarching goal is to gather sufficient biological, medical, and behavioral data to allow definition of clinically meaningful subtypes of ASD. One reasonable hypothesis is that different subtypes of autism will demonstrate different patterns of altered brain organization or development i.e., different neurophenotypes. In this Commentary, we discuss one neurophenotype that is defined by megalencephaly, or having brain size that is large and disproportionate to body size. We have found that 15% of the boys with autism demonstrate this neurophenotype, though it is far less common in girls. We review behavioral and medical characteristics of the large-brained group of boys with autism in comparison to those with typically sized brains. While brain size in typically developing individuals is positively correlated with cognitive function, the children with autism and larger brains have more severe disabilities and poorer prognosis. This research indicates that phenotyping in autism, like genotyping, requires a very substantial cohort of subjects. Moreover, since brain and behavior relationships may emerge at different times during development, this effort highlights the need for longitudinal analyses to carry out meaningful phenotyping. PMID:28239961

Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.

PubMed

Jusakul, Apinya; Cutcutache, Ioana; Yong, Chern Han; Lim, Jing Quan; Huang, Mi Ni; Padmanabhan, Nisha; Nellore, Vishwa; Kongpetch, Sarinya; Ng, Alvin Wei Tian; Ng, Ley Moy; Choo, Su Pin; Myint, Swe Swe; Thanan, Raynoo; Nagarajan, Sanjanaa; Lim, Weng Khong; Ng, Cedric Chuan Young; Boot, Arnoud; Liu, Mo; Ong, Choon Kiat; Rajasegaran, Vikneswari; Lie, Stefanus; Lim, Alvin Soon Tiong; Lim, Tse Hui; Tan, Jing; Loh, Jia Liang; McPherson, John R; Khuntikeo, Narong; Bhudhisawasdi, Vajaraphongsa; Yongvanit, Puangrat; Wongkham, Sopit; Totoki, Yasushi; Nakamura, Hiromi; Arai, Yasuhito; Yamasaki, Satoshi; Chow, Pierce Kah-Hoe; Chung, Alexander Yaw Fui; Ooi, London Lucien Peng Jin; Lim, Kiat Hon; Dima, Simona; Duda, Dan G; Popescu, Irinel; Broet, Philippe; Hsieh, Sen-Yung; Yu, Ming-Chin; Scarpa, Aldo; Lai, Jiaming; Luo, Di-Xian; Carvalho, André Lopes; Vettore, André Luiz; Rhee, Hyungjin; Park, Young Nyun; Alexandrov, Ludmil B; Gordân, Raluca; Rozen, Steven G; Shibata, Tatsuhiro; Pairojkul, Chawalit; Teh, Bin Tean; Tan, Patrick

2017-10-01

Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters-fluke-positive CCAs (clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and PD-1 / PD-L2 expression, or epigenetic mutations ( IDH1/2, BAP1 ) and FGFR / PRKA -related gene rearrangements. Whole-genome analysis highlighted FGFR2 3' untranslated region deletion as a mechanism of FGFR2 upregulation. Integration of noncoding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores-mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer. Significance: Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes. Cancer Discov; 7(10); 1116-35. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047 . ©2017 American Association for Cancer Research.

Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB.

PubMed

Ribasés, M; Ramos-Quiroga, J A; Hervás, A; Bosch, R; Bielsa, A; Gastaminza, X; Artigas, J; Rodriguez-Ben, S; Estivill, X; Casas, M; Cormand, B; Bayés, M

2009-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in which different genetic and environmental susceptibility factors are involved. Several lines of evidence support the view that at least 30% of ADHD patients diagnosed in childhood continue to suffer the disorder during adulthood and that genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. Genetic, biochemical and pharmacological studies support the idea that the serotonin system participates in the etiology of ADHD. Based on these data, we aimed to analyze single nucleotide polymorphisms across 19 genes involved in the serotoninergic neurotransmission in a clinical sample of 451 ADHD patients (188 adults and 263 children) and 400 controls using a population-based association study. Several significant associations were found after correcting for multiple testing: (1) the DDC gene was strongly associated with both adulthood (P=0.00053; odds ratio (OR)=2.17) and childhood ADHD (P=0.0017; OR=1.90); (2) the MAOB gene was found specifically associated in the adult ADHD sample (P=0.0029; OR=1.90) and (3) the 5HT2A gene showed evidence of association only with the combined ADHD subtype both in adults (P=0.0036; OR=1.63) and children (P=0.0084; OR=1.49). Our data support the contribution of the serotoninergic system in the genetic predisposition to ADHD, identifying common childhood and adulthood ADHD susceptibility factors, associations that are specific to ADHD subtypes and one variant potentially involved in the continuity of the disorder throughout lifespan.

Ancestry as a potential modifier of gene expression in breast tumors from Colombian women

PubMed Central

Serrano-Gómez, Silvia J.; Sanabria-Salas, María Carolina; Garay, Jone; Baddoo, Melody C.; Hernández-Suarez, Gustavo; Mejía, Juan Carlos; García, Oscar; Miele, Lucio

2017-01-01

Background Hispanic/Latino populations are a genetically admixed and heterogeneous group, with variable fractions of European, Indigenous American and African ancestries. The molecular profile of breast cancer has been widely described in non-Hispanic Whites but equivalent knowledge is lacking in Hispanic/Latinas. We have previously reported that the most prevalent breast cancer intrinsic subtype in Colombian women was Luminal B as defined by St. Gallen 2013 criteria. In this study we explored ancestry-associated differences in molecular profiles of Luminal B tumors among these highly admixed women. Methods We performed whole-transcriptome RNA-seq analysis in 42 Luminal tumors (21 Luminal A and 21 Luminal B) from Colombian women. Genetic ancestry was estimated from a panel of 80 ancestry-informative markers (AIM). We categorized patients according to Luminal subtype and to the proportion of European and Indigenous American ancestry and performed differential expression analysis comparing Luminal B against Luminal A tumors according to the assigned ancestry groups. Results We found 5 genes potentially modulated by genetic ancestry: ERBB2 (log2FC = 2.367, padj<0.01), GRB7 (log2FC = 2.327, padj<0.01), GSDMB (log2FC = 1.723, padj<0.01, MIEN1 (log2FC = 2.195, padj<0.01 and ONECUT2 (log2FC = 2.204, padj<0.01). In the replication set we found a statistical significant association between ERBB2 expression with Indigenous American ancestry (p = 0.02, B = 3.11). This association was not biased by the distribution of HER2+ tumors among the groups analyzed. Conclusions Our results suggest that genetic ancestry in Hispanic/Latina women might modify ERBB2 gene expression in Luminal tumors. Further analyses are needed to confirm these findings and explore their prognostic value. PMID:28832682

Clinical and genetic study of hereditary spastic paraplegia in Canada.

PubMed

Chrestian, Nicolas; Dupré, Nicolas; Gan-Or, Ziv; Szuto, Anna; Chen, Shiyi; Venkitachalam, Anil; Brisson, Jean-Denis; Warman-Chardon, Jodi; Ahmed, Sohnee; Ashtiani, Setareh; MacDonald, Heather; Mohsin, Noreen; Mourabit-Amari, Karim; Provencher, Pierre; Boycott, Kym M; Stavropoulos, Dimitri J; Dion, Patrick A; Ray, Peter N; Suchowersky, Oksana; Rouleau, Guy A; Yoon, Grace

2017-02-01

To describe the clinical, genetic, and epidemiologic features of hereditary spastic paraplegia (HSP) in Canada and to determine which clinical, radiologic, and genetic factors determine functional outcomes for patients with HSP. We conducted a multicenter observational study of patients who met clinical criteria for the diagnosis of HSP in the provinces of Alberta, Ontario, and Quebec from 2012 to 2015. Characteristics of the participants were analyzed using descriptive statistics. The main outcome measure for a subset of the cohort (n = 48) was the Spastic Paraplegia Rating Scale. We also used the SPATAX-EUROSPA disability stage (disability score) to assess disability (n = 65). A total of 526 patients were identified with HSP across the country, and 150 patients had a confirmed genetic diagnosis. Mutations were identified in 15 different genes; the most common were SPAST (SPG4, 48%), ATL1 (SPG3A, 16%), SPG11 (8%), SPG7 (7%), and KIAA0196 (SPG8, 5%). The diagnosis of SPG4 was associated with older age at symptom onset ( p = 0.0017). SPG4 and SPG3A were less associated with learning disabilities compared to other subtypes of HSP, and SPG11 was strongly associated with progressive cognitive deficits (odds ratio 87.75, 95% confidence interval 14.04-548.24, p < 0.0001). SPG3A was associated with better functional outcomes compared to other HSP subtypes ( p = 0.04) on multivariate analysis. The strongest predictor of significant disability was abnormal brain MRI ( p = 0.014). The most important predictors of disability in our HSP cohort were SPG11 mutations and abnormal brain MRI. Accurate molecular characterization of well-phenotyped cohorts and international collaboration are essential to establish the natural history of these rare neurodegenerative disorders.

Generation and comparison of CRISPR-Cas9 and Cre-mediated genetically engineered mouse models of sarcoma

PubMed Central

Huang, Jianguo; Chen, Mark; Whitley, Melodi Javid; Kuo, Hsuan-Cheng; Xu, Eric S.; Walens, Andrea; Mowery, Yvonne M.; Van Mater, David; Eward, William C.; Cardona, Diana M.; Luo, Lixia; Ma, Yan; Lopez, Omar M.; Nelson, Christopher E.; Robinson-Hamm, Jacqueline N.; Reddy, Anupama; Dave, Sandeep S.; Gersbach, Charles A.; Dodd, Rebecca D.; Kirsch, David G.

2017-01-01

Genetically engineered mouse models that employ site-specific recombinase technology are important tools for cancer research but can be costly and time-consuming. The CRISPR-Cas9 system has been adapted to generate autochthonous tumours in mice, but how these tumours compare to tumours generated by conventional recombinase technology remains to be fully explored. Here we use CRISPR-Cas9 to generate multiple subtypes of primary sarcomas efficiently in wild type and genetically engineered mice. These data demonstrate that CRISPR-Cas9 can be used to generate multiple subtypes of soft tissue sarcomas in mice. Primary sarcomas generated with CRISPR-Cas9 and Cre recombinase technology had similar histology, growth kinetics, copy number variation and mutational load as assessed by whole exome sequencing. These results show that sarcomas generated with CRISPR-Cas9 technology are similar to sarcomas generated with conventional modelling techniques and suggest that CRISPR-Cas9 can be used to more rapidly generate genotypically and phenotypically similar cancers. PMID:28691711

Genetic diversity of Venezuelan alphaviruses and circulation of a Venezuelan equine encephalitis virus subtype IAB strain during an interepizootic period.

PubMed

Medina, Gladys; Garzaro, Domingo J; Barrios, Miguel; Auguste, Albert J; Weaver, Scott C; Pujol, Flor H

2015-07-01

Several species of alphaviruses have been previously described in the Americas, some of which are associated with encephalitis and others are associated with arthralgia. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV) are endemic to Venezuela, with the former being responsible for major outbreaks of severe and often fatal disease in animals and humans. The aim of this study was to analyze the genetic diversity of Venezuelan alphaviruses isolated during two decades (1973-1999) of surveillance in northern Venezuela. Phylogenetic analysis indicated the circulation of a VEEV subtype IAB strain 8 years after the last reported outbreak. Thirteen strains within two subclades of South American lineage III of EEEV were also found in Venezuela. Considerable genetic variability was observed among Venezuelan Una virus strains, which were widely distributed among the clades. The first Venezuelan Mayaro sequence was also characterized. © The American Society of Tropical Medicine and Hygiene.

Endemic Venezuelan Equine Encephalitis in Northern Peru

PubMed Central

Aguilar, Patricia V.; Greene, Ivorlyne P.; Coffey, Lark L.; Medina, Gladys; Moncayo, Abelardo C.; Anishchenko, Michael; Ludwig, George V.; Turell, Michael J.; O’Guinn, Monica L.; Lee, John; Tesh, Robert B.; Watts, Douglas M.; Russell, Kevin L.; Hice, Christine; Yanoviak, Stephen; Morrison, Amy C.; Klein, Terry A.; Dohm, David J.; Guzman, Hilda; Travassos da Rosa, Amelia P.A.; Guevara, Carolina; Kochel, Tadeusz; Olson, James; Cabezas, Cesar

2004-01-01

Since Venezuelan equine encephalitis virus (VEEV) was isolated in Peru in 1942, >70 isolates have been obtained from mosquitoes, humans, and sylvatic mammals primarily in the Amazon region. To investigate genetic relationships among the Peru VEEV isolates and between the Peru isolates and other VEEV strains, a fragment of the PE2 gene was amplified and analyzed by single-stranded conformation polymorphism. Representatives of seven genotypes underwent sequencing and phylogenetic analysis. The results identified four VEE complex lineages that cocirculate in the Amazon region: subtypes ID (Panama and Colombia/Venezuela genotypes), IIIC, and a new, proposed subtype IIID, which was isolated from a febrile human, mosquitoes, and spiny rats. Both ID lineages and the IIID subtype are associated with febrile human illness. Most of the subtype ID isolates belonged to the Panama genotype, but the Colombia/Venezuela genotype, which is phylogenetically related to epizootic strains, also continues to circulate in the Amazon basin. PMID:15200823

Endemic Venezuelan equine encephalitis in northern Peru.

PubMed

Aguilar, Patricia V; Greene, Ivorlyne P; Coffey, Lark L; Medina, Gladys; Moncayo, Abelardo C; Anishchenko, Michael; Ludwig, George V; Turell, Michael J; O'Guinn, Monica L; Lee, John; Tesh, Robert B; Watts, Douglas M; Russell, Kevin L; Hice, Christine; Yanoviak, Stephen; Morrison, Amy C; Klein, Terry A; Dohm, David J; Guzman, Hilda; Travassos da Rosa, Amelia P A; Guevara, Carolina; Kochel, Tadeusz; Olson, James; Cabezas, Cesar; Weaver, Scott C

2004-05-01

Since Venezuelan equine encephalitis virus (VEEV) was isolated in Peru in 1942, >70 isolates have been obtained from mosquitoes, humans, and sylvatic mammals primarily in the Amazon region. To investigate genetic relationships among the Peru VEEV isolates and between the Peru isolates and other VEEV strains, a fragment of the PE2 gene was amplified and analyzed by single-stranded conformation polymorphism. Representatives of seven genotypes underwent sequencing and phylogenetic analysis. The results identified four VEE complex lineages that cocirculate in the Amazon region: subtypes ID (Panama and Colombia/Venezuela genotypes), IIIC, and a new, proposed subtype IIID, which was isolated from a febrile human, mosquitoes, and spiny rats. Both ID lineages and the IIID subtype are associated with febrile human illness. Most of the subtype ID isolates belonged to the Panama genotype, but the Colombia/Venezuela genotype, which is phylogenetically related to epizootic strains, also continues to circulate in the Amazon basin.

The combined expression patterns of Ikaros isoforms characterize different hematological tumor subtypes.

PubMed

Orozco, Carlos A; Acevedo, Andrés; Cortina, Lazaro; Cuellar, Gina E; Duarte, Mónica; Martín, Liliana; Mesa, Néstor M; Muñoz, Javier; Portilla, Carlos A; Quijano, Sandra M; Quintero, Guillermo; Rodriguez, Miriam; Saavedra, Carlos E; Groot, Helena; Torres, María M; López-Segura, Valeriano

2013-01-01

A variety of genetic alterations are considered hallmarks of cancer development and progression. The Ikaros gene family, encoding for key transcription factors in hematopoietic development, provides several examples as genetic defects in these genes are associated with the development of different types of leukemia. However, the complex patterns of expression of isoforms in Ikaros family genes has prevented their use as clinical markers. In this study, we propose the use of the expression profiles of the Ikaros isoforms to classify various hematological tumor diseases. We have standardized a quantitative PCR protocol to estimate the expression levels of the Ikaros gene exons. Our analysis reveals that these levels are associated with specific types of leukemia and we have found differences in the levels of expression relative to five interexonic Ikaros regions for all diseases studied. In conclusion, our method has allowed us to precisely discriminate between B-ALL, CLL and MM cases. Differences between the groups of lymphoid and myeloid pathologies were also identified in the same way.

Molecular phylogeny of edge hill virus supports its position in the yellow Fever virus group and identifies a new genetic variant.

PubMed

Macdonald, Joanne; Poidinger, Michael; Mackenzie, John S; Russell, Richard C; Doggett, Stephen; Broom, Annette K; Phillips, Debra; Potamski, Joseph; Gard, Geoff; Whelan, Peter; Weir, Richard; Young, Paul R; Gendle, Debra; Maher, Sheryl; Barnard, Ross T; Hall, Roy A

2010-06-15

Edge Hill virus (EHV) is a mosquito-borne flavivirus isolated throughout Australia during mosquito surveillance programs. While not posing an immediate threat to the human population, EHV is a taxonomically interesting flavivirus since it remains the only member of the yellow fever virus (YFV) sub-group to be detected within Australia. Here we present both an antigenic and genetic investigation of collected isolates, and confirm taxonomic classification of the virus within the YFV-group. Isolates were not clustered based on geographical origin or time of isolation, suggesting that minimal genetic evolution of EHV has occurred over geographic distance or time within the EHV cluster. However, two isolates showed significant differences in antigenic reactivity patterns, and had a much larger divergence from the EHV prototype (19% nucleotide and 6% amino acid divergence), indicating a distinct subtype or variant within the EHV subgroup.

New trend in the epidemiology of thalassaemia.

PubMed

Li, Chi-Kong

2017-02-01

Thalassaemia is the most common monogenic disorder worldwide. It is common in areas with prevalent malaria as thalassaemic red cells provide immunity against the parasite. The incidence of thalassaemia carriers is high in regions such as Mediterranean, Middle East, Indian subcontinent, Southeast Asia and South China. In the past few decades, migrants from the thalassaemia prevalent countries to non-prevalent countries, mainly North America and Central and North Europe, are rapidly increasing in number. The non-prevalent countries may not have established pre-natal screening system for thalassaemia. The genetic subtypes among the different ethnic groups vary; this may pose challenges in prenatal diagnosis. Genetic counselling on the postnatal course of thalassaemia may be affected by the genotype-phenotype correlation and coinheritance of other genetic diseases. New treatment methods improve the survival of patient with thalassaemia major, but some late complications that occur with longer survival have been recently discovered. Copyright © 2016. Published by Elsevier Ltd.

A national study of the molecular epidemiology of HIV-1 in Australia 2005–2012

PubMed Central

Castley, Alison; Sawleshwarkar, Shailendra; Varma, Rick; Herring, Belinda; Thapa, Kiran; Dwyer, Dominic; Chibo, Doris; Nguyen, Nam; Hawke, Karen; Ratcliff, Rodney; Garsia, Roger; Kelleher, Anthony; Nolan, David

2017-01-01

Introduction Rates of new HIV-1 diagnoses are increasing in Australia, with evidence of an increasing proportion of non-B HIV-1 subtypes reflecting a growing impact of migration and travel. The present study aims to define HIV-1 subtype diversity patterns and investigate possible HIV-1 transmission networks within Australia. Methods The Australian Molecular Epidemiology Network (AMEN) HIV collaborating sites in Western Australia, South Australia, Victoria, Queensland and western Sydney (New South Wales), provided baseline HIV-1 partial pol sequence, age and gender information for 4,873 patients who had genotypes performed during 2005–2012. HIV-1 phylogenetic analyses utilised MEGA V6, with a stringent classification of transmission pairs or clusters (bootstrap ≥98%, genetic distance ≤1.5% from at least one other sequence in the cluster). Results HIV-1 subtype B represented 74.5% of the 4,873 sequences (WA 59%, SA 68.4%, w-Syd 73.8%, Vic 75.6%, Qld 82.1%), with similar proportion of transmission pairs and clusters found in the B and non-B cohorts (23% vs 24.5% of sequences, p = 0.3). Significantly more subtype B clusters were comprised of ≥3 sequences compared with non-B clusters (45.0% vs 24.0%, p = 0.021) and significantly more subtype B pairs and clusters were male-only (88% compared to 53% CRF01_AE and 17% subtype C clusters). Factors associated with being in a cluster of any size included; being sequenced in a more recent time period (p<0.001), being younger (p<0.001), being male (p = 0.023) and having a B subtype (p = 0.02). Being in a larger cluster (>3) was associated with being sequenced in a more recent time period (p = 0.05) and being male (p = 0.008). Conclusion This nationwide HIV-1 study of 4,873 patient sequences highlights the increased diversity of HIV-1 subtypes within the Australian epidemic, as well as differences in transmission networks associated with these HIV-1 subtypes. These findings provide epidemiological insights not readily available using standard surveillance methods and can inform the development of effective public health strategies in the current paradigm of HIV prevention in Australia. PMID:28489920

A longitudinal study of Stargardt disease: quantitative assessment of fundus autofluorescence, progression, and genotype correlations.

PubMed

Fujinami, Kaoru; Lois, Noemi; Mukherjee, Rajarshi; McBain, Vikki A; Tsunoda, Kazushige; Tsubota, Kazuo; Stone, Edwin M; Fitzke, Fred W; Bunce, Catey; Moore, Anthony T; Webster, Andrew R; Michaelides, Michel

2013-12-17

We characterized subtypes of fundus autofluorescence (AF) and the progression of retinal atrophy, and correlated these findings with genotype in Stargardt disease. Full clinical examination and AF imaging was undertaken in 68 patients with Stargardt disease. The baseline data were compared to those at follow-up. Patients were classified into three AF subtypes: type 1 had a localized low signal at the fovea surrounded by a homogeneous background, type 2 had a localized low signal at the macula surrounded by a heterogeneous background with numerous foci of abnormal signal, and type 3 had multiple low signal areas at the posterior pole with a heterogeneous background. At baseline, there were 19 patients with type 1, 41 with type 2, and 8 with type 3 disease. The areas of reduced AF signal were measured and rate of atrophy enlargement (RAE) was calculated as the difference of the atrophy size over time (mm²) divided by the follow-up interval (years). Molecular screening of ABCA4 was undertaken. The mean follow-up interval was 9.1 years. A total of 42% cases with type 1 disease progressed to type 2, and 12% with type 2 progressed to type 3. The RAE (mm²/y) based upon baseline AF subtypes was significantly different; 0.06 in type 1, 0.67 in type 2, and 4.37 in type 3. ABCA4 variants were identified in 57 patients. There was a significant association between AF subtype and genotype. The AF pattern at baseline influences the enlargement of atrophy over time and has genetic correlates. These data are likely to assist in the provision of counseling on prognosis in Stargardt disease and be valuable for future clinical trials.

Co-expression of mitosis-regulating genes contributes to malignant progression and prognosis in oligodendrogliomas

PubMed Central

Liu, Yanwei; Hu, Huimin; Zhang, Chuanbao; Wang, Haoyuan; Zhang, Wenlong; Wang, Zheng; Li, Mingyang; Zhang, Wei; Zhou, Dabiao; Jiang, Tao

2015-01-01

The clinical prognosis of patients with glioma is determined by tumor grades, but tumors of different subtypes with equal malignancy grade usually have different prognosis that is largely determined by genetic abnormalities. Oligodendrogliomas (ODs) are the second most common type of gliomas. In this study, integrative analyses found that distribution of TCGA transcriptomic subtypes was associated with grade progression in ODs. To identify critical gene(s) associated with tumor grades and TCGA subtypes, we analyzed 34 normal brain tissue (NBT), 146 WHO grade II and 130 grade III ODs by microarray and RNA sequencing, and identified a co-expression network of six genes (AURKA, NDC80,CENPK, KIAA0101, TIMELESS and MELK) that was associated with tumor grades and TCGA subtypes as well as Ki-67 expression. Validation of the six genes was performed by qPCR in additional 28 ODs. Importantly, these genes also were validated in four high-grade recurrent gliomas and the initial lower-grade gliomas resected from the same patients. Finally, the RNA data on two genes with the highest discrimination potential (AURKA and NDC80) and Ki-67 were validated on an independent cohort (5 NBTs and 86 ODs) by immunohistochemistry. Knockdown of AURKA and NDC80 by siRNAs suppressed Ki-67 expression and proliferation of gliomas cells. Survival analysis showed that high expression of the six genes corporately indicated a poor survival outcome. Correlation and protein interaction analysis provided further evidence for this co-expression network. These data suggest that the co-expression of the six mitosis-regulating genes was associated with malignant progression and prognosis in ODs. PMID:26468983

Comparison of Detection Limits of 4th Generation Combination HIV Antigen/Antibody, p24 Antigen and Viral Load Assays on Diverse HIV Isolates.

PubMed

Stone, Mars; Bainbridge, John; Sanchez, Ana M; Keating, Sheila M; Pappas, Andrea; Rountree, Wes; Todd, Chris; Bakkour, Sonia; Manak, Mark; Peel, Sheila A; Coombs, Robert W; Ramos, Eric M; Shriver, M Kathleen; Contestable, Paul; Nair, Sangeetha Vijaysri; Wilson, David H; Stengelin, Martin; Murphy, Gary; Hewlett, Indira; Denny, Thomas N; Busch, Michael P

2018-05-23

Detection of acute HIV infection is critical for HIV public health and diagnostics. Clinical 4 th generation antigen-antibody (Ag/Ab) combination (combo) and p24 Ag immunoassays have enhanced detection of acute infection compared to Ab alone assays, but require ongoing evaluation with currently circulating diverse subtypes. Genetically and geographically diverse HIV clinical isolates were used to assess clinical HIV diagnostic, blood screening and next generation assays. Blinded 300 member panels of 20 serially diluted well-characterized antibody negative HIV isolates were distributed to manufacturers and end-user labs to assess relative analytic sensitivity of currently approved and pre-approved clinical HIV 4 th generation Ag/Ab combo or p24 Ag alone immunoassays across diverse subtypes. The limits of virus detection (LODs) were estimated for different subtypes relative to confirmed viral loads. Analysis of immunoassay sensitivity was benchmarked against confirmed viral load measurements on the blinded panel. Based on the proportion of positive results on 300 observations all Ag/Ab combo and standard sensitivity p24 Ag assays performed similarly and within half log LODs, illustrating similar breadth of reactivity and diagnostic utility. Ultrasensitive p24 Ag assays achieved dramatically increased sensitivities, while the rapid combo-assays performed poorly. Similar performance of the different commercially available 4 th gen assays on diverse subtypes supports their use in broad geographic settings with locally circulating HIV clades and recombinant strains. Next generation pre-clinical ultrasensitive p24 Ag assays achieved dramatically improved sensitivity, while p24 Ag detection by rapid 4 th gen assays performed poorly. Copyright © 2018 American Society for Microbiology.

Familial influence and childhood trauma in female alcoholism

PubMed Central

Magnusson, Å.; Lundholm, C.; Göransson, M.; Copeland, W.; Heilig, M.; Pedersen, N. L.

2013-01-01

Background To assess the role of genetic and environmental factors in female alcoholism using a large population-based twin sample, taking into account possible differences between early and late onset disease subtype. Method Twins aged 20–47 years from the Swedish Twin Registry (n = 24 119) answered questions to establish lifetime alcohol use disorders. Subjects with alcoholism were classified for subtype. Structural equation modeling was used to quantify the proportion of phenotypic variance due to genetic and environmental factors and test whether heritability in women differed from that in men. The association between childhood trauma and alcoholism was then examined in females, controlling for background familial factors. Results Lifetime prevalence of alcohol dependence was 4.9% in women and 8.6% in men. Overall, heritability for alcohol dependence was 55%, and did not differ significantly between men and women, although women had a significantly greater heritability for late onset (type I). Childhood physical trauma and sexual abuse had a stronger association with early onset compared to late onset alcoholism [odds ratio (OR) 2.54, 95% confidence interval (CI) 1.53–3.88 and OR 2.29, 95% CI 1.38–3.79 respectively]. Co-twin analysis indicated that familial factors largely accounted for the influence of physical trauma whereas the association with childhood sexual abuse reflected both familial and specific effects. Conclusions Heritability of alcoholism in women is similar to that in men. Early onset alcoholism is strongly association with childhood trauma, which seems to be both a marker of familial background factors and a specific individual risk factor per se. PMID:21798111

Genomic characterization of H14 subtype influenza A viruses in New World waterfowl and experimental infectivity in mallards Anas platyrhynchos

USGS Publications Warehouse

Ramey, Andy M.; Poulson, Rebecca L.; Gonzalez-Reiche, Ana S.; Perez, Daniel R.; Stalknecht, David E.; Brown, Justin D.

2014-01-01

Recent repeated isolation of H14 hemagglutinin subtype influenza A viruses (IAVs) in the New World waterfowl provides evidence to suggest that host and/or geographic ranges for viruses of this subtype may be expanding. In this study, we used genomic analyses to gain inference on the origin and evolution of H14 viruses in New World waterfowl and conducted an experimental challenge study in mallards (Anas platyrhynchos) to evaluate pathogenicity, viral replication, and transmissibility of a representative viral strain in a natural host species. Genomic characterization of H14 subtype IAVs isolated from New World waterfowl, including three isolates sequenced specifically for this study, revealed high nucleotide identity among individual gene segments (e.g. ≥95% shared identity among H14 HA gene segments). In contrast, lower shared identity was observed among internal gene segments. Furthermore, multiple neuraminidase subtypes were observed for H14 IAVs isolated in the New World. Gene segments of H14 viruses isolated after 2010 shared ancestral genetic lineages with IAVs isolated from wild birds throughout North America. Thus, genomic characterization provided evidence for viral evolution in New World waterfowl through genetic drift and genetic shift since purported introduction from Eurasia. In the challenge study, no clinical disease or lesions were observed among mallards experimentally inoculated with A/blue-winged teal/Texas/AI13-1028/2013(H14N5) or exposed via contact with infected birds. Titers of viral shedding for mallards challenged with the H14N5 IAV were highest at two days post-inoculation (DPI); however shedding was detected up to nine DPI using cloacal swabs. The distribution of viral antigen among mallards infected with H14N5 IAV was largely restricted to enterocytes lining the villi in the lower intestinal tract and in the epithelium of the bursa of Fabricius. Characterization of the infectivity of A/blue-winged teal/Texas/AI13-1028/2013(H14N5) in mallards provides support for similarities in viral replication and shedding as compared to previously described waterfowl-adapted, low pathogenic IAV strains in ducks.

Origin, imports and exports of HIV-1 subtype C in South Africa: A historical perspective.

PubMed

Wilkinson, Eduan; Rasmussen, David; Ratmann, Oliver; Stadler, Tanja; Engelbrecht, Susan; de Oliveira, Tulio

2016-12-01

While the HIV epidemic in South Africa had a later onset than epidemics in other southern African countries, prevalence grew rapidly during the 1990's when the country was going through socio-political changes with the end of Apartheid. South Africa currently has the largest number of people living with HIV in the world and the epidemic is dominated by a unique subtype, HIV-1 subtype C. This large epidemic is also characterized by high level of genetic diversity. We hypothesize that this diversity is due to multiple introductions of the virus during the period of change. In this paper, we apply novel phylogeographic methods to estimate the number of viral imports and exports from the start of the epidemic to the present. We assembled 11,289 unique subtype C pol sequences from southern Africa. These represent one of the largest sequence datasets ever analyzed in the region. Sequences were stratified based on country of sampling and levels of genetic diversity were estimated for each country. Sequences were aligned and a maximum-likelihood evolutionary tree was inferred. Least-Squares Dating was then used to obtain a dated phylogeny from which we estimated the number of introductions into and exports out of South Africa using parsimony-based ancestral location reconstructions. Our results identified 189 viral introductions into South Africa with the largest number of introductions attributed to Zambia (n=109), Botswana (n=32), Malawi (n=26) and Zimbabwe (n=13). South Africa also exported many viral lineages to its neighbours. The bulk viral imports and exports appear to have occurred between 1985 and 2000, coincident with the period of socio-political transition. The high level of subtype C genetic diversity in South Africa is related to multiple introductions of the virus to the country. While the number of viral imports and exports we identified was highly sensitive to the number of samples included from each country, they mostly clustered around the period of rapid political and socio-economic change in South Africa. Copyright © 2016. Published by Elsevier B.V.

Genetic uniqueness of Cryptosporidium parvum from dairy calves in Colombia.

PubMed

Avendaño, Catalina; Ramo, Ana; Vergara-Castiblanco, Claudia; Sánchez-Acedo, Caridad; Quílez, Joaquín

2018-05-01

Fecal specimens from 432 pre-weaned calves younger than 35 days were collected over a 2-year period (2010-2012) from 74 dairy cattle farms in the central area of Colombia. These samples were microscopically examined for the presence of Cryptosporidium oocysts, and positive specimens were selected for molecular examination. Microscopy revealed that 115 calves (26.6%) from 44 farms (59.5%) tested positive. Oocyst shedding was recorded in calves aged 3-day-old onwards, although the infection rate peaked at 8-14 days (40.7%). Infection rates were higher in diarrheic (52.2%) than in non-diarrheic calves (19.9%) (p < 0.0001, χ 2 ), and infected calves had up to seven times more probability of having diarrhea than non-infected calves. Cryptosporidium species and subtypes were successfully identified in 73 samples from 32 farms. Restriction and sequence analyses of the SSU rRNA gene revealed C. parvum in all but two isolates identified as Cryptosporidium bovis. Sequence analyses of the 60-KDa glycoprotein (gp60) gene revealed eight subtypes within the IIa family. An unusual subtype (IIaA18G5R1) was the most prevalent and widely distributed (more than 66% specimens and 68% farms) while the subtype most frequently reported in cattle worldwide (IIaA15G2R1) was found in less than 13% of specimens and 16% farms. The remaining subtypes (IIaA16G2R1, IIaA17G4R1, IIaA20G5R1, IIaA19G6R1, IIaA20G6R1, and IIaA20G7R1) were restricted to 1-3 farms. This is the first large-sample size study of Cryptosporidium species and subtypes in Colombia and demonstrates the genetic uniqueness of this protozoan in cattle farms in this geographical area.

Polygenic overlap between kidney function and large artery atherosclerotic stroke

PubMed Central

Holliday, Elizabeth G.; Traylor, Matthew; Malik, Rainer; Bevan, Stephen; Maguire, Jane; Koblar, Simon A.; Sturm, Jonathan; Hankey, Graeme J.; Oldmeadow, Christopher; McEvoy, Mark; Sudlow, Cathie; Rothwell, Peter M.; Coresh, Josef; Hamet, Pavel; Tremblay, Johanne; Turner, Stephen T.; de Andrade, Mariza; Rao, Madhumathi; Schmidt, Reinhold; Crick, Peter A.; Robino, Antonietta; Peralta, Carmen A.; Jukema, J. Wouter; Mitchell, Paul; Rosas, Sylvia E.; Wang, Jie Jin; Scott, Rodney J.; Dichgans, Martin; Mitchell, Braxton D.; Linda Kao, W. H.; Fox, Caroline S.; Levi, Christopher; Attia, John; Markus, Hugh S

2014-01-01

Background and Purpose Epidemiological studies show strong associations between kidney dysfunction and risk of ischaemic stroke, the mechanisms of which are incompletely understood. We investigated whether these associations may reflect shared heritability due to a common polygenic basis and whether this differed for ischaemic stroke subtypes. Methods Polygenic models were derived using GWAS meta-analysis results for three kidney traits: estimated glomerular filtration rate using serum creatinine (eGFRcrea: N=73,998), eGFR using cystatin C (eGFRcys: N=22,937) and urinary albumin to creatinine ratio (UACR: N=31,580). For each, SNPs passing ten P-value thresholds were used to form profile scores in 4,561 ischaemic stroke cases and 7,094 controls from the UK, Germany and Australia. Scores were tested for association with ischaemic stroke and its three aetiological subtypes: large artery atherosclerosis (LAA), cardioembolism (CE) and small vessel disease (SVD). Results Polygenic scores correlating with higher eGFRcrea were associated with reduced risk of LAA, with five scores reaching P<0.05 (peak P=0.004) and all showing the epidemiologically expected direction of effect. A similar pattern was observed for polygenic scores reflecting higher UACR, of which three associated with LAA (peak P=0.01) and all showed the expected directional association. One UACR-based score also associated with SVD (P=0.03). The global pattern of results was unlikely to have occurred by chance (P=0.02). Conclusions This study suggests possible polygenic correlation between renal dysfunction and ischaemic stroke. The shared genetic components may be specific to stroke subtypes, particularly large artery atherosclerotic stroke. Further study of the genetic relationships between these disorders appears merited. PMID:25352485

Size and sequence polymorphisms in the glutamate-rich protein gene of the human malaria parasite Plasmodium falciparum in Thailand.

PubMed

Pattaradilokrat, Sittiporn; Trakoolsoontorn, Chawinya; Simpalipan, Phumin; Warrit, Natapot; Kaewthamasorn, Morakot; Harnyuttanakorn, Pongchai

2018-01-22

The glutamate-rich protein (GLURP) of the malaria parasite Plasmodium falciparum is a key surface antigen that serves as a component of a clinical vaccine. Moreover, the GLURP gene is also employed routinely as a genetic marker for malarial genotyping in epidemiological studies. While extensive size polymorphisms in GLURP are well recorded, the extent of the sequence diversity of this gene is rarely investigated. The present study aimed to explore the genetic diversity of GLURP in natural populations of P. falciparum. The polymorphic C-terminal repetitive R2 region of GLURP sequences from 65 P. falciparum isolates in Thailand were generated and combined with the data from 103 worldwide isolates to generate a GLURP database. The collection was comprised of 168 alleles, encoding 105 unique GLURP subtypes, characterized by 18 types of amino acid repeat units (AAU). Of these, 28 GLURP subtypes, formed by 10 AAU types, were detected in P. falciparum in Thailand. Among them, 19 GLURP subtypes and 2 AAU types are described for the first time in the Thai parasite population. The AAU sequences were highly conserved, which is likely due to negative selection. Standard Fst analysis revealed the shared distributions of GLURP types among the P. falciparum populations, providing evidence of gene flow among the different demographic populations. Sequence diversity causing size variations in GLURP in Thai P. falciparum populations were detected, and caused by non-synonymous substitutions in repeat units and some insertion/deletion of aspartic acid or glutamic acid codons between repeat units. The P. falciparum population structure based on GLURP showed promising implications for the development of GLURP-based vaccines and for monitoring vaccine efficacy.

Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 211 cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph)

PubMed Central

Slager, Susan L.; Brennan, Paul; Holly, Elizabeth A.; De Sanjose, Silvia; Bernstein, Leslie; Boffetta, Paolo; Cerhan, James R.; Maynadie, Marc; Spinelli, John J.; Chiu, Brian C. H.; Cocco, Pier Luigi; Mensah, Fiona; Zhang, Yawei; Nieters, Alexandra; Dal Maso, Luigino; Bracci, Paige M.; Costantini, Adele Seniori; Vineis, Paolo; Severson, Richard K.; Roman, Eve; Cozen, Wendy; Weisenburger, Dennis; Davis, Scott; Franceschi, Silvia; La Vecchia, Carlo; Foretova, Lenka; Becker, Nikolaus; Staines, Anthony; Vornanen, Martine; Zheng, Tongzhang; Hartge, Patricia

2007-01-01

A role for genetic susceptibility in non-Hodgkin lymphoma (NHL) is supported by the accumulating evidence of common genetic variations altering NHL risk. However, the pattern of NHL heritability remains poorly understood. We conducted a pooled analysis of 10 211 NHL cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph) to evaluate NHL risk among those with hematopoietic malignancies in first-degree relatives. Odds ratios (ORs) and 95% confidence intervals (CIs) of NHL and its subtypes were estimated from unconditional logistic regression models with adjustment for confounders. NHL risk was elevated for individuals who reported first-degree relatives with NHL (OR = 1.5; 95% CI = 1.2-1.9), Hodgkin lymphoma (OR = 1.6; 95% CI = 1.1-2.3), and leukemia (OR = 1.4; 95% CI = 1.2-2.7). Risk was highest among individuals who reported a brother with NHL (OR = 2.8; 95% CI = 1.6-4.8) and was consistent for all NHL subtypes evaluated. If a first-degree relative had Hodgkin lymphoma, NHL risk was highest if the relative was a parent (OR = 1.7; 95% CI = 1.0-2.9). If a first-degree relative had leukemia, NHL risk was highest among women who reported a sister with leukemia (OR = 3.0; 95% CI = 1.6-5.6). The pattern of NHL heritability appeared to be uniform across NHL subtypes, but risk patterns differed by specific hematopoietic malignancies and the sex of the relative, revealing critical clues to disease etiology. PMID:17185468

Homopolymeric tract heteroplasmy in mtDNA from tissues and single oocytes: support for a genetic bottleneck.

PubMed Central

Marchington, D R; Hartshorne, G M; Barlow, D; Poulton, J

1997-01-01

While mtDNA polymorphisms at single base positions are common, the overwhelming majority of the mitochondrial genomes within a single individual are usually identical. When there is a point-mutation difference between a mother and her offspring, there may be a complete switching of mtDNA type within a single generation. It is generally assumed that there is a genetic bottleneck whereby a single or small number of founder mtDNA(s) populate the organism, but it is not known at which stages the restriction/amplification of mtDNA subtype(s) occur, and this uncertainty impedes antenatal diagnosis for mtDNA disorders. Length polymorphisms in homopolymeric tracts have been demonstrated in the large noncoding region of mtDNA. We have developed a new method, T-PCR (trimmed PCR), to quantitate heteroplasmy for two of these tracts (D310 and D16189). D310 variation is sufficient to indicate clonal origins of tissues and single oocytes. Tissues from normal individuals often possessed more than one length variant (heteroplasmy). However, there was no difference in the pattern of the length variants between somatic tissues in any control individual when bulk samples were taken. Oocytes from normal women undergoing in vitro fertilization were frequently heteroplasmic for length variants, and in two cases the modal length of the D310 tract differed in individual oocytes from the same woman. These data suggest that a restriction/amplification event, which we attribute to clonal expansion of founder mtDNA(s), has occurred by the time oocytes are mature, although further segregation may occur at a later stage. In contrast to controls, the length distribution of the D310 tract varied between tissues in a patient with heteroplasmic mtDNA rearrangements, suggesting that these mutants influence segregation. These findings have important implications for the genetic counselling of patients with pathogenic mtDNA mutations. Images Figure 2 Figure 1 Figure 3 Figure 4 Figure 5 PMID:9012414

Novel reassortant H9N2 viruses in pigeons and evidence for antigenic diversity of H9N2 viruses isolated from quails in Egypt

PubMed Central

Kandeil, Ahmed; El-Shesheny, Rabeh; Maatouq, Asmaa; Moatasim, Yassmin; Cai, Zhipeng; McKenzie, Pamela; Webby, Richard

2017-01-01

The endemicity of avian influenza viruses (AIVs) among Egyptian poultry represents a public health risk. Co-circulation of low pathogenic AIV H9N2 subtype with highly pathogenic AIV H5N1 subtype in Egyptian farms provides a possibility to generate novel reassortant viruses. Here, the genetic characteristics of surface glycoproteins of 59 Egyptian H9N2 viruses, isolated between 2013 and 2015, were analysed. To elucidate the potential of genetic reassortment, 10 H9N2 isolates were selected based on different avian hosts (chickens, ducks, pigeons and quails) and phylogenetic analyses of their full genome sequences were conducted. Additionally, we performed antigenic analysis to further investigate the antigenic evolution of H9N2 viruses isolated during 2011–2015. Different viral characteristics including receptor-binding affinity and drug resistance of representative Egyptian H9N2 viruses were further investigated. The surface glycoproteins of current Egyptian H9N2 viruses were closely related to viruses of the G1-like lineage isolated from Egypt. Several genetic markers that enhance virulence in poultry and transmission to humans were detected. Analysis of the full genome of 10 H9N2 isolates indicated that two pigeon isolates inherited five internal genes from Eurasian AIVs circulating in wild birds. Antigenic conservation of different Egyptian H9N2 isolates from chickens, pigeons and ducks was observed, whereas quail isolates showed antigenic drift. The Egyptian H9N2 viruses preferentially bound to the human-like receptor rather than to the avian-like receptor. Our results suggest that the endemic H9N2 viruses in Egypt contain elements that may favour avian-to-human transmission and thus represent a public health risk. PMID:27902350

Comorbid obsessive-compulsive personality disorder in obsessive-compulsive disorder (OCD): a marker of severity.

PubMed

Lochner, Christine; Serebro, Paul; van der Merwe, Lize; Hemmings, Sian; Kinnear, Craig; Seedat, Soraya; Stein, Dan J

2011-06-01

Comorbid obsessive-compulsive personality disorder (OCPD) is well-described in obsessive-compulsive disorder (OCD). It remains unclear, however, whether OCPD in OCD represents a distinct subtype of OCD or whether it is simply a marker of severity in OCD. The aim of this study was to compare a large sample of OCD subjects (n=403) with and without OCPD on a range of demographic, clinical and genetic characteristics to evaluate whether comorbid OCPD in OCD represents a distinct subtype of OCD, or is a marker of severity. Our findings suggest that OCD with and without OCPD are similar in terms of gender distribution and age at onset of OC symptoms. Compared to OCD-OCPD (n=267, 66%), those with OCD+OCPD (n=136, 34%) are more likely to present with the OC symptom dimensions which reflect the diagnostic criteria for OCPD (e.g., hoarding), and have significantly greater OCD severity, comorbidity, functional impairment, and poorer insight. Furthermore there are no differences in distribution of gene variants, or response to treatment in the two groups. The majority of our findings suggest that in OCD, patients with OCPD do not have a highly distinctive phenomenological or genetic profile, but rather that OCPD represents a marker of severity. Copyright © 2011 Elsevier Inc. All rights reserved.

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers.

PubMed

Kuchenbaecker, Karoline B; Neuhausen, Susan L; Robson, Mark; Barrowdale, Daniel; McGuffog, Lesley; Mulligan, Anna Marie; Andrulis, Irene L; Spurdle, Amanda B; Schmidt, Marjanka K; Schmutzler, Rita K; Engel, Christoph; Wappenschmidt, Barbara; Nevanlinna, Heli; Thomassen, Mads; Southey, Melissa; Radice, Paolo; Ramus, Susan J; Domchek, Susan M; Nathanson, Katherine L; Lee, Andrew; Healey, Sue; Nussbaum, Robert L; Rebbeck, Timothy R; Arun, Banu K; James, Paul; Karlan, Beth Y; Lester, Jenny; Cass, Ilana; Terry, Mary Beth; Daly, Mary B; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Steele, Linda; v O Hansen, Thomas; Ejlertsen, Bent; Gerdes, Anne-Marie; Nielsen, Finn C; Dennis, Joe; Cunningham, Julie; Hart, Steven; Slager, Susan; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Weitzel, Jeffrey N; Tafur, Isaac; Hander, Mary; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Roversi, Gaia; Scuvera, Giulietta; Bonanni, Bernardo; Mariani, Paolo; Volorio, Sara; Dolcetti, Riccardo; Varesco, Liliana; Papi, Laura; Tibiletti, Maria Grazia; Giannini, Giuseppe; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Hamann, Ute; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D Gareth; Frost, Debra; Eccles, Diana; Douglas, Fiona; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Ong, Kai-ren; Walker, Lisa; Izatt, Louise; Side, Lucy E; Kennedy, M John; Rogers, Mark T; Porteous, Mary E; Morrison, Patrick J; Platte, Radka; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Ellis, Steve; Godwin, Andrew K; Rhiem, Kerstin; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg; Niederacher, Dieter; Sutter, Christian; Steinemann, Doris; Bogdanova-Markov, Nadja; Kast, Karin; Varon-Mateeva, Raymonda; Wang-Gohrke, Shan; Gehrig, Andrea; Markiefka, Birgid; Buecher, Bruno; Lefol, Cédrick; Stoppa-Lyonnet, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Barjhoux, Laure; Faivre, Laurence; Longy, Michel; Sevenet, Nicolas; Sinilnikova, Olga M; Mazoyer, Sylvie; Bonadona, Valérie; Caux-Moncoutier, Virginie; Isaacs, Claudine; Van Maerken, Tom; Claes, Kathleen; Piedmonte, Marion; Andrews, Lesley; Hays, John; Rodriguez, Gustavo C; Caldes, Trinidad; de la Hoya, Miguel; Khan, Sofia; Hogervorst, Frans B L; Aalfs, Cora M; de Lange, J L; Meijers-Heijboer, Hanne E J; van der Hout, Annemarie H; Wijnen, Juul T; van Roozendaal, K E P; Mensenkamp, Arjen R; van den Ouweland, Ans M W; van Deurzen, Carolien H M; van der Luijt, Rob B; Olah, Edith; Diez, Orland; Lazaro, Conxi; Blanco, Ignacio; Teulé, Alex; Menendez, Mireia; Jakubowska, Anna; Lubinski, Jan; Cybulski, Cezary; Gronwald, Jacek; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Arason, Adalgeir; Maugard, Christine; Soucy, Penny; Montagna, Marco; Agata, Simona; Teixeira, Manuel R; Olswold, Curtis; Lindor, Noralane; Pankratz, Vernon S; Hallberg, Emily; Wang, Xianshu; Szabo, Csilla I; Vijai, Joseph; Jacobs, Lauren; Corines, Marina; Lincoln, Anne; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Kaulich, Daphne Gschwantler; Pfeiler, Georg; Tea, Muy-Kheng; Phelan, Catherine M; Mai, Phuong L; Greene, Mark H; Rennert, Gad; Imyanitov, Evgeny N; Glendon, Gord; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Jensen, Uffe Birk; Caligo, Maria A; Friedman, Eitan; Berger, Raanan; Laitman, Yael; Rantala, Johanna; Arver, Brita; Loman, Niklas; Borg, Ake; Ehrencrona, Hans; Olopade, Olufunmilayo I; Simard, Jacques; Easton, Douglas F; Chenevix-Trench, Georgia; Offit, Kenneth; Couch, Fergus J; Antoniou, Antonis C

2014-12-31

More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

Antigenic Variation of Clade 2.1 H5N1 Virus Is Determined by a Few Amino Acid Substitutions Immediately Adjacent to the Receptor Binding Site

PubMed Central

Koel, Björn F.; van der Vliet, Stefan; Burke, David F.; Bestebroer, Theo M.; Bharoto, Eny E.; Yasa, I. Wayan W.; Herliana, Inna; Laksono, Brigitta M.; Xu, Kemin; Skepner, Eugene; Russell, Colin A.; Rimmelzwaan, Guus F.; Perez, Daniel R.; Osterhaus, Albert D. M. E.; Smith, Derek J.; Prajitno, Teguh Y.

2014-01-01

ABSTRACT Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype are genetically highly variable and have diversified into multiple phylogenetic clades over the past decade. Antigenic drift is a well-studied phenomenon for seasonal human influenza viruses, but much less is known about the antigenic evolution of HPAI H5N1 viruses that circulate in poultry. In this study, we focused on HPAI H5N1 viruses that are enzootic to Indonesia. We selected representative viruses from genetically distinct lineages that are currently circulating and determined their antigenic properties by hemagglutination inhibition assays. At least six antigenic variants have circulated between 2003, when H5N1 clade 2.1 viruses were first detected in Indonesia, and 2011. During this period, multiple antigenic variants cocirculated in the same geographic regions. Mutant viruses were constructed by site-directed mutagenesis to represent each of the circulating antigenic variants, revealing that antigenic differences between clade 2.1 viruses were due to only one or very few amino acid substitutions immediately adjacent to the receptor binding site. Antigenic variants of H5N1 virus evaded recognition by both ferret and chicken antibodies. The molecular basis for antigenic change in clade 2.1 viruses closely resembled that of seasonal human influenza viruses, indicating that the hemagglutinin of influenza viruses from different hosts and subtypes may be similarly restricted to evade antibody recognition. PMID:24917596

The Genetics of Major Depression

PubMed Central

Flint, Jonathan; Kendler, Kenneth S.

2014-01-01

Major depression is the commonest psychiatric disorder and in the U.S. has the greatest impact of all biomedical diseases on disability. Here we review evidence of the genetic contribution to disease susceptibility and the current state of molecular approaches. Genome-wide association and linkage results provide constraints on the allele frequencies and effect sizes of susceptibility loci, which we use to interpret the voluminous candidate gene literature. We consider evidence for the genetic heterogeneity of the disorder and the likelihood that subtypes exist that represent more genetically homogenous conditions than have hitherto been analyzed. PMID:24507187

Genetic history of hepatitis C virus in Venezuela: high diversity and long time of evolution of HCV genotype 2.

PubMed

Sulbarán, Maria Z; Di Lello, Federico A; Sulbarán, Yoneira; Cosson, Clarisa; Loureiro, Carmen L; Rangel, Héctor R; Cantaloube, Jean F; Campos, Rodolfo H; Moratorio, Gonzalo; Cristina, Juan; Pujol, Flor H

2010-12-13

The subtype diversity of the hepatitis C virus (HCV) genotypes is unknown in Venezuela. Partial sequencing of the NS5B region was performed in 310 isolates circulating in patients from 1995 to 2007. In the samples collected between 2005 and 2007, HCV genotype 1 (G1) was the most common genotype (63%), composed as expected of mainly G1a and G1b. G2 was the second most common genotype (33%), being G2a almost absent and G2j the most frequent subtype. Sequence analysis of the core region confirmed the subtype assignment performed within the NS5b region in 63 isolates. The complete genome sequence of G2j was obtained. G2j has been described in France, Canada and Burkina Fasso, but it was not found in Martinique, where several subtypes of G2 circulate in the general population. Bayesian coalescence analysis indicated a most recent common ancestor (MRCA) of G2j around 1785, before the introduction of G1b (1869) and G1a (1922). While HCV G1a and G1b experienced a growth reduction since 1990, coincident with the time when blood testing was implemented in Venezuela, HCV G2j did not seem to reach growth equilibrium during this period. Assuming the introduction of G2j from Africa during the slave trade, the high frequency of G2j found in Venezuela could suggest: 1- the introduction of African ethnic groups different from the ones introduced to Martinique or 2- the occurrence of a founder effect. This study represents an in-depth analysis of the subtype diversity of HCV in Venezuela, which is still unexplored in the Americas and deserves further studies.

Clinical, Cellular, and Molecular Aspects in the Pathophysiology of Rosacea

PubMed Central

Steinhoff, Martin; Buddenkotte, Jörg; Aubert, Jerome; Sulk, Mathias; Novak, Pawel; Schwab, Verena D.; Mess, Christian; Cevikbas, Ferda; Rivier, Michel; Carlavan, Isabelle; Déret, Sophie; Rosignoli, Carine; Metze, Dieter; Luger, Thomas A.; Voegel, Johannes J.

2013-01-01

Rosacea is a chronic inflammatory skin disease of unknown etiology. Although described centuries ago, the pathophysiology of this disease is still poorly understood. Epidemiological studies indicate a genetic component, but a rosacea gene has not been identified yet. Four subtypes and several variants of rosacea have been described. It is still unclear whether these subtypes represent a “developmental march” of different stages or are merely part of a syndrome that develops independently but overlaps clinically. Clinical and histopathological characteristics of rosacea make it a fascinating “human disease model” for learning about the connection between the cutaneous vascular, nervous, and immune systems. Innate immune mechanisms and dysregulation of the neurovascular system are involved in rosacea initiation and perpetuation, although the complex network of primary induction and secondary reaction of neuroimmune communication is still unclear. Later, rosacea may result in fibrotic facial changes, suggesting a strong connection between chronic inflammatory processes and skin fibrosis development. This review highlights recent molecular (gene array) and cellular findings and aims to integrate the different body defense mechanisms into a modern concept of rosacea pathophysiology. PMID:22076321

Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

PubMed Central

Jusakul, Apinya; Cutcutache, Ioana; Yong, Chern Han; Lim, Jing Quan; Huang, Mi Ni; Padmanabhan, Nisha; Nellore, Vishwa; Kongpetch, Sarinya; Ng, Alvin Wei Tian; Ng, Ley Moy; Choo, Su Pin; Myint, Swe Swe; Thanan, Raynoo; Nagarajan, Sanjanaa; Lim, Weng Khong; Ng, Cedric Chuan Young; Boot, Arnoud; Liu, Mo; Ong, Choon Kiat; Rajasegaran, Vikneswari; Lie, Stefanus; Lim, Alvin Soon Tiong; Lim, Tse Hui; Tan, Jing; Loh, Jia Liang; McPherson, John R.; Khuntikeo, Narong; Bhudhisawasdi, Vajaraphongsa; Yongvanit, Puangrat; Wongkham, Sopit; Totoki, Yasushi; Nakamura, Hiromi; Arai, Yasuhito; Yamasaki, Satoshi; Chow, Pierce Kah-Hoe; Chung, Alexander Yaw Fui; Ooi, London Lucien Peng Jin; Lim, Kiat Hon; Dima, Simona; Duda, Dan G.; Popescu, Irinel; Broet, Philippe; Hsieh, Sen-Yung; Yu, Ming-Chin; Scarpa, Aldo; Lai, Jiaming; Luo, Di-Xian; Carvalho, André Lopes; Vettore, André Luiz; Rhee, Hyungjin; Park, Young Nyun; Alexandrov, Ludmil B.; Gordân, Raluca; Rozen, Steven G.; Shibata, Tatsuhiro; Pairojkul, Chawalit; Teh, Bin Tean; Tan, Patrick

2017-01-01

Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analysed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined four CCA clusters – Fluke-Positive CCAs (Clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations, conversely Fluke-Negative CCAs (Clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3′UTR deletion as a mechanism of FGFR2 upregulation. Integration of non-coding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores – mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer. PMID:28667006

Heterogeneous impact of smoking on major salivary gland cancer according to histopathological subtype: A case-control study.

PubMed

Sawabe, Michi; Ito, Hidemi; Takahara, Taishi; Oze, Isao; Kawakita, Daisuke; Yatabe, Yasushi; Hasegawa, Yasuhisa; Murakami, Shingo; Matsuo, Keitaro

2018-01-01

Major salivary gland cancers (M-SGCs) are rare, and have distinct heterogeneous histopathological subtypes. To the authors' knowledge, no consistent evidence of an association between cigarette smoking and the risk of M-SGCs has appeared to date. Furthermore, evidence of potential heterogeneity in the impact of smoking on histopathological subtypes is scarce, despite the fact that the histopathological subtypes of M-SGC exhibit different genetic features. The authors conducted a case-control study to investigate the association between smoking and M-SGC by histopathological subtype. Cases were 81 patients with M-SGCs and the controls were 810 age-matched and sex-matched first-visit outpatients without cancer treated at Aichi Cancer Center Hospital from 1988 to 2005. Odds ratios (OR) and 95% confidence intervals (95% CI) were assessed by conditional logistic regression analysis with adjustment for potential confounders. Smoking was found to be associated with a significantly increased risk of M-SGC overall, with an OR of 3.45 (95% CI, 1.58-7.51; P =.001) for heavy smokers compared with never-smokers. A significant dose-response relationship was observed (P for trend, .001). When stratified by histological subtype, no obvious impact of smoking was observed among patients with mucoepidermoid carcinoma (MEC). In contrast, smoking demonstrated a significantly increased risk of M-SGCs other than MEC, with an OR of 5.15 (95% CI, 2.06-12.87; P<.001) for heavy smokers compared with never-smokers. The authors observed possible heterogeneity with regard to the impact of smoking on risk between MEC and M-SGCs other than MEC (P for heterogeneity, .052). The results of the current study demonstrate a significant positive association between cigarette smoking and the risk of M-SGC overall. However, the impact of smoking appeared to be limited to M-SGCs other than MEC. Cancer 2018;124:118-24. © 2017 American Cancer Society. © 2017 American Cancer Society.

A miRNA-based classification of renal cell carcinoma subtypes by PCR and in situ hybridization

PubMed Central

Di Meo, Ashley; Saleeb, Rola; Wala, Samantha J.; Khella, Heba W.; Ding, Qiang; Zhai, Haiyan; Krishan, Kalra; Krizova, Adriana; Gabril, Manal; Evans, Andrew; Brimo, Fadi; Pasic, Maria D.; Finelli, Antonio; Diamandis, Eleftherios P.; Yousef, George M.

2018-01-01

Renal cell carcinoma (RCC) constitutes an array of morphologically and genetically distinct tumors the most prevalent of which are clear cell, papillary, and chromophobe RCC. Accurate distinction between the typically benign-behaving renal oncocytoma and RCC subtypes is a frequent challenge for pathologists. This is critical for clinical decision making. Subtypes also have different survival outcomes and responses to therapy. We extracted RNA from ninety formalin-fixed paraffin-embedded (FFPE) tissues (27 clear cell, 29 papillary, 19 chromophobe, 4 unclassified RCC and 11 oncocytomas). We quantified the expression of six miRNAs (miR-221, miR-222, miR-126, miR-182, miR-200b and miR-200c) by qRT-PCR, and by in situ hybridization in an independent set of tumors. We developed a two-step classifier. In the first step, it uses expression of either miR-221 or miR-222 to distinguish the clear cell and papillary subtypes from chromophobe RCC and oncocytoma (miR-221 AUC: 0.96, 95% CI: 0.9132–1.014, p < 0.0001 and miR-222 AUC: 0.91, 95% CI: 0.8478–0.9772, p < 0.0001). In the second step, it uses miR-126 to discriminate clear cell from papillary RCC (AUC: 1, p < 0.0001) and miR-200b to discriminate chromophobe RCC from oncocytoma (AUC: 0.95, 95% CI: 0.8933–1.021, p < 0.0001). In situ hybridization showed a nuclear staining pattern. miR-126, miR-222 and miR-200b were significantly differentially expressed between the subtypes by in situ hybridization. miRNA expression could distinguish RCC subtypes and oncocytoma. miRNA expression assessed by either PCR or in situ hybridization can be a clinically useful diagnostic tool to complement morphologic renal tumor classification, improving diagnosis and patient management. PMID:29416756

Circulation of HIV-1 Multiple Complexity Recombinant Forms Among Female Sex Workers Recently Infected with HIV-1 in Thailand.

PubMed

Saeng-Aroon, Siriphan; Loket, Ruangchai; Plipat, Tanarak; Lumyai, Suttiwat; Chu, Pei-Yu; Sangkitporn, Somchai; Nakayama, Emi E; Takeda, Naokazu; Shioda, Tatsuo; Motomura, Kazushi

2016-07-01

The circulating subtype distribution of HIV-1 has not been well characterized in female sex worker (FSW) populations in Thailand. To understand the mechanisms and interrelationships of epidemics involving FSWs in Thailand, we performed a large molecular epidemiological study of FSWs aged 25 years with recently acquired HIV-1 infections. The samples were collected in 2005, 2007, 2009, and 2011 in 38 provinces, representing every region of Thailand. After gag (p24), pol (pro-RT), and env (C2/V3) were sequenced, comprehensive genome analysis was performed. Genetic subtypes were determined in 159 plasma samples. The percentage of circulating recombinant forms (CRFs) CRF01_AE (90.6%) predominated, while subtype B (1.3%), other CRFs (1.9%), and unique recombinant forms (URFs) (6.2%) were identified as minor populations. Interestingly, the unique recombinant nature of these HIV-1 strains was verified in 10 specimens, indicating the presence of new forms of HIV-1 intersubtypes G/A, C/B, AE/B/C, and AE/B with different recombination breakpoints. Subtype B has contributed to these new generations of unique CRF01/B recombinants, especially in the pol (RT) gene, in which the template switching of the RT genomes occurred during reverse transcription. These results imply that the several unique recombinant viruses circulating in Thailand were probably generated in the population or introduced from neighboring countries. Our study helps clarify the patterns of viral transmission and define transmission pathways in Thailand.

Genetic Diversity of Giardia duodenalis: Multilocus Genotyping Reveals Zoonotic Potential between Clinical and Environmental Sources in a Metropolitan Region of Brazil

PubMed Central

Durigan, Mauricio; Abreu, Aluana Gonçalves; Zucchi, Maria Imaculada; Franco, Regina Maura Bueno; de Souza, Anete Pereira

2014-01-01

Background Giardia duodenalis is a flagellate protozoan that parasitizes humans and several other mammals. Protozoan contamination has been regularly documented at important environmental sites, although most of these studies were performed at the species level. There is a lack of studies that correlate environmental contamination and clinical infections in the same region. The aim of this study is to evaluate the genetic diversity of a set of clinical and environmental samples and to use the obtained data to characterize the genetic profile of the distribution of G. duodenalis and the potential for zoonotic transmission in a metropolitan region of Brazil. Methodology/Principal Findings The genetic assemblages and subtypes of G. duodenalis isolates obtained from hospitals, a veterinary clinic, a day-care center and important environmental sites were determined via multilocus sequence-based genotyping using three unlinked gene loci. Cysts of Giardia were detected at all of the environmental sites. Mixed assemblages were detected in 25% of the total samples, and an elevated number of haplotypes was identified. The main haplotypes were shared among the groups, and new subtypes were identified at all loci. Ten multilocus genotypes were identified: 7 for assemblage A and 3 for assemblage B. Conclusions/Significance There is persistent G. duodenalis contamination at important environmental sites in the city. The identified mixed assemblages likely represent mixed infections, suggesting high endemicity of Giardia in these hosts. Most Giardia isolates obtained in this study displayed zoonotic potential. The high degree of genetic diversity in the isolates obtained from both clinical and environmental samples suggests that multiple sources of infection are likely responsible for the detected contamination events. The finding that many multilocus genotypes (MLGs) and haplotypes are shared by different groups suggests that these sources of infection may be related and indicates that there is a notable risk of human infection caused by Giardia in this region. PMID:25536055

Diversity, Frequency, and Persistence of Escherichia coli O157 Strains from Range Cattle Environments†

PubMed Central

Renter, David G.; Sargeant, Jan M.; Oberst, Richard D.; Samadpour, Mansour

2003-01-01

Genetic diversity, isolation frequency, and persistence were determined for Escherichia coli O157 strains from range cattle production environments. Over the 11-month study, analysis of 9,122 cattle fecal samples, 4,083 water source samples, and 521 wildlife fecal samples resulted in 263 isolates from 107 samples presumptively considered E. coli O157 as determined by culture and latex agglutination. Most isolates (90.1%) were confirmed to be E. coli O157 by PCR detection of intimin and Shiga toxin genes. Pulsed-field gel electrophoresis (PFGE) of XbaI-digested preparations revealed 79 unique patterns (XbaI-PFGE subtypes) from 235 typeable isolates confirmed to be E. coli O157. By analyzing up to three isolates per positive sample, we detected an average of 1.80 XbaI-PFGE subtypes per sample. Most XbaI-PFGE subtypes (54 subtypes) were identified only once, yet the seven most frequently isolated subtypes represented over one-half of the E. coli O157 isolates (124 of 235 isolates). Recurring XbaI-PFGE subtypes were recovered from samples on up to 10 sampling occasions and up to 10 months apart. Seven XbaI-PFGE subtypes were isolated from both cattle feces and water sources, and one of these also was isolated from the feces of a wild opossum (Didelphis sp.). The number of XbaI-PFGE subtypes, the variable frequency and persistence of subtypes, and the presence of identical subtypes in cattle feces, free-flowing water sources, and wildlife feces indicate that the complex molecular epidemiology of E. coli O157 previously described for confined cattle operations is also evident in extensively managed range cattle environments. PMID:12514039

The Relationship between Compulsive Behaviour and Academic Achievement across the Three Genetic Subtypes of Prader-Willi Syndrome

ERIC Educational Resources Information Center

Zarcone, J.; Napolitano, D.; Peterson, C.; Breidbord, J.; Ferraioli, S.; Caruso-Anderson, M.; Holsen, L.; Butler, M. G.; Thompson, T.

2007-01-01

Background: Prader-Willi syndrome (PWS) is a genetic syndrome associated with several physical, cognitive and behavioural characteristics. For many individuals with this syndrome, compulsive behaviour is often noted in both food and non-food situations. The focus of this paper is on the non-food-related compulsions in individuals with PWS and…

A Direct Comparison of Two Densely Sampled HIV Epidemics: The UK and Switzerland

NASA Astrophysics Data System (ADS)

Ragonnet-Cronin, Manon L.; Shilaih, Mohaned; Günthard, Huldrych F.; Hodcroft, Emma B.; Böni, Jürg; Fearnhill, Esther; Dunn, David; Yerly, Sabine; Klimkait, Thomas; Aubert, Vincent; Yang, Wan-Lin; Brown, Alison E.; Lycett, Samantha J.; Kouyos, Roger; Brown, Andrew J. Leigh

2016-09-01

Phylogenetic clustering approaches can elucidate HIV transmission dynamics. Comparisons across countries are essential for evaluating public health policies. Here, we used a standardised approach to compare the UK HIV Drug Resistance Database and the Swiss HIV Cohort Study while maintaining data-protection requirements. Clusters were identified in subtype A1, B and C pol phylogenies. We generated degree distributions for each risk group and compared distributions between countries using Kolmogorov-Smirnov (KS) tests, Degree Distribution Quantification and Comparison (DDQC) and bootstrapping. We used logistic regression to predict cluster membership based on country, sampling date, risk group, ethnicity and sex. We analysed >8,000 Swiss and >30,000 UK subtype B sequences. At 4.5% genetic distance, the UK was more clustered and MSM and heterosexual degree distributions differed significantly by the KS test. The KS test is sensitive to variation in network scale, and jackknifing the UK MSM dataset to the size of the Swiss dataset removed the difference. Only heterosexuals varied based on the DDQC, due to UK male heterosexuals who clustered exclusively with MSM. Their removal eliminated this difference. In conclusion, the UK and Swiss HIV epidemics have similar underlying dynamics and observed differences in clustering are mainly due to different population sizes.

In Vitro and in Vivo Molecular Imaging of Estrogen Receptor α and β Homo- and Heterodimerization: Exploration of New Modes of Receptor Regulation

PubMed Central

Tamrazi, Anobel; Massoud, Tarik F.; Katzenellenbogen, John A.; Gambhir, Sanjiv S.

2011-01-01

Estrogen receptor (ER) biology reflects the actions of estrogens through the two receptors, ERα and ERβ, although little is known regarding the preference for formation of ER homo- vs. heterodimers, and how this is affected by the level of ligand occupancy and preferential ligand affinity for one of the ER subtypes. In this report, we use a split optical reporter-protein complementation system to demonstrate the physical interaction between ERα and ERβ in response to different ER ligands in cells and, for the first time, by in vivo imaging in living animals. The genetically encoded reporter vectors constructed with the ligand-binding domains of ERα and ERβ, fused to split firefly or Renilla luciferase (Fluc or hRluc) fragments, were used for this study. This molecular proteomic technique was used to detect ERα/ERα or ERβ/ERβ homodimerization, or ERα/ERβ heterodimerization induced by ER subtype-selective and nonselective ligands, and selective ER modulators (SERM), as well as in dimers in which one mutant monomer was unable to bind estradiol. The SERM-bound ERα and ERβ form the strongest dimers, and subtype-preferential homodimerization was seen with ERα-selective ligands (methyl piperidino pyrazole/propyl pyrazole triol) and the ERβ-selective ligands (diarylpropionitrile/tetrahydrochrysene/genistein). We also demonstrated that a single ligand-bound monomer can form homo- or heterodimers with an apo-monomer. Xenografts of human embryonic kidney 293T cells imaged in living mice by bioluminescence showed real-time ligand induction of ERα/ERβ heterodimerization and reversal of dimerization upon ligand withdrawal. The results from this study demonstrate the value of the split luciferase-based complementation system for studying ER-subtype interactions in cells and for evaluating them in living animals by noninvasive imaging. They also probe what combinations of ERα and ERβ dimers might be the mediators of the effects of different types of ER ligands given at different doses. PMID:22052998

Epidemiology of Stuttering: 21st Century Advances

PubMed Central

Yairi, Ehud; Ambrose, Nicoline

2012-01-01

Epidemiological advances in stuttering during the current century are reviewed within the perspectives of past knowledge. The review is organized in six sections: (a) onset (b) incidence (c) prevalence (d) developmental paths, (e) genetics and (f) subtypes. It is concluded that: (1) most of the risk for stuttering onset is over by age 5, earlier than has been previously thought, with a male-to-female ratio near onset smaller than what has been thought, (2) there are indications that the lifespan incidence in the general population may be higher than the 5% commonly cited in past work, (3) the average prevalence over the lifespan may be lower than the commonly held 1%, (4) the effects of race, ethnicity, culture, bilingualism, and socioeconomic status on the incidence/prevalence of stuttering remain uncertain, (5) longitudinal, as well as incidence and prevalence studies support high levels of natural recovery from stuttering, (6) advances in biological genetic research have brought within reach the identification of candidate genes that contribute to stuttering in the population at large, (7) subtype-differentiation has attracted growing interest, with most of the accumulated evidence supporting a distinction between persistent and recovered subtypes. PMID:23773662

The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing.

PubMed Central

Sanchez, A; Trappier, S G; Mahy, B W; Peters, C J; Nichol, S T

1996-01-01

In late 1994 and early 1995, Ebola (EBO) virus dramatically reemerged in Africa, causing human disease in the Ivory Coast and Zaire. Analysis of the entire glycoprotein genes of these viruses and those of other EBO virus subtypes has shown that the virion glycoprotein (130 kDa) is encoded in two reading frames, which are linked by transcriptional editing. This editing results in the addition of an extra nontemplated adenosine within a run of seven adenosines near the middle of the coding region. The primary gene product is a smaller (50-70 kDa), nonstructural, secreted glycoprotein, which is produced in large amounts and has an unknown function. Phylogenetic analysis indicates that EBO virus subtypes are genetically diverse and that the recent Ivory Coast isolate represents a new (fourth) subtype of EBO virus. In contrast, the EBO virus isolate from the 1995 outbreak in Kikwit, Zaire, is virtually identical to the virus that caused a similar epidemic in Yambuku, Zaire, almost 20 years earlier. This genetic stability may indicate that EBO viruses have coevolved with their natural reservoirs and do not change appreciably in the wild. Images Fig. 2 Fig. 3 PMID:8622982

Advances in Molecular Serotyping and Subtyping of Escherichia coli.

PubMed

Fratamico, Pina M; DebRoy, Chitrita; Liu, Yanhong; Needleman, David S; Baranzoni, Gian Marco; Feng, Peter

2016-01-01

Escherichia coli plays an important role as a member of the gut microbiota; however, pathogenic strains also exist, including various diarrheagenic E. coli pathotypes and extraintestinal pathogenic E. coli that cause illness outside of the GI-tract. E. coli have traditionally been serotyped using antisera against the ca. 186 O-antigens and 53 H-flagellar antigens. Phenotypic methods, including bacteriophage typing and O- and H- serotyping for differentiating and characterizing E. coli have been used for many years; however, these methods are generally time consuming and not always accurate. Advances in next generation sequencing technologies have made it possible to develop genetic-based subtyping and molecular serotyping methods for E. coli, which are more discriminatory compared to phenotypic typing methods. Furthermore, whole genome sequencing (WGS) of E. coli is replacing established subtyping methods such as pulsed-field gel electrophoresis, providing a major advancement in the ability to investigate food-borne disease outbreaks and for trace-back to sources. A variety of sequence analysis tools and bioinformatic pipelines are being developed to analyze the vast amount of data generated by WGS and to obtain specific information such as O- and H-group determination and the presence of virulence genes and other genetic markers.

A comprehensive strategy for the subtyping of patients with Fanconi anaemia: conclusions from the Spanish Fanconi Anemia Research Network.

PubMed

Antonio Casado, José; Callén, Elsa; Jacome, Ariana; Río, Paula; Castella, Maria; Lobitz, Stephan; Ferro, Teresa; Muñoz, Arturo; Sevilla, Julián; Cantalejo, Angeles; Cela, Elena; Cervera, José; Sánchez-Calero, Jesús; Badell, Isabel; Estella, Jesús; Dasí, Angeles; Olivé, Teresa; José Ortega, Juan; Rodriguez-Villa, Antonia; Tapia, María; Molinés, Antonio; Madero, Luis; Segovia, José C; Neveling, Kornelia; Kalb, Reinhard; Schindler, Detlev; Hanenberg, Helmut; Surrallés, Jordi; Bueren, Juan A

2007-04-01

Fanconi anaemia is a heterogeneous genetic disease, where 12 complementation groups have been already described. Identifying the complementation group in patients with Fanconi anaemia constitutes a direct procedure to confirm the diagnosis of the disease and is required for the recruitment of these patients in gene therapy trials. To determine the subtype of Fanconi anaemia patients in Spain, a Mediterranean country with a relatively high population (23%) of Fanconi anaemia patients belonging to the gypsy race. Most patients could be subtyped by retroviral complementation approaches in peripheral blood T cells, although some mosaic patients were subtyped in cultured skin fibroblasts. Other approaches, mainly based on western blot analysis and generation of nuclear RAD51 and FANCJ foci, were required for the subtyping of a minor number of patients. From a total of 125 patients included in the Registry of Fanconi Anaemia, samples from 102 patients were available for subtyping analyses. In 89 cases the subtype could be determined and in 8 cases exclusions of common complementation groups were made. Compared with other international studies, a skewed distribution of complementation groups was observed in Spain, where 80% of the families belonged to the Fanconi anaemia group A (FA-A) complementation group. The high proportion of gypsy patients, all of them FA-A, and the absence of patients with FA-C account for this characteristic distribution of complementation groups.

Genetic and Functional Diversity of Human Immunodeficiency Virus Type 1 Subtype B Nef Primary Isolates

PubMed Central

Foster, John L.; Molina, Rene P.; Luo, Tianci; Arora, Vivek K.; Huang, Yaoxing; Ho, David D.; Garcia, J. Victor

2001-01-01

We have characterized the functional integrity of seven primary Nef isolates: five from a long-term nonprogressing human immunodeficiency virus (HIV)-infected individual and one each from two patients with AIDS. One of the seven Nefs was defective for CD4 downregulation, two others were defective for PAK-2 activation, and one Nef was defective for PAK-2 activation and major histocompatibility complex (MHC) class I downregulation. Five of the Nefs were tested and found to be functional for the enhancement of virus particle infectivity. The structural basis for each of the functional defects has been analyzed by constructing a consensus nef, followed by mutational analysis of the variant amino acid residues. Mutations A29V and F193I were deleterious to CD4 downregulation and PAK-2 activation, respectively, while S189R rendered Nef defective for both MHC class I downregulation and PAK-2 activation. A search of the literature identified HIVs from five patients with Nefs predominantly mutated at F193 and from one patient with Nefs predominantly mutated at A29. A29 is highly conserved in all HIV subtypes except for subtype E. F193 is conserved in subtype B (and possibly in the closely related subtype D), but none of the other HIV group M subtypes. Our results suggest that functional distinctions may exist between HIV subtypes. PMID:11160665

Widespread Occurrence of Zoonotic Cryptosporidium Species and Subtypes in Dairy Cattle from Northeast China: Public Health Concerns.

PubMed

Tao, Wei; Li, Yijing; Yang, Hang; Song, Mingxin; Lu, Yixin; Li, Wei

2018-02-01

Bovine cryptosporidiosis constitutes a threat to the livestock industry and public health worldwide. In the present study we investigated dairy cattle of all ages in northeast China for the prevalence and genetic traits of Cryptosporidium. Nested polymerase chain reaction of the small subunit rRNA gene was used to identify Cryptosporidium species or genotype. The parasite was detected in 130 of 537 (24.2%) animals sampled from the cities of Harbin (35.2%, 69/196) and Qiqihar (32.1%, 61/190). Cryptosporidium parvum (87/130) was identified as the dominant species by sequence analysis followed by Cryptosporidium bovis (28/130), Cryptosporidium ryanae (5/130), Cryptosporidium andersoni (2/130), Cryptosporidium suis-like genotype (2/130), and mixed C. ryanae/ C. bovis (1/130). Subtyping of C. parvum isolates was based on the DNA polymorphisms of the 60-kDa glycoprotein gene. Subtyping of the C. parvum isolates recognized subtypes IIdA15G1 (24/87) in Harbin and IIdA20G1 (48/87) in Qiqihar. A diversity of Cryptosporidium species/genotype and subtypes was identified in cattle from northeast China. Widespread occurrence of human-pathogenic Cryptosporidium species and subtypes is of public health significance. This is the first study reporting C. parvum subtype IIdA20G1 in China. The findings improve the epidemiological knowledge of bovine cryptosporidiosis in China, highlighting the importance of ongoing Cryptosporidium surveillance.

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

PubMed

Malik, Rainer; Chauhan, Ganesh; Traylor, Matthew; Sargurupremraj, Muralidharan; Okada, Yukinori; Mishra, Aniket; Rutten-Jacobs, Loes; Giese, Anne-Katrin; van der Laan, Sander W; Gretarsdottir, Solveig; Anderson, Christopher D; Chong, Michael; Adams, Hieab H H; Ago, Tetsuro; Almgren, Peter; Amouyel, Philippe; Ay, Hakan; Bartz, Traci M; Benavente, Oscar R; Bevan, Steve; Boncoraglio, Giorgio B; Brown, Robert D; Butterworth, Adam S; Carrera, Caty; Carty, Cara L; Chasman, Daniel I; Chen, Wei-Min; Cole, John W; Correa, Adolfo; Cotlarciuc, Ioana; Cruchaga, Carlos; Danesh, John; de Bakker, Paul I W; DeStefano, Anita L; den Hoed, Marcel; Duan, Qing; Engelter, Stefan T; Falcone, Guido J; Gottesman, Rebecca F; Grewal, Raji P; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeffrey; Harris, Tamara B; Hassan, Ahamad; Havulinna, Aki S; Heckbert, Susan R; Holliday, Elizabeth G; Howard, George; Hsu, Fang-Chi; Hyacinth, Hyacinth I; Ikram, M Arfan; Ingelsson, Erik; Irvin, Marguerite R; Jian, Xueqiu; Jiménez-Conde, Jordi; Johnson, Julie A; Jukema, J Wouter; Kanai, Masahiro; Keene, Keith L; Kissela, Brett M; Kleindorfer, Dawn O; Kooperberg, Charles; Kubo, Michiaki; Lange, Leslie A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lee, Jin-Moo; Lemmens, Robin; Leys, Didier; Lewis, Cathryn M; Lin, Wei-Yu; Lindgren, Arne G; Lorentzen, Erik; Magnusson, Patrik K; Maguire, Jane; Manichaikul, Ani; McArdle, Patrick F; Meschia, James F; Mitchell, Braxton D; Mosley, Thomas H; Nalls, Michael A; Ninomiya, Toshiharu; O'Donnell, Martin J; Psaty, Bruce M; Pulit, Sara L; Rannikmäe, Kristiina; Reiner, Alexander P; Rexrode, Kathryn M; Rice, Kenneth; Rich, Stephen S; Ridker, Paul M; Rost, Natalia S; Rothwell, Peter M; Rotter, Jerome I; Rundek, Tatjana; Sacco, Ralph L; Sakaue, Saori; Sale, Michele M; Salomaa, Veikko; Sapkota, Bishwa R; Schmidt, Reinhold; Schmidt, Carsten O; Schminke, Ulf; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie L M; Tanislav, Christian; Tatlisumak, Turgut; Taylor, Kent D; Thijs, Vincent N S; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tiedt, Steffen; Trompet, Stella; Tzourio, Christophe; van Duijn, Cornelia M; Walters, Matthew; Wareham, Nicholas J; Wassertheil-Smoller, Sylvia; Wilson, James G; Wiggins, Kerri L; Yang, Qiong; Yusuf, Salim; Bis, Joshua C; Pastinen, Tomi; Ruusalepp, Arno; Schadt, Eric E; Koplev, Simon; Björkegren, Johan L M; Codoni, Veronica; Civelek, Mete; Smith, Nicholas L; Trégouët, David A; Christophersen, Ingrid E; Roselli, Carolina; Lubitz, Steven A; Ellinor, Patrick T; Tai, E Shyong; Kooner, Jaspal S; Kato, Norihiro; He, Jiang; van der Harst, Pim; Elliott, Paul; Chambers, John C; Takeuchi, Fumihiko; Johnson, Andrew D; Sanghera, Dharambir K; Melander, Olle; Jern, Christina; Strbian, Daniel; Fernandez-Cadenas, Israel; Longstreth, W T; Rolfs, Arndt; Hata, Jun; Woo, Daniel; Rosand, Jonathan; Pare, Guillaume; Hopewell, Jemma C; Saleheen, Danish; Stefansson, Kari; Worrall, Bradford B; Kittner, Steven J; Seshadri, Sudha; Fornage, Myriam; Markus, Hugh S; Howson, Joanna M M; Kamatani, Yoichiro; Debette, Stephanie; Dichgans, Martin; Malik, Rainer; Chauhan, Ganesh; Traylor, Matthew; Sargurupremraj, Muralidharan; Okada, Yukinori; Mishra, Aniket; Rutten-Jacobs, Loes; Giese, Anne-Katrin; van der Laan, Sander W; Gretarsdottir, Solveig; Anderson, Christopher D; Chong, Michael; Adams, Hieab H H; Ago, Tetsuro; Almgren, Peter; Amouyel, Philippe; Ay, Hakan; Bartz, Traci M; Benavente, Oscar R; Bevan, Steve; Boncoraglio, Giorgio B; Brown, Robert D; Butterworth, Adam S; Carrera, Caty; Carty, Cara L; Chasman, Daniel I; Chen, Wei-Min; Cole, John W; Correa, Adolfo; Cotlarciuc, Ioana; Cruchaga, Carlos; Danesh, John; de Bakker, Paul I W; DeStefano, Anita L; Hoed, Marcel den; Duan, Qing; Engelter, Stefan T; Falcone, Guido J; Gottesman, Rebecca F; Grewal, Raji P; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeffrey; Harris, Tamara B; Hassan, Ahamad; Havulinna, Aki S; Heckbert, Susan R; Holliday, Elizabeth G; Howard, George; Hsu, Fang-Chi; Hyacinth, Hyacinth I; Ikram, M Arfan; Ingelsson, Erik; Irvin, Marguerite R; Jian, Xueqiu; Jiménez-Conde, Jordi; Johnson, Julie A; Jukema, J Wouter; Kanai, Masahiro; Keene, Keith L; Kissela, Brett M; Kleindorfer, Dawn O; Kooperberg, Charles; Kubo, Michiaki; Lange, Leslie A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lee, Jin-Moo; Lemmens, Robin; Leys, Didier; Lewis, Cathryn M; Lin, Wei-Yu; Lindgren, Arne G; Lorentzen, Erik; Magnusson, Patrik K; Maguire, Jane; Manichaikul, Ani; McArdle, Patrick F; Meschia, James F; Mitchell, Braxton D; Mosley, Thomas H; Nalls, Michael A; Ninomiya, Toshiharu; O'Donnell, Martin J; Psaty, Bruce M; Pulit, Sara L; Rannikmäe, Kristiina; Reiner, Alexander P; Rexrode, Kathryn M; Rice, Kenneth; Rich, Stephen S; Ridker, Paul M; Rost, Natalia S; Rothwell, Peter M; Rotter, Jerome I; Rundek, Tatjana; Sacco, Ralph L; Sakaue, Saori; Sale, Michele M; Salomaa, Veikko; Sapkota, Bishwa R; Schmidt, Reinhold; Schmidt, Carsten O; Schminke, Ulf; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie L M; Tanislav, Christian; Tatlisumak, Turgut; Taylor, Kent D; Thijs, Vincent N S; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tiedt, Steffen; Trompet, Stella; Tzourio, Christophe; van Duijn, Cornelia M; Walters, Matthew; Wareham, Nicholas J; Wassertheil-Smoller, Sylvia; Wilson, James G; Wiggins, Kerri L; Yang, Qiong; Yusuf, Salim; Amin, Najaf; Aparicio, Hugo S; Arnett, Donna K; Attia, John; Beiser, Alexa S; Berr, Claudine; Buring, Julie E; Bustamante, Mariana; Caso, Valeria; Cheng, Yu-Ching; Choi, Seung Hoan; Chowhan, Ayesha; Cullell, Natalia; Dartigues, Jean-François; Delavaran, Hossein; Delgado, Pilar; Dörr, Marcus; Engström, Gunnar; Ford, Ian; Gurpreet, Wander S; Hamsten, Anders; Heitsch, Laura; Hozawa, Atsushi; Ibanez, Laura; Ilinca, Andreea; Ingelsson, Martin; Iwasaki, Motoki; Jackson, Rebecca D; Jood, Katarina; Jousilahti, Pekka; Kaffashian, Sara; Kalra, Lalit; Kamouchi, Masahiro; Kitazono, Takanari; Kjartansson, Olafur; Kloss, Manja; Koudstaal, Peter J; Krupinski, Jerzy; Labovitz, Daniel L; Laurie, Cathy C; Levi, Christopher R; Li, Linxin; Lind, Lars; Lindgren, Cecilia M; Lioutas, Vasileios; Liu, Yong Mei; Lopez, Oscar L; Makoto, Hirata; Martinez-Majander, Nicolas; Matsuda, Koichi; Minegishi, Naoko; Montaner, Joan; Morris, Andrew P; Muiño, Elena; Müller-Nurasyid, Martina; Norrving, Bo; Ogishima, Soichi; Parati, Eugenio A; Peddareddygari, Leema Reddy; Pedersen, Nancy L; Pera, Joanna; Perola, Markus; Pezzini, Alessandro; Pileggi, Silvana; Rabionet, Raquel; Riba-Llena, Iolanda; Ribasés, Marta; Romero, Jose R; Roquer, Jaume; Rudd, Anthony G; Sarin, Antti-Pekka; Sarju, Ralhan; Sarnowski, Chloe; Sasaki, Makoto; Satizabal, Claudia L; Satoh, Mamoru; Sattar, Naveed; Sawada, Norie; Sibolt, Gerli; Sigurdsson, Ásgeir; Smith, Albert; Sobue, Kenji; Soriano-Tárraga, Carolina; Stanne, Tara; Stine, O Colin; Stott, David J; Strauch, Konstantin; Takai, Takako; Tanaka, Hideo; Tanno, Kozo; Teumer, Alexander; Tomppo, Liisa; Torres-Aguila, Nuria P; Touze, Emmanuel; Tsugane, Shoichiro; Uitterlinden, Andre G; Valdimarsson, Einar M; van der Lee, Sven J; Völzke, Henry; Wakai, Kenji; Weir, David; Williams, Stephen R; Wolfe, Charles D A; Wong, Quenna; Xu, Huichun; Yamaji, Taiki; Sanghera, Dharambir K; Melander, Olle; Jern, Christina; Strbian, Daniel; Fernandez-Cadenas, Israel; Longstreth, W T; Rolfs, Arndt; Hata, Jun; Woo, Daniel; Rosand, Jonathan; Pare, Guillaume; Hopewell, Jemma C; Saleheen, Danish; Stefansson, Kari; Worrall, Bradford B; Kittner, Steven J; Seshadri, Sudha; Fornage, Myriam; Markus, Hugh S; Howson, Joanna M M; Kamatani, Yoichiro; Debette, Stephanie; Dichgans, Martin

2018-04-01

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

PubMed Central

Malik, Rainer; Chauhan, Ganesh; Traylor, Matthew; Sargurupremraj, Muralidharan; Okada, Yukinori; Mishra, Aniket; Rutten-Jacobs, Loes; Giese, Anne-Katrin; van der Laan, Sander W.; Gretarsdottir, Solveig; Anderson, Christopher D.; Chong, Michael; Adams, Hieab H. H.; Ago, Tetsuro; Almgren, Peter; Amouyel, Philippe; Ay, Hakan; Bartz, Traci M.; Benavente, Oscar R.; Bevan, Steve; Boncoraglio, Giorgio B.; Brown, Robert D.; Butterworth, Adam S.; Carrera, Caty; Carty, Cara L.; Chasman, Daniel I.; Chen, Wei-Min; Cole, John W.; Correa, Adolfo; Cotlarciuc, Ioana; Cruchaga, Carlos; Danesh, John; de Bakker, Paul I. W.; DeStefano, Anita L.; den Hoed, Marcel; Duan, Qing; Engelter, Stefan T.; Falcone, Guido J.; Gottesman, Rebecca F.; Grewal, Raji P.; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeffrey; Harris, Tamara B.; Hassan, Ahamad; Havulinna, Aki S.; Heckbert, Susan R.; Holliday, Elizabeth G.; Howard, George; Hsu, Fang-Chi; Hyacinth, Hyacinth I.; Ikram, M. Arfan; ingelsson, Erik; Irvin, Marguerite R.; Jian, Xueqiu; Jimenez-Conde, Jordi; Johnson, Julie A.; Jukema, J. Wouter; Kanai, Masahiro; Keene, Keith L.; Kissela, Brett M.; Kleindorfer, Dawn O.; Kooperberg, Charles; Kubo, Michiaki; Lange, Leslie A.; Langefeld, Carl D.; Langenberg, Claudia; Launer, Lenore J.; Lee, Jin-Moo; Lemmens, Robin; Leys, Didier; Lewis, Cathryn M.; Lin, Wei-Yu; Lindgren, Arne G.; Lorentzen, Erik; Magnusson, Patrik K.; Maguire, Jane; Manichaikul, Ani; McArdle, Patrick F.; Meschia, James F.; Mitchell, Braxton D.; Mosley, Thomas H.; Nalls, Michael A.; Ninomiya, Toshiharu; O’Donnell, Martin J.; Psaty, Bruce M.; Pulit, Sara L.; Rannikmäe, Kristiina; Reiner, Alexander P.; Rexrode, Kathryn M.; Rice, Kenneth; Rich, Stephen S.; Ridker, Paul M.; Rost, Natalia S.; Rothwell, Peter M.; Rotter, Jerome I.; Rundek, Tatjana; Sacco, Ralph L.; Sakaue, Saori; Sale, Michele M.; Salomaa, Veikko; Sapkota, Bishwa R.; Schmidt, Reinhold; Schmidt, Carsten O.; Schminke, Ulf; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie L. M.; Tanislav, Christian; Tatlisumak, Turgut; Taylor, Kent D.; Thijs, Vincent N. S.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tiedt, Steffen; Trompet, Stella; Tzourio, Christophe; van Duijn, Cornelia M.; Walters, Matthew; Wareham, Nicholas J.; Wassertheil-Smoller, Sylvia; Wilson, James G.; Wiggins, Kerri L.; Yang, Qiong; Yusuf, Salim; Bis, Joshua C.; Pastinen, Tomi; Ruusalepp, Arno; Schadt, Eric E.; Koplev, Simon; Björkegren, Johan L. M.; Codoni, Veronica; Civelek, Mete; Smith, Nicholas L.; Tregouet, David A.; Christophersen, Ingrid E.; Roselli, Carolina; Lubitz, Steven A.; Ellinor, Patrick T.; Tai, E. Shyong; Kooner, Jaspal S.; Kato, Norihiro; He, Jiang; van der Harst, Pim; Elliott, Paul; Chambers, John C.; Takeuchi, Fumihiko; Johnson, Andrew D.; Sanghera, Dharambir K.; Melander, Olle; Jern, Christina; Strbian, Daniel; Fernandez-Cadenas, Israel; Longstreth, W. T.; Rolfs, Arndt; Hata, Jun; Woo, Daniel; Rosand, Jonathan; Pare, Guillaume; Hopewell, Jemma C.; Saleheen, Danish; Stefansson, Kari; Worrall, Bradford B.; Kittner, Steven J.; Seshadri, Sudha; Fornage, Myriam; Markus, Hugh S.; Howson, Joanna M. M.; Kamatani, Yoichiro; Debette, Stephanie; Dichgans, Martin

2018-01-01

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy. PMID:29531354

Spinocerebellar ataxias in Venezuela: genetic epidemiology and their most likely ethnic descent.

PubMed

Paradisi, Irene; Ikonomu, Vassiliki; Arias, Sergio

2016-03-01

Dominantly inherited ataxias (spinocerebellar ataxias, SCAs) are a genetically heterogeneous group of neurologic diseases characterized by progressive cerebellar and spinal tract degeneration with ataxia and other signs, common to all known subtypes. Several types are relatively frequent worldwide, but in several countries, one specific SCA may show a higher prevalence owing to founder phenomena. In Venezuela, genetic epidemiological features of SCAs have been assessed during the last 30 years; mutations in ATXN1 (SCA1), ATXN2 (SCA2), ATXN3 (SCA3), CACNA1A (SCA6), ATXN7 (SCA7), ATXN8 (SCA8), ATXN10 (SCA10), TBP (SCA17) and ATN1 (dentatorubral pallidoluysian atrophy, DRPLA) loci were searched among 115 independent families. SCA7 was the most frequent subtype (26.6%), followed by SCA3 (25.0%), SCA2 (21.9%), SCA1 (17.2%), SCA10 (4.7%) and DRPLA (3.1%); in 43% of the families, the subtype remained unidentified. SCA7 mutations displayed strong geographic aggregation in two independent founder foci, and SCA1 showed a very remote founder effect for a subset of families. SCA10 families were scattered across the country, but all had an identical in-phase haplotype carried also by Mexican, Brazilian and Sioux patients, supporting a very old common Amerindian origin. Prevalence for dominant SCAs in Venezuela was estimated as 1:25 000 nuclear families, provenances of which are either Caucasoid, African or Amerindian.

Common occurrence of Cryptosporidium hominis in horses and donkeys.

PubMed

Jian, Fuchun; Liu, Aiqin; Wang, Rongjun; Zhang, Sumei; Qi, Meng; Zhao, Wei; Shi, Yadong; Wang, Jianling; Wei, Jiujian; Zhang, Longxian; Xiao, Lihua

2016-09-01

Extensive genetic variation is observed within the genus Cryptosporidium and the distribution of Cryptosporidium species/genotypes in humans and animals appears to vary by geography and host species. To better understand the genetic diversity of Cryptosporidium spp. in horses and donkeys, we characterized five horse-derived and 82 donkey-derived Cryptosporidium isolates from five provinces or autonomous regions (Sichuan, Gansu, Henan, Inner Mongolia and Shandong) in China at the species/genotype and subtype levels. Three Cryptosporidium species/genotypes were identified based on the analysis of the SSU rRNA gene, including Cryptosporidium parvum (n=22), the Cryptosporidium horse genotype (n=4), and Cryptosporidium hominis (n=61). The identification of C. hominis was confirmed by sequence analysis of the HSP70 and actin genes. Subtyping using sequence analysis of the 60kDa glycoprotein gene identified 21 C. parvum isolates as subtype IIdA19G1, the four horse genotype isolates as subtypes VIaA15G4 (n=2) and VIaA11G3 (n=2), and the 61 C. hominis isolates as IkA16G1 (n=59) and IkA16 (n=2). The common finding of C. hominis reaffirms the heterogeneity of Cryptosporidium spp. in horses and donkeys and is possibly a reflection of endemic transmission of C. hominis in these animals. Data of the study suggest that horses and donkeys as companion animals may potentially transmit Cryptosporidium infections to humans. Copyright © 2016 Elsevier B.V. All rights reserved.

Evidence-based guideline summary: Evaluation, diagnosis, and management of congenital muscular dystrophy

PubMed Central

Kang, Peter B.; Morrison, Leslie; Iannaccone, Susan T.; Graham, Robert J.; Bönnemann, Carsten G.; Rutkowski, Anne; Hornyak, Joseph; Wang, Ching H.; North, Kathryn; Oskoui, Maryam; Getchius, Thomas S.D.; Cox, Julie A.; Hagen, Erin E.; Gronseth, Gary; Griggs, Robert C.

2015-01-01

Objective: To delineate optimal diagnostic and therapeutic approaches to congenital muscular dystrophy (CMD) through a systematic review and analysis of the currently available literature. Methods: Relevant, peer-reviewed research articles were identified using a literature search of the MEDLINE, EMBASE, and Scopus databases. Diagnostic and therapeutic data from these articles were extracted and analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and therapeutic studies. Recommendations were linked to the strength of the evidence, other related literature, and general principles of care. Results: The geographic and ethnic backgrounds, clinical features, brain imaging studies, muscle imaging studies, and muscle biopsies of children with suspected CMD help predict subtype-specific diagnoses. Genetic testing can confirm some subtype-specific diagnoses, but not all causative genes for CMD have been described. Seizures and respiratory complications occur in specific subtypes. There is insufficient evidence to determine the efficacy of various treatment interventions to optimize respiratory, orthopedic, and nutritional outcomes, and more data are needed regarding complications. Recommendations: Multidisciplinary care by experienced teams is important for diagnosing and promoting the health of children with CMD. Accurate assessment of clinical presentations and genetic data will help in identifying the correct subtype-specific diagnosis in many cases. Multiorgan system complications occur frequently; surveillance and prompt interventions are likely to be beneficial for affected children. More research is needed to fill gaps in knowledge regarding this category of muscular dystrophies. PMID:25825463

Breast cancer subtypes: two decades of journey from cell culture to patients.

PubMed

Zhao, Xiangshan; Gurumurthy, Channabasavaiah Basavaraju; Malhotra, Gautam; Mirza, Sameer; Mohibi, Shakur; Bele, Aditya; Quinn, Meghan G; Band, Hamid; Band, Vimla

2011-01-01

Recent molecular profiling has identified six major subtypes of breast cancers that exhibit different survival outcomes for patients. To address the origin of different subtypes of breast cancers, we have now identified, isolated, and immortalized (using hTERT) mammary stem/progenitor cells which maintain their stem/progenitor properties even after immortalization. Our decade long research has shown that these stem/progenitor cells are highly susceptible to oncogenesis. Given the emerging evidence that stem/progenitor cells are precursors of cancers and that distinct subtypes of breast cancer have different survival outcome, these cellular models provide novel tools to understand the oncogenic process leading to various subtypes of breast cancers and for future development of novel therapeutic strategies to treat different subtypes of breast cancers.

Amyotrophic Lateral Sclerosis: A Genetic Point of View.

PubMed

Carlesi, C; Ienco, E Caldarazzo; Mancuso, M; Siciliano, G

2014-01-01

In the last twenty years the rapid advances in neurogenetic have revolutionized not only the molecular, pathological, inheritance but also the clinical concept of ALS. Here we review the current genetic breakthrough in familial and sporadic ALS, considering how this knowledge has allowed widening of the scenario on the possible pathogenic disease mechanisms and better understanding of the relationship between the genetic, pathological and clinical subtypes. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Progranulin gene variability influences the risk for bipolar I disorder, but not bipolar II disorder.

PubMed

Galimberti, Daniela; Prunas, Cecilia; Paoli, Riccardo A; Dell'Osso, Bernardo; Fenoglio, Chiara; Villa, Chiara; Palazzo, Carlotta; Cigliobianco, Michela; Camuri, Giulia; Serpente, Maria; Scarpini, Elio; Altamura, A Carlo

2014-11-01

Recent data have shown that genetic variability in the progranulin (GRN) gene may contribute to the susceptibility to developing bipolar disorder (BD). However, in regard to patients with BD, no information is available on the role of genetic variability and plasma progranulin levels in different types of this disorder. In this study, we performed an association analysis of GRN in an Italian population consisting of 134 patients with BD and 232 controls to evaluate progranulin plasma levels. The presence of the polymorphic variant of the rs5848 single nucleotide polymorphism is protective for the development of bipolar I disorder (BD-I) (odds ratio = 0.55, 95% confidence interval: 0.33-0.93; p = 0.024) but not bipolar II disorder (BD-II) (p > 0.05). In addition, plasma progranulin levels are significantly decreased in BD [mean ± standard deviation (SD) 112 ± 35 versus 183 ± 93 ng/mL in controls; p < 0.001]. Regarding the influence of GRN variability on BD susceptibility, the predisposing genetic background differs between BD-I and BD-II, possibly implying that pathogenic mechanisms differ between the two subtypes of BD. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A study of the influence of different genotypes on the physical and behavioral phenotypes of children and adults ascertained clinically as having PWS.

PubMed

Webb, T; Whittington, J; Clarke, D; Boer, H; Butler, J; Holland, A

2002-10-01

A population-based cohort of people with a clinical diagnosis of Prader-Willi syndrome (PWS) was genetically assessed using molecular diagnostic methods and subsequently divided into the following genetic subtypes involving chromosome 15: 'deletion', 'disomy' and genetically negative (referred to as 'PWS-like'). The physical and behavioral characteristics of the three groups were compared in order to evaluate the unique characteristics of the phenotype resulting from loss of expression of imprinted genes at 15q11q13 (PWS vs. PWS-like cases), the possible effect of either haploid insufficiency of non-imprinted genes (deletion cases), or gain of function of imprinted genes (disomy cases) located within the PWS critical region at 15q11q13. In this study, the main differences between probands with either a deletion or disomy are considered, and the possible involvement of contributing genes discussed. The differences within the PWS group proved difficult to quantify. It would appear that haploid insufficiency or gain of function are more subtle contributors than gender-specific genomic imprinting in the production of the PWS phenotype.

Morphologic changes in the mesolimbic pathway in Parkinson's disease motor subtypes.

PubMed

Nyberg, Eric M; Tanabe, Jody; Honce, Justin M; Krmpotich, Theodore; Shelton, Erika; Hedeman, Jessica; Berman, Brian D

2015-05-01

Parkinson's disease (PD) is a common neurodegenerative disorder associated with gray matter atrophy. Cortical atrophy patterns may further help distinguish between PD motor subtypes. Comparable differences in subcortical volumes have not been found. Twenty-one cognitively intact and treated PD patients, including 12 tremor dominant (TD) subtype, Nine postural instability gait dominant (PIGD) subtype, and 20 matched healthy control subjects underwent 3.0 T high-resolution structural MRI scanning. Subcortical volumetric analysis was performed using FreeSurfer and shape analysis was performed with FIRST to assess for differences between PD patients and controls and between PD subtypes. No significant differences in subcortical volumes were found between motor PD subtypes, but comparing grouped PD patients with controls revealed a significant increase in hippocampal volume in PD patients (p = 0.03). A significant shape difference was detected in the right nucleus accumbens (NAcc) between PD and controls and between motor subtypes. Shape differences were driven by positive deviations in the TD subtype. Correlation analysis revealed a trend between hippocampal volume and decreasing MDS-UPDRS (p = 0.06). While no significant differences in subcortical volumes between PD motor subtypes were found, increased hippocampal volumes were observed in PD patients compared to controls. Right NAcc shape differences in PD patients were driven by changes in the TD subtype. These unexpected findings may be related to the effects of chronic dopaminergic replacement on the mesolimbic pathway. Further studies are needed to replicate and determine the clinical significance of such morphologic changes. Copyright © 2015 Elsevier Ltd. All rights reserved.

The evolutionary dynamics of the lion Panthera leo revealed by host and viral population genomics.

PubMed

Antunes, Agostinho; Troyer, Jennifer L; Roelke, Melody E; Pecon-Slattery, Jill; Packer, Craig; Winterbach, Christiaan; Winterbach, Hanlie; Hemson, Graham; Frank, Laurence; Stander, Philip; Siefert, Ludwig; Driciru, Margaret; Funston, Paul J; Alexander, Kathy A; Prager, Katherine C; Mills, Gus; Wildt, David; Bush, Mitch; O'Brien, Stephen J; Johnson, Warren E

2008-11-01

The lion Panthera leo is one of the world's most charismatic carnivores and is one of Africa's key predators. Here, we used a large dataset from 357 lions comprehending 1.13 megabases of sequence data and genotypes from 22 microsatellite loci to characterize its recent evolutionary history. Patterns of molecular genetic variation in multiple maternal (mtDNA), paternal (Y-chromosome), and biparental nuclear (nDNA) genetic markers were compared with patterns of sequence and subtype variation of the lion feline immunodeficiency virus (FIV(Ple)), a lentivirus analogous to human immunodeficiency virus (HIV). In spite of the ability of lions to disperse long distances, patterns of lion genetic diversity suggest substantial population subdivision (mtDNA Phi(ST) = 0.92; nDNA F(ST) = 0.18), and reduced gene flow, which, along with large differences in sero-prevalence of six distinct FIV(Ple) subtypes among lion populations, refute the hypothesis that African lions consist of a single panmictic population. Our results suggest that extant lion populations derive from several Pleistocene refugia in East and Southern Africa ( approximately 324,000-169,000 years ago), which expanded during the Late Pleistocene ( approximately 100,000 years ago) into Central and North Africa and into Asia. During the Pleistocene/Holocene transition ( approximately 14,000-7,000 years), another expansion occurred from southern refugia northwards towards East Africa, causing population interbreeding. In particular, lion and FIV(Ple) variation affirms that the large, well-studied lion population occupying the greater Serengeti Ecosystem is derived from three distinct populations that admixed recently.

Delineating the genetic heterogeneity of OCA in Hungarian patients.

PubMed

Fábos, Beáta; Farkas, Katalin; Tóth, Lola; Sulák, Adrienn; Tripolszki, Kornélia; Tihanyi, Mariann; Németh, Réka; Vas, Krisztina; Csoma, Zsanett; Kemény, Lajos; Széll, Márta; Nagy, Nikoletta

2017-06-19

Oculocutaneous albinism (OCA) is a clinically and genetically heterogenic group of pigmentation abnormalities characterized by variable hair, skin, and ocular hypopigmentation. Six known genes and a locus on human chromosome 4q24 have been implicated in the etiology of isolated OCA forms (OCA 1-7). The most frequent OCA types among Caucasians are OCA1, OCA2, and OCA4. We aimed to investigate genes responsible for the development of these OCA forms in Hungarian OCA patients (n = 13). Mutation screening and polymorphism analysis were performed by direct sequencing on TYR, OCA2, SLC45A2 genes. Although the clinical features of the investigated Hungarian OCA patients were identical, the molecular genetic data suggested OCA1 subtype in eight cases and OCA4 subtype in two cases. The molecular diagnosis was not clearly identifiable in three cases. In four patients, two different heterozygous known pathogenic or predicted to be pathogenic mutations were present. Seven patients had only one pathogenic mutation, which was associated with non-pathogenic variants in six cases. In two patients no pathogenic mutation was identified. Our results suggest that the concomitant screening of the non-pathogenic variants-which alone do not cause the development of OCA, but might have clinical significance in association with a pathogenic variant-is important. Our results also show significant variation in the disease spectrum compared to other populations. These data also confirm that the concomitant analysis of OCA genes is critical, providing new insights to the phenotypic diversity of OCA and expanding the mutation spectrum of OCA genes in Hungarian patients.

Recent human-to-poultry host jump, adaptation, and pandemic spread of Staphylococcus aureus

PubMed Central

Lowder, Bethan V.; Guinane, Caitriona M.; Ben Zakour, Nouri L.; Weinert, Lucy A.; Conway-Morris, Andrew; Cartwright, Robyn A.; Simpson, A. John; Rambaut, Andrew; Nübel, Ulrich; Fitzgerald, J. Ross

2009-01-01

The impact of globalization on the emergence and spread of pathogens is an important veterinary and public health issue. Staphylococcus aureus is a notorious human pathogen associated with serious nosocomial and community-acquired infections. In addition, S. aureus is a major cause of animal diseases including skeletal infections of poultry, which are a large economic burden on the global broiler chicken industry. Here, we provide evidence that the majority of S. aureus isolates from broiler chickens are the descendants of a single human-to-poultry host jump that occurred approximately 38 years ago (range, 30 to 63 years ago) by a subtype of the worldwide human ST5 clonal lineage unique to Poland. In contrast to human subtypes of the ST5 radiation, which demonstrate strong geographic clustering, the poultry ST5 clade was distributed in different continents, consistent with wide dissemination via the global poultry industry distribution network. The poultry ST5 clade has undergone genetic diversification from its human progenitor strain by acquisition of novel mobile genetic elements from an avian-specific accessory gene pool, and by the inactivation of several proteins important for human disease pathogenesis. These genetic events have resulted in enhanced resistance to killing by chicken heterophils, reflecting avian host-adaptive evolution. Taken together, we have determined the evolutionary history of a major new animal pathogen that has undergone rapid avian host adaptation and intercontinental dissemination. These data provide a new paradigm for the impact of human activities on the emergence of animal pathogens. PMID:19884497

The Evolutionary Dynamics of the Lion Panthera leo Revealed by Host and Viral Population Genomics

PubMed Central

Antunes, Agostinho; Troyer, Jennifer L.; Roelke, Melody E.; Pecon-Slattery, Jill; Packer, Craig; Winterbach, Christiaan; Winterbach, Hanlie; Hemson, Graham; Frank, Laurence; Stander, Philip; Siefert, Ludwig; Driciru, Margaret; Funston, Paul J.; Alexander, Kathy A.; Prager, Katherine C.; Mills, Gus; Wildt, David; Bush, Mitch; O'Brien, Stephen J.; Johnson, Warren E.

2008-01-01

The lion Panthera leo is one of the world's most charismatic carnivores and is one of Africa's key predators. Here, we used a large dataset from 357 lions comprehending 1.13 megabases of sequence data and genotypes from 22 microsatellite loci to characterize its recent evolutionary history. Patterns of molecular genetic variation in multiple maternal (mtDNA), paternal (Y-chromosome), and biparental nuclear (nDNA) genetic markers were compared with patterns of sequence and subtype variation of the lion feline immunodeficiency virus (FIVPle), a lentivirus analogous to human immunodeficiency virus (HIV). In spite of the ability of lions to disperse long distances, patterns of lion genetic diversity suggest substantial population subdivision (mtDNA ΦST = 0.92; nDNA F ST = 0.18), and reduced gene flow, which, along with large differences in sero-prevalence of six distinct FIVPle subtypes among lion populations, refute the hypothesis that African lions consist of a single panmictic population. Our results suggest that extant lion populations derive from several Pleistocene refugia in East and Southern Africa (∼324,000–169,000 years ago), which expanded during the Late Pleistocene (∼100,000 years ago) into Central and North Africa and into Asia. During the Pleistocene/Holocene transition (∼14,000–7,000 years), another expansion occurred from southern refugia northwards towards East Africa, causing population interbreeding. In particular, lion and FIVPle variation affirms that the large, well-studied lion population occupying the greater Serengeti Ecosystem is derived from three distinct populations that admixed recently. PMID:18989457

Advancing Our Understanding of the Etiologies and Mutational Landscapes of Basal-Like, Luminal A, and Luminal B Breast Cancers

DTIC Science & Technology

2017-10-01

various breast cancer risk factors differ in their relationships to different molecular subtypes of breast cancer and to further characterize... molecular differences between these subtypes. To address the existing research gaps regarding the etiologies of different molecular subtypes of breast... molecular subtypes of breast cancer, basal-like, luminal A, and luminal B tumors, breast cancer risk factors 16. SECURITY CLASSIFICATION OF: 17. LIMITATION

Canine congenital portosystemic shunts: Disconnections dissected.

PubMed

Van den Bossche, L; van Steenbeek, F G

2016-05-01

Canine congenital portosystemic shunts (CPSS) are vascular anomalies that connect the portal vein with the systemic circulation, therefore bypassing the hepatic parenchyma. Portosystemic shunts exist in two different subtypes: extrahepatic and intrahepatic. This congenital disorder is also described in mice, cat, sheep and man. Research has been focused on pathophysiology, diagnostics and treatment of CPSS and this has resulted in increased knowledge, although the aetiology of the disease remains unclear. This review focuses on the aetiology and genetic basis of both intra- and extrahepatic shunts. Copyright © 2016 Elsevier Ltd. All rights reserved.

Association of BRCA Mutation Types, Imaging Features, and Pathologic Findings in Patients With Breast Cancer With BRCA1 and BRCA2 Mutations.

PubMed

Ha, Su Min; Chae, Eun Young; Cha, Joo Hee; Kim, Hak Hee; Shin, Hee Jung; Choi, Woo Jung

2017-10-01

The purpose of this study is to retrospectively evaluate the relationships between the BRCA mutation types, imaging features, and pathologic findings of breast cancers in BRCA1 and BRCA2 mutation carriers. We identified patients with breast cancer with BRCA gene mutations from January 2000 to December 2014. After excluding patients who underwent lesion excision before MRI, 99 BRCA1 and 103 BRCA2 lesions in 187 women (mean age, 39.7 and 40.4 years, respectively) were enrolled. Mammographic, sonographic, and MRI scans were reviewed according to the BI-RADS lexicon (5th edition). Pathologic data were reviewed, including the immunohistochemistry findings. The relationships between the BRCA mutations and both imaging and pathologic findings were analyzed. The distribution of molecular subtypes of tumors significantly differed by the mutation type. BRCA1 tumors were associated with the triple-negative subtype, whereas BRCA2 tumors were associated with the luminal B subtype (p = 0.002). At MRI, breast cancers with BRCA1 mutations exhibited a circumscribed margin (p = 0.032) and rim enhancement (p = 0.013). No significant differences in mass shape or kinetic features were observed at MRI. Cancers in BRCA1 mutation carriers tended to develop in the posterior location in the breast (p = 0.034). At mammography, no significant difference in the prevalence of calcifications was observed according to the mutation type. At sonography, BRCA1 lesions were found to be associated with posterior acoustic enhancement (p < 0.0001). Breast cancers with BRCA1 mutations tend to exhibit benign morphologic features at MRI, mammography, and sonography, compared with BRCA2 mutations. Lesion location may represent another difference on imaging among various genetic phenotypes.

Pleiotropic Contribution of MECOM and AVPR1A to Aggression and Subcortical Brain Volumes

PubMed Central

van Donkelaar, Marjolein M. J.; Hoogman, Martine; Pappa, Irene; Tiemeier, Henning; Buitelaar, Jan K.; Franke, Barbara; Bralten, Janita

2018-01-01

Reactive and proactive subtypes of aggression have been recognized to help parse etiological heterogeneity of this complex phenotype. With a heritability of about 50%, genetic factors play a role in the development of aggressive behavior. Imaging studies implicate brain structures related to social behavior in aggression etiology, most notably the amygdala and striatum. This study aimed to gain more insight into the pathways from genetic risk factors for aggression to aggression phenotypes. To this end, we conducted genome-wide gene-based cross-trait meta-analyses of aggression with the volumes of amygdala, nucleus accumbens and caudate nucleus to identify genes influencing both aggression and aggression-related brain volumes. We used data of large-scale genome-wide association studies (GWAS) of: (a) aggressive behavior in children and adolescents (EAGLE, N = 18,988); and (b) Magnetic Resonance Imaging (MRI)-based volume measures of aggression-relevant subcortical brain regions (ENIGMA2, N = 13,171). Second, the identified genes were further investigated in a sample of healthy adults (mean age (SD) = 25.28 (4.62) years; 43% male) who had genome-wide genotyping data and questionnaire data on aggression subtypes available (Brain Imaging Genetics, BIG, N = 501) to study their effect on reactive and proactive subtypes of aggression. Our meta-analysis identified two genes, MECOM and AVPR1A, significantly associated with both aggression risk and nucleus accumbens (MECOM) and amygdala (AVPR1A) brain volume. Subsequent in-depth analysis of these genes in healthy adults (BIG), including sex as an interaction term in the model, revealed no significant subtype-specific gene-wide associations. Using cross-trait meta-analysis of brain measures and psychiatric phenotypes, this study generated new hypotheses about specific links between genes, the brain and behavior. Results indicate that MECOM and AVPR1A may exert an effect on aggression through mechanisms involving nucleus accumbens and amygdala volumes, respectively. PMID:29666571

Salmonella enterica Prophage Sequence Profiles Reflect Genome Diversity and Can Be Used for High Discrimination Subtyping.

PubMed

Mottawea, Walid; Duceppe, Marc-Olivier; Dupras, Andrée A; Usongo, Valentine; Jeukens, Julie; Freschi, Luca; Emond-Rheault, Jean-Guillaume; Hamel, Jeremie; Kukavica-Ibrulj, Irena; Boyle, Brian; Gill, Alexander; Burnett, Elton; Franz, Eelco; Arya, Gitanjali; Weadge, Joel T; Gruenheid, Samantha; Wiedmann, Martin; Huang, Hongsheng; Daigle, France; Moineau, Sylvain; Bekal, Sadjia; Levesque, Roger C; Goodridge, Lawrence D; Ogunremi, Dele

2018-01-01

Non-typhoidal Salmonella is a leading cause of foodborne illness worldwide. Prompt and accurate identification of the sources of Salmonella responsible for disease outbreaks is crucial to minimize infections and eliminate ongoing sources of contamination. Current subtyping tools including single nucleotide polymorphism (SNP) typing may be inadequate, in some instances, to provide the required discrimination among epidemiologically unrelated Salmonella strains. Prophage genes represent the majority of the accessory genes in bacteria genomes and have potential to be used as high discrimination markers in Salmonella . In this study, the prophage sequence diversity in different Salmonella serovars and genetically related strains was investigated. Using whole genome sequences of 1,760 isolates of S. enterica representing 151 Salmonella serovars and 66 closely related bacteria, prophage sequences were identified from assembled contigs using PHASTER. We detected 154 different prophages in S. enterica genomes. Prophage sequences were highly variable among S. enterica serovars with a median ± interquartile range (IQR) of 5 ± 3 prophage regions per genome. While some prophage sequences were highly conserved among the strains of specific serovars, few regions were lineage specific. Therefore, strains belonging to each serovar could be clustered separately based on their prophage content. Analysis of S . Enteritidis isolates from seven outbreaks generated distinct prophage profiles for each outbreak. Taken altogether, the diversity of the prophage sequences correlates with genome diversity. Prophage repertoires provide an additional marker for differentiating S. enterica subtypes during foodborne outbreaks.

Haptoglobin gene subtypes in three Brazilian population groups of different ethnicities

PubMed Central

2009-01-01

Haptoglobin is a plasma hemoglobin-binding protein that limits iron loss during normal erythrocyte turnover and hemolysis, thereby preventing oxidative damage mediated by iron excess in the circulation. Haptoglobin polymorphism in humans, characterized by the Hp*1 and Hp *2 alleles, results in distinct phenotypes known as Hp1-1, Hp2-1 and Hp2-2, whose frequencies vary according to the ethnic origin of the population. The Hp*1 allele has two subtypes, Hp *1F and Hp *1S , that also vary in their frequencies among populations worldwide. In this work, we examined the distribution frequencies of haptoglobin subtypes in three Brazilian population groups of different ethnicities. The haptoglobin genotypes of Kayabi Amerindians (n = 56), Kalunga Afro-descendants (n = 70) and an urban population (n = 132) were determined by allele-specific PCR. The Hp*1F allele frequency was highest in Kalunga (29.3%) and lowest in Kayabi (2.6%). The Hp*1F/Hp*1S allele frequency ratios were 0.6, 1.0 and 0.26 for the Kayabi, Kalunga and urban populations, respectively. This variation was attributable largely to the Hp*1F allele. However, despite the large variation in Hp*1F frequencies, results of F ST (0.0291) indicated slight genetic differentiation among subpopulations of the general Brazilian population studied here. This is the first Brazilian report of variations in the Hp*1F and Hp*1S frequencies among non-Amerindian Brazilians. PMID:21637505

Haptoglobin gene subtypes in three Brazilian population groups of different ethnicities.

PubMed

Miranda-Vilela, Ana L; Akimoto, Arthur K; Alves, Penha C Z; Hiragi, Cássia O; Penalva, Guilherme C; Oliveira, Silviene F; Grisolia, Cesar K; Klautau-Guimarães, Maria N

2009-07-01

Haptoglobin is a plasma hemoglobin-binding protein that limits iron loss during normal erythrocyte turnover and hemolysis, thereby preventing oxidative damage mediated by iron excess in the circulation. Haptoglobin polymorphism in humans, characterized by the Hp(*1) and Hp (*2) alleles, results in distinct phenotypes known as Hp1-1, Hp2-1 and Hp2-2, whose frequencies vary according to the ethnic origin of the population. The Hp(*1) allele has two subtypes, Hp (*1F) and Hp (*1S) , that also vary in their frequencies among populations worldwide. In this work, we examined the distribution frequencies of haptoglobin subtypes in three Brazilian population groups of different ethnicities. The haptoglobin genotypes of Kayabi Amerindians (n = 56), Kalunga Afro-descendants (n = 70) and an urban population (n = 132) were determined by allele-specific PCR. The Hp(*1F) allele frequency was highest in Kalunga (29.3%) and lowest in Kayabi (2.6%). The Hp(*1F)/Hp(*1S) allele frequency ratios were 0.6, 1.0 and 0.26 for the Kayabi, Kalunga and urban populations, respectively. This variation was attributable largely to the Hp(*1F) allele. However, despite the large variation in Hp(*1F) frequencies, results of F (ST) (0.0291) indicated slight genetic differentiation among subpopulations of the general Brazilian population studied here. This is the first Brazilian report of variations in the Hp(*1F) and Hp(*1S) frequencies among non-Amerindian Brazilians.

Analysis of swine leukocyte antigen class I gene profiles and porcine endogenous retrovirus viremia level in a transgenic porcine herd inbred for xenotransplantation research

PubMed Central

Sypniewski, Daniel; Gałka, Sabina; Sołtysik, Dagna; Loch, Tomasz; Nowak, Ewa; Smorąg, Zdzisław; Bednarek, Ilona

2018-01-01

Molecular characterization of swine leukocyte antigen (SLA) genes is important for elucidating the immune responses between swine-donor and human-recipient in xenotransplantation. Examination of associations between alleles of SLA class I genes, type of pig genetic modification, porcine endogenous retrovirus (PERV) viral titer, and PERV subtypes may shed light on the nature of xenograft acceptance or rejection and the safety of xenotransplantation. No significant difference in PERV gag RNA level between transgenic and non-transgenic pigs was noted; likewise, the type of applied transgene had no impact on PERV viremia. SLA-1 gene profile type may correspond with PERV level in blood and thereby influence infectiveness. Screening of pigs should provide selection of animals with low PERV expression and exclusion of specimens with PERV-C in the genome due to possible recombination between A and C subtypes, which may lead to autoinfection. Presence of PERV-C integrated in the genome was detected in 31.25% of specimens, but statistically significant increased viremia in specimens with PERV-C was not observed. There is a need for multidirectional molecular characterization (SLA typing, viremia estimation, and PERV subtype screening) of animals intended for xenotransplantation research in the interest of xeno-recipient safety. PMID:29366300

Comorbidity of obsessive-compulsive disorder with obsessive-compulsive personality disorder: Does it imply a specific subtype of obsessive-compulsive disorder?

PubMed

Garyfallos, George; Katsigiannopoulos, Konstantinos; Adamopoulou, Aravela; Papazisis, Georgios; Karastergiou, Anastasia; Bozikas, Vasilios P

2010-05-15

The present study examined whether the comorbidity of obsessive-compulsive personality disorder (OCPD) and obsessive-compulsive disorder (OCD) constitute a specific subtype of OCD. The study sample consisted of 146 consecutive outpatients with a DSM-IV diagnosis of OCD. Diagnoses were established using MINI, IPDE, YBOCS and YBOCS-SC. OCD patients with comorbid OCPD were compared with OCD patients without OCPD on various sociodemographic and clinical variables. Almost one third of the OCD subjects met criteria for comorbid OCPD. OCD+OCPD patients had a significantly earlier age at onset of initial OC symptoms, earlier age at onset of OCD and more obsessions and compulsions than pure obsessions compared to the patients with OCDOCPD. OCD+OCPD patients also had a higher rate of comorbidity with avoidant personality disorder and showed more impairment in global functioning. There were not differences between the two sub-groups on severity of OCD symptoms and also on type of OCD onset. Our results indicate that the comorbidity of OCD with OCPD is associated with a number of specific clinical characteristics of OCD. These findings in conjunction with of current clinical, family and genetic studies provide some initial evidence that OCD comorbid with OCPD constitute a specific subtype of OCD. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Molecular classification of gastric cancer.

PubMed

Chia, N-Y; Tan, P

2016-05-01

Gastric cancer (GC), a heterogeneous disease characterized by epidemiologic and histopathologic differences across countries, is a leading cause of cancer-related death. Treatment of GC patients is currently suboptimal due to patients being commonly treated in a uniform fashion irrespective of disease subtype. With the advent of next-generation sequencing and other genomic technologies, GCs are now being investigated in great detail at the molecular level. High-throughput technologies now allow a comprehensive study of genomic and epigenomic alterations associated with GC. Gene mutations, chromosomal aberrations, differential gene expression and epigenetic alterations are some of the genetic/epigenetic influences on GC pathogenesis. In addition, integrative analyses of molecular profiling data have led to the identification of key dysregulated pathways and importantly, the establishment of GC molecular classifiers. Recently, The Cancer Genome Atlas (TCGA) network proposed a four subtype classification scheme for GC based on the underlying tumor molecular biology of each subtype. This landmark study, together with other studies, has expanded our understanding on the characteristics of GC at the molecular level. Such knowledge may improve the medical management of GC in the future. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Immunohistochemistry and Fluorescence In Situ Hybridization Can Inform the Differential Diagnosis of Low-Grade Noninvasive Urothelial Carcinoma with an Inverted Growth Pattern and Inverted Urothelial Papilloma

PubMed Central

Lu, Yong-Ming; Zhang, Hui-Zhi; Wang, Tao; Yang, Xiao-Qun; Sun, Meng-Hong; Wang, Chao-Fu

2015-01-01

Urothelial carcinoma (UC) comprises a heterogeneous group of epithelial neoplasms with diverse biological behaviors and variable clinical outcomes. Distinguishing UC histological subtypes has become increasingly important because prognoses and therapy can dramatically differ among subtypes. In clinical work, overlapping morphological findings between low-grade noninvasive UC (LGNUC), which exhibits an inverted growth pattern, and inverted urothelial papilloma (IUP) can make subclassification difficult. We propose a combination of immunohistochemistry (IHC) and molecular cytogenetics for subtyping these clinical entities. In our study, tissue microarray immunohistochemical profiles of Ki-67, p53, cytokeratin 20 (CK20) and cyclinD1 were assessed. Molecular genetic alterations such as the gain of chromosomes 3, 7 or 17 or the homozygous loss of 9p21 were also assessed for their usefulness in differentiating these conditions. Based on our analysis, Ki-67 and CK20 may be useful for the differential diagnosis of these two tumor types. Fluorescence in situ hybridization (FISH) can also provide important data in cases in which the malignant nature of an inverted urothelial neoplasm is unclear. LGNUC with an inverted growth pattern that is negative for both Ki-67 and CK20 can be positively detected using FISH. PMID:26208279

Significant contribution of subtype G to HIV-1 genetic complexity in Nigeria identified by a newly developed subtyping assay specific for subtype G and CRF02_AG

PubMed Central

Heipertz, Richard A.; Ayemoba, Ojor; Sanders-Buell, Eric; Poltavee, Kultida; Pham, Phuc; Kijak, Gustavo H.; Lei, Esther; Bose, Meera; Howell, Shana; O'Sullivan, Anne Marie; Bates, Adam; Cervenka, Taylor; Kuroiwa, Janelle; Akintunde, Akindiran; Ibezim, Onyekachukwu; Alabi, Abraham; Okoye, Obumneke; Manak, Mark; Malia, Jennifer; Peel, Sheila; Maisaka, Mohammed; Singer, Darrell; O’Connell, Robert J.; Robb, Merlin L.; Kim, Jerome H.; Michael, Nelson L.; Njoku, Ogbonnaya; Tovanabutra, Sodsai

2016-01-01

Abstract While abundant sequence information is available from human immunodeficiency virus type 1 (HIV-1) subtypes A, B, C and CRF01_AE for HIV-1 vaccine design, sequences from West Africa are less represented. We sought to augment our understanding of HIV-1 variants circulating in 6 Nigerian cities as a step to subsequent HIV-1 vaccine development. The G/CRF02_AG multi-region hybridization assay (MHA) was developed to differentiate subtype G, CRF02_AG and their recombinants from other subtypes based on 7 HIV-1 segments. Plasma from 224 HIV-1 infected volunteers enrolled in a cohort examining HIV-1 prevalence, risk factor, and subtype from Makurdi (30), Abuja (18), Enugu (11), Kaduna (12), Tafa (95), and Ojo/Lagos (58) was analyzed using MHA. HIV-1 genomes from 42 samples were sequenced to validate the MHA and fully explore the recombinant structure of G and CRF02_AG variants. The sensitivity and specificity of MHA varied between 73–100% and 90–100%, respectively. The subtype distribution as identified by MHA among 224 samples revealed 38% CRF02_AG, 28% G, and 26% G/CRF02_AG recombinants while 8% remained nontypeable strains. In envelope (env) gp120, 38.84% of the samples reacted to a G probe while 31.25% reacted to a CRF02 (subtype A) probe. Full genome characterization of 42 sequences revealed the complexity of Nigerian HIV-1 variants. CRF02_AG, subtype G, and their recombinants were the major circulating HIV-1 variants in 6 Nigerian cities. High proportions of samples reacted to a G probe in env gp120 confirms that subtype G infections are abundant and should be considered in strategies for global HIV-1 vaccine development. PMID:27512845

SYBR green-based real-time reverse transcription-PCR for typing and subtyping of all hemagglutinin and neuraminidase genes of avian influenza viruses and comparison to standard serological subtyping tests.

PubMed

Tsukamoto, Kenji; Panei, Carlos Javier; Javier, Panei Carlos; Shishido, Makiko; Noguchi, Daigo; Pearce, John; Kang, Hyun-Mi; Jeong, Ok Mi; Lee, Youn-Jeong; Nakanishi, Koji; Ashizawa, Takayoshi

2012-01-01

Continuing outbreaks of H5N1 highly pathogenic (HP) avian influenza virus (AIV) infections of wild birds and poultry worldwide emphasize the need for global surveillance of wild birds. To support the future surveillance activities, we developed a SYBR green-based, real-time reverse transcriptase PCR (rRT-PCR) for detecting nucleoprotein (NP) genes and subtyping 16 hemagglutinin (HA) and 9 neuraminidase (NA) genes simultaneously. Primers were improved by focusing on Eurasian or North American lineage genes; the number of mixed-base positions per primer was set to five or fewer, and the concentration of each primer set was optimized empirically. Also, 30 cycles of amplification of 1:10 dilutions of cDNAs from cultured viruses effectively reduced minor cross- or nonspecific reactions. Under these conditions, 346 HA and 345 NA genes of 349 AIVs were detected, with average sensitivities of NP, HA, and NA genes of 10(1.5), 10(2.3), and 10(3.1) 50% egg infective doses, respectively. Utility of rRT-PCR for subtyping AIVs was compared with that of current standard serological tests by using 104 recent migratory duck virus isolates. As a result, all HA genes and 99% of the NA genes were genetically subtyped, while only 45% of HA genes and 74% of NA genes were serologically subtyped. Additionally, direct subtyping of AIVs in fecal samples was possible by 40 cycles of amplification: approximately 70% of HA and NA genes of NP gene-positive samples were successfully subtyped. This validation study indicates that rRT-PCR with optimized primers and reaction conditions is a powerful tool for subtyping varied AIVs in clinical and cultured samples.

Management of Charcot–Marie–Tooth disease: improving long-term care with a multidisciplinary approach

PubMed Central

McCorquodale, Donald; Pucillo, Evan M; Johnson, Nicholas E

2016-01-01

Charcot–Marie–Tooth (CMT) disease is the most common inherited neuropathy and one of the most common inherited diseases in humans. The diagnosis of CMT is traditionally made by the neurologic specialist, yet the optimal management of CMT patients includes genetic counselors, physical and occupational therapists, physiatrists, orthotists, mental health providers, and community resources. Rapidly developing genetic discoveries and novel gene discovery techniques continue to add a growing number of genetic subtypes of CMT. The first large clinical natural history and therapeutic trials have added to our knowledge of each CMT subtype and revealed how CMT impacts patient quality of life. In this review, we discuss several important trends in CMT research factors that will require a collaborative multidisciplinary approach. These include the development of large multicenter patient registries, standardized clinical instruments to assess disease progression and disability, and increasing recognition and use of patient-reported outcome measures. These developments will continue to guide strategies in long-term multidisciplinary efforts to maintain quality of life and preserve functionality in CMT patients. PMID:26855581

Genomic alterations and molecular subtypes of gastric cancers in Asians.

PubMed

Ye, Xiang S; Yu, Chunping; Aggarwal, Amit; Reinhard, Christoph

2016-05-09

Gastric cancer (GC) is a highly heterogenic disease, and it is the second leading cause of cancer death in the world. Common chemotherapies are not very effective for GC, which often presents as an advanced or metastatic disease at diagnosis. Treatment options are limited, and the prognosis for advanced GCs is poor. The landscape of genomic alterations in GCs has recently been characterized by several international cancer genome programs, including studies that focused exclusively on GCs in Asians. These studies identified major recurrent driver mutations and provided new insights into the mutational heterogeneity and genetic profiles of GCs. An analysis of gene expression data by the Asian Cancer Research Group (ACRG) further uncovered four distinct molecular subtypes with well-defined clinical features and their intersections with actionable genetic alterations to which targeted therapeutic agents are either already available or under clinical development. In this article, we review the ACRG GC project. We also discuss the implications of the genetic and molecular findings from various GC genomic studies with respect to developing more precise diagnoses and treatment approaches for GCs.

Male Lineages in Brazil: Intercontinental Admixture and Stratification of the European Background.

PubMed

Resque, Rafael; Gusmão, Leonor; Geppert, Maria; Roewer, Lutz; Palha, Teresinha; Alvarez, Luis; Ribeiro-dos-Santos, Ândrea; Santos, Sidney

2016-01-01

The non-recombining nature of the Y chromosome and the well-established phylogeny of Y-specific Single Nucleotide Polymorphisms (Y-SNPs) make them useful for defining haplogroups with high geographical specificity; therefore, they are more apt than the Y-STRs to detect population stratification in admixed populations from diverse continental origins. Different Y-SNP typing strategies have been described to address issues of population history and movements within geographic territories of interest. In this study, we investigated a set of 41 Y-SNPs in 1217 unrelated males from the five Brazilian geopolitical regions, aiming to disclose the genetic structure of male lineages in the country. A population comparison based on pairwise FST genetic distances did not reveal statistically significant differences in haplogroup frequency distributions among populations from the different regions. The genetic differences observed among regions were, however, consistent with the colonization history of the country. The sample from the Northern region presented the highest Native American ancestry (8.4%), whereas the more pronounced African contribution could be observed in the Northeastern population (15.1%). The Central-Western and Southern samples showed the higher European contributions (95.7% and 93.6%, respectively). The Southeastern region presented significant European (86.1%) and African (12.0%) contributions. The subtyping of the most frequent European lineage in Brazil (R1b1a-M269) allowed differences in the genetic European background of the five Brazilian regions to be investigated for the first time.

Male Lineages in Brazil: Intercontinental Admixture and Stratification of the European Background

PubMed Central

Geppert, Maria; Roewer, Lutz; Palha, Teresinha; Alvarez, Luis; Ribeiro-dos-Santos, Ândrea; Santos, Sidney

2016-01-01

The non-recombining nature of the Y chromosome and the well-established phylogeny of Y-specific Single Nucleotide Polymorphisms (Y-SNPs) make them useful for defining haplogroups with high geographical specificity; therefore, they are more apt than the Y-STRs to detect population stratification in admixed populations from diverse continental origins. Different Y-SNP typing strategies have been described to address issues of population history and movements within geographic territories of interest. In this study, we investigated a set of 41 Y-SNPs in 1217 unrelated males from the five Brazilian geopolitical regions, aiming to disclose the genetic structure of male lineages in the country. A population comparison based on pairwise FST genetic distances did not reveal statistically significant differences in haplogroup frequency distributions among populations from the different regions. The genetic differences observed among regions were, however, consistent with the colonization history of the country. The sample from the Northern region presented the highest Native American ancestry (8.4%), whereas the more pronounced African contribution could be observed in the Northeastern population (15.1%). The Central-Western and Southern samples showed the higher European contributions (95.7% and 93.6%, respectively). The Southeastern region presented significant European (86.1%) and African (12.0%) contributions. The subtyping of the most frequent European lineage in Brazil (R1b1a-M269) allowed differences in the genetic European background of the five Brazilian regions to be investigated for the first time. PMID:27046235

Molecular and Genomic Alterations in Glioblastoma Multiforme.

PubMed

Crespo, Ines; Vital, Ana Louisa; Gonzalez-Tablas, María; Patino, María del Carmen; Otero, Alvaro; Lopes, María Celeste; de Oliveira, Catarina; Domingues, Patricia; Orfao, Alberto; Tabernero, Maria Dolores

2015-07-01

In recent years, important advances have been achieved in the understanding of the molecular biology of glioblastoma multiforme (GBM); thus, complex genetic alterations and genomic profiles, which recurrently involve multiple signaling pathways, have been defined, leading to the first molecular/genetic classification of the disease. In this regard, different genetic alterations and genetic pathways appear to distinguish primary (eg, EGFR amplification) versus secondary (eg, IDH1/2 or TP53 mutation) GBM. Such genetic alterations target distinct combinations of the growth factor receptor-ras signaling pathways, as well as the phosphatidylinositol 3-kinase/phosphatase and tensin homolog/AKT, retinoblastoma/cyclin-dependent kinase (CDK) N2A-p16(INK4A), and TP53/mouse double minute (MDM) 2/MDM4/CDKN2A-p14(ARF) pathways, in cells that present features associated with key stages of normal neurogenesis and (normal) central nervous system cell types. This translates into well-defined genomic profiles that have been recently classified by The Cancer Genome Atlas Consortium into four subtypes: classic, mesenchymal, proneural, and neural GBM. Herein, we review the most relevant genetic alterations of primary versus secondary GBM, the specific signaling pathways involved, and the overall genomic profile of this genetically heterogeneous group of malignant tumors. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Advances in sarcoma genomics and new therapeutic targets

PubMed Central

Taylor, Barry S.; Barretina, Jordi; Maki, Robert G.; Antonescu, Cristina R.; Singer, Samuel; Ladanyi, Marc

2012-01-01

Preface Increasingly, human mesenchymal malignancies are classified by the abnormalities that drive their pathogenesis. While many of these aberrations are highly prevalent within particular sarcoma subtypes, few are currently targeted therapeutically. Indeed, most subtypes of sarcoma are still treated with traditional therapeutic modalities and in many cases are resistant to adjuvant therapies. In this Review, we discuss the core molecular determinants of sarcomagenesis and emphasize the emerging genomic and functional genetic approaches that, coupled to novel therapeutic strategies, have the potential to transform the care of patients with sarcoma. PMID:21753790

The relation between dimensions of normal and pathological personality and childhood maltreatment in incarcerated boys.

PubMed

Nederlof, E; Van der Ham, J M; Dingemans, P M J A; Oei, T I

2010-12-01

The relation between subtypes of maltreatment and dimensions of personality and personality pathology was investigated in a representative sample of 142 incarcerated Dutch male juveniles. Normal personality dimensions were assessed with the Big Five Inventory, the Dimensional Assessment of Personality Pathology-Basic Questionnaire for Adolescents was used to measure pathological personality dimensions, and the Childhood Trauma Questionnaire was used to assess childhood maltreatment. The five maltreatment subtypes were found to be differentially and uniquely related to the normal and pathological personality dimensions in juvenile delinquents. The association between the abusive subtypes and Emotional Dysregulation depended on the co-occurrence of neglect. It was concluded that subtypes of maltreatment are distinctively related to dimensions of personality and personality pathology, possibly due to specific gene-environment interactions. Further research on this interplay is needed to be able to recognize genetic vulnerability. Early identification of children at risk could aid to limit the long-term consequences of maltreatment.

Activity of Tachykinin1-Expressing Pet1 Raphe Neurons Modulates the Respiratory Chemoreflex.

PubMed

Hennessy, Morgan L; Corcoran, Andrea E; Brust, Rachael D; Chang, YoonJeung; Nattie, Eugene E; Dymecki, Susan M

2017-02-15

Homeostatic control of breathing, heart rate, and body temperature relies on circuits within the brainstem modulated by the neurotransmitter serotonin (5-HT). Mounting evidence points to specialized neuronal subtypes within the serotonergic neuronal system, borne out in functional studies, for the modulation of distinct facets of homeostasis. Such functional differences, read out at the organismal level, are likely subserved by differences among 5-HT neuron subtypes at the cellular and molecular levels, including differences in the capacity to coexpress other neurotransmitters such as glutamate, GABA, thyrotropin releasing hormone, and substance P encoded by the Tachykinin-1 ( Tac1 ) gene. Here, we characterize in mice a 5-HT neuron subtype identified by expression of Tac1 and the serotonergic transcription factor gene Pet1 , referred to as the Tac1-Pet1 neuron subtype. Transgenic cell labeling showed Tac1-Pet1 soma resident largely in the caudal medulla. Chemogenetic [clozapine -N- oxide (CNO)-hM4Di] perturbation of Tac1-Pet1 neuron activity blunted the ventilatory response of the respiratory CO 2 chemoreflex, which normally augments ventilation in response to hypercapnic acidosis to restore normal pH and PCO 2 Tac1-Pet1 axonal boutons were found localized to brainstem areas implicated in respiratory modulation, with highest density in motor regions. These findings demonstrate that the activity of a Pet1 neuron subtype with the potential to release both 5-HT and substance P is necessary for normal respiratory dynamics, perhaps via motor outputs that engage muscles of respiration and maintain airway patency. These Tac1-Pet1 neurons may act downstream of Egr2-Pet1 serotonergic neurons, which were previously established in respiratory chemoreception, but do not innervate respiratory motor nuclei. SIGNIFICANCE STATEMENT Serotonin (5-HT) neurons modulate physiological processes and behaviors as diverse as body temperature, respiration, aggression, and mood. Using genetic tools, we characterize a 5-HT neuron subtype defined by expression of Tachykinin1 and Pet1 ( Tac1-Pet1 neurons), mapping soma localization to the caudal medulla primarily and axonal projections to brainstem motor nuclei most prominently, and, when silenced, observed blunting of the ventilatory response to inhaled CO 2 Tac1-Pet1 neurons thus appear distinct from and contrast previously described Egr2-Pet1 neurons, which project primarily to chemosensory integration centers and are themselves chemosensitive. Copyright © 2017 the authors 0270-6474/17/371807-13$15.00/0.

The prognostic value of node status in different breast cancer subtypes

PubMed Central

Hou, Xin-Wei; Chi, Jiang-Rui; Ge, Jie; Wang, Xin; Cao, Xu-Chen

2017-01-01

Nodal metastases and breast cancer subtypes (BCS) are both well-recognized prognostic indicators. However, the association between nodal metastases and BCS, and the prognostic value of nodal metastases in different BCS are still remains unclear. Our aim was to investigate the association between nodal metastases and BCS, and the prognostic value of nodal metastases in the different BCS. We found that the breast cancer subtype was closely associated with the pN stage. pN stage and breast cancer subtype were significantly associated with disease-free survival. The subgroup analysis showed that the patients in higher pN stage had a poor outcome than patients in lower pN stage in each breast cancer subtype. Furthermore, when the analysis was stratified by breast cancer subtype, we found that even in the same pN stage (pN0-pN2), there was significant survival difference among patients in different BCS, and Luminal A breast cancer patients had the best survival outcome. However, there were no significant survival difference between Luminal A patients and other breast cancer subtype when patients in pN3 stage. Thus, our study suggested that both lymph node status and molecular subtype played important roles in the outcome of breast cancer patients and they cannot replace each other. PMID:27999188

Admixture Mapping of African-American Women in the AMBER Consortium Identifies New Loci for Breast Cancer and Estrogen-Receptor Subtypes.

PubMed

Ruiz-Narváez, Edward A; Sucheston-Campbell, Lara; Bensen, Jeannette T; Yao, Song; Haddad, Stephen; Haiman, Christopher A; Bandera, Elisa V; John, Esther M; Bernstein, Leslie; Hu, Jennifer J; Ziegler, Regina G; Deming, Sandra L; Olshan, Andrew F; Ambrosone, Christine B; Palmer, Julie R; Lunetta, Kathryn L

2016-01-01

Recent genetic admixture coupled with striking differences in incidence of estrogen receptor (ER) breast cancer subtypes, as well as severity, between women of African and European ancestry, provides an excellent rationale for performing admixture mapping in African American women with breast cancer risk. We performed the largest breast cancer admixture mapping study with in African American women to identify novel genomic regions associated with the disease. We conducted a genome-wide admixture scan using 2,624 autosomal ancestry informative markers (AIMs) in 3,629 breast cancer cases (including 1,968 ER-positive, 1093 ER-negative, and 601 triple-negative) and 4,658 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a collaborative study of four large geographically different epidemiological studies of breast cancer in African American women. We used an independent case-control study to test for SNP association in regions with genome-wide significant admixture signals. We found two novel genome-wide significant regions of excess African ancestry, 4p16.1 and 17q25.1, associated with ER-positive breast cancer. Two regions known to harbor breast cancer variants, 10q26 and 11q13, were also identified with excess of African ancestry. Fine-mapping of the identified genome-wide significant regions suggests the presence of significant genetic associations with ER-positive breast cancer in 4p16.1 and 11q13. In summary, we identified three novel genomic regions associated with breast cancer risk by ER status, suggesting that additional previously unidentified variants may contribute to the racial differences in breast cancer risk in the African American population.

Genetic testing improves identification of transthyretin amyloid (ATTR) subtype in cardiac amyloidosis.

PubMed

Brown, Emily E; Lee, Yi Zhen Joan; Halushka, Marc K; Steenbergen, Charles; Johnson, Nicole M; Almansa, Johana; Tedford, Ryan J; Cingolani, Oscar; Russell, Stuart D; Sharma, Kavita; Judge, Daniel P

2017-06-01

Amyloidosis is a group of conditions characterized by the accumulation of amyloid deposits in various tissues. Among these disorders, ATTR amyloidosis occurs either with or without a TTR pathogenic variant. Treatment for amyloidosis depends on the subtype, which is often identified through a tissue biopsy followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Genetic testing may be done to confirm these results for patients with ATTR amyloidosis; however, the necessity of genetic testing after LC-MS/MS has not been evaluated. A retrospective review identified 153 patients diagnosed with biopsy-proven ATTR amyloidosis, and 56 of these patients underwent both genetic testing and LC-MS/MS. LC-MS/MS and proteomics correctly reported the mutant peptide and heterozygosity in 47/56 (84%) cases. It failed to identify two individuals who were homozygous for the ATTRV122I mutation and failed to detect the following mutations in six other individuals: ATTRA19D, ATTRF44L, ATTRT60A, ATTRI68L and ATTRV122I. Therefore, LC-MS/MS is not sufficient to rule out a pathogenic mutation in cases of ATTR amyloid, and genetic testing should be performed in most cases of ATTR amyloidosis. Correct recognition of hereditary ATTR amyloidosis is important for estimating prognosis, proper familial counselling and guiding use of therapies, such as liver transplantation.

Cutaneous and Mucosal Lichen Planus: A Comprehensive Review of Clinical Subtypes, Risk Factors, Diagnosis, and Prognosis

PubMed Central

2014-01-01

Lichen planus (LP) is a chronic inflammatory disorder that most often affects middle-aged adults. LP can involve the skin or mucous membranes including the oral, vulvovaginal, esophageal, laryngeal, and conjunctival mucosa. It has different variants based on the morphology of the lesions and the site of involvement. The literature suggests that certain presentations of the disease such as esophageal or ophthalmological involvement are underdiagnosed. The burden of the disease is higher in some variants including hypertrophic LP and erosive oral LP, which may have a more chronic pattern. LP can significantly affect the quality of life of patients as well. Drugs or contact allergens can cause lichenoid reactions as the main differential diagnosis of LP. LP is a T-cell mediated immunologic disease but the responsible antigen remains unidentified. In this paper, we review the history, epidemiology, and clinical subtypes of LP. We also review the histopathologic aspects of the disease, differential diagnoses, immunopathogenesis, and the clinical and genetic correlations. PMID:24672362

A gene variation of 14-3-3 zeta isoform in rat hippocampus.

PubMed

Murakami, K; Situ, S Y; Eshete, F

1996-11-14

A variant form of 14-3-3 zeta was isolated from the rat hippocampal cDNA library. The cloned cDNA is 1687 bp in length and it contains an entire ORF (nt = 63-797) with 245 amino acids that is characteristic to 14-3-3 zeta subtype. By comparing with reported sequences of 14-3-3 zeta, we found three nucleotide substitutions within the coding sequence in our clone; C<-->T transition at nt = 325 and G<-->C transversions at nt = 387 and 388. Both are missense mutations, leading ACG (Thr) to ATG (Met) and CGT (Arg) to GCT (Ala) conversions at residue 88 and 109, respectively. Our results show that at least three different genetic variants of 14-3-3 zeta are present in rat species which results in protein variations. Such mutation in the amino acid sequence is an important indication of the diverse functions of this protein and may also contribute to the recent contradictory observations regarding the role of the 14-3-3 zeta subtype.

Adaptive changes in HIV-1 subtype C proteins during early infection are driven by changes in HLA-associated immune pressure

PubMed Central

Treurnicht, F.K.; Seoighe, C.; Martin, D.P.; Wood, N.; Abrahams, M-R.; de Assis Rosa, D.; Bredell, H.; Woodman, Z.; Hide, W.; Mlisana, K.; Karim, S Abdool; Gray, C.M.; Williamson, C.

2009-01-01

It is unresolved whether recently transmitted human immunodeficiency viruses (HIV) have genetic features that specifically favour their transmissibility. To identify potential “transmission signatures”, we compared 20 full-length HIV-1 subtype C genomes from primary infections, with 66 sampled from ethnically and geographically matched individuals with chronic infections. Controlling for recombination and phylogenetic relatedness, we identified 39 sites at which amino acid frequency spectra differed significantly between groups. These sites were predominantly located within Env, Pol and Gag (14/39, 9/39 and 6/39 respectively) and were significantly clustered (33/39) within known immunoreactive peptides. Within 6 months of infection we detected reversion-to-consensus mutations at 14 sites and potential CTL escape mutations at seven. Here we provide evidence that frequent reversion mutations probably allows the virus to recover replicative fitness which, together with immune escape driven by the HLA alleles of the new hosts, differentiate sequences from chronic infections from those sampled shortly after transmission. PMID:19913270

Circulation of multiple subtypes of bovine viral diarrhoea virus type 1 with no evidence for HoBi-like pestivirus in cattle herds of southern Italy.

PubMed

Lanave, G; Decaro, N; Lucente, M S; Guercio, A; Cavaliere, N; Purpari, G; Padalino, I; Larocca, V; Antoci, F; Marino, P A; Buonavoglia, C; Elia, G

2017-06-01

Pestiviruses of cattle include bovine viral diarrhoea 1 (BVDV-1) and 2 (BVDV-2) plus an emerging group, named HoBi-like pestivirus. In the present paper, the results of an epidemiological survey for pestiviruses circulating in cattle in southern Italy are presented. Molecular assays carried out on a total of 924 bovine samples detected 74 BVDV strains, including 73 BVDV-1 and 1 BVDV-2 viruses. Phylogenetic analysis carried out on partial 5'UTR and N pro sequences revealed the presence of 6 different subtypes of BVDV-1 and a single BVDV-2c strain. BVDV-1 displayed a high level of genetic heterogeneity, which can have both prophylactic and diagnostic implications. In addition, the detection of BVDV-2c highlights the need for a continuous surveillance for the emergence of new pestivirus strains in cattle farms in southern Italy. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison of the Genomic Landscape Between Primary Breast Cancer in African American Versus White Women and the Association of Racial Differences With Tumor Recurrence

PubMed Central

Keenan, Tanya; Moy, Beverly; Mroz, Edmund A.; Ross, Kenneth; Niemierko, Andrzej; Rocco, James W.; Isakoff, Steven; Ellisen, Leif W.; Bardia, Aditya

2015-01-01

Purpose African American women are more likely to die as a result of breast cancer than white women. The influence of somatic genomic profiles on this racial disparity is unclear. We aimed to compare the racial distribution of tumor genomic characteristics and breast cancer recurrence. Methods We assessed white and African American women with stage I to III breast cancer diagnosed from 1988 to 2013 and primary tumors submitted to The Cancer Genome Atlas from 2010 to 2014. We used Cox proportional hazards models to evaluate the association of race and genetic traits with tumor recurrence. Results We investigated exome sequencing and gene expression data in 663 and 711 white and 105 and 159 African American women, respectively. African Americans had more TP53 mutations (42.9% v 27.6%; P = .003) and fewer PIK3CA mutations (20.0% v 33.9%; P = .008). Intratumor genetic heterogeneity was greater in African American than white tumors overall by 5.1 units (95% CI, 2.4 to 7.7) and within triple-negative tumors by 4.1 units (95% CI, 1.4 to 6.8). African Americans had more basal tumors by the 50-gene set predictor using the predication analysis of microarray method (PAM50; 39.0% v 18.6%; P < .001) and fewer PAM50 luminal A tumors (17.0% v 34.7%; P < .001). Among triple-negative subtypes, African Americans had more basal-like 1 and mesenchymal stem-like tumors. African Americans had a higher risk of tumor recurrence than whites (hazard ratio, 2.22; 95% CI, 1.05 to 4.67). Racial differences in TP53 mutation, PAM50 basal subtype, and triple-negative tumor prevalence but not intratumor genetic heterogeneity influenced the magnitude and significance of the racial disparity in tumor recurrence. Conclusion African Americans had greater intratumor genetic heterogeneity and more basal gene expression tumors, even within triple-negative breast cancer. This pattern suggests more aggressive tumor biology in African Americans than whites, which could contribute to racial disparity in breast cancer outcome. PMID:26371147

Comparison of the Genomic Landscape Between Primary Breast Cancer in African American Versus White Women and the Association of Racial Differences With Tumor Recurrence.

PubMed

Keenan, Tanya; Moy, Beverly; Mroz, Edmund A; Ross, Kenneth; Niemierko, Andrzej; Rocco, James W; Isakoff, Steven; Ellisen, Leif W; Bardia, Aditya

2015-11-01

African American women are more likely to die as a result of breast cancer than white women. The influence of somatic genomic profiles on this racial disparity is unclear. We aimed to compare the racial distribution of tumor genomic characteristics and breast cancer recurrence. We assessed white and African American women with stage I to III breast cancer diagnosed from 1988 to 2013 and primary tumors submitted to The Cancer Genome Atlas from 2010 to 2014. We used Cox proportional hazards models to evaluate the association of race and genetic traits with tumor recurrence. We investigated exome sequencing and gene expression data in 663 and 711 white and 105 and 159 African American women, respectively. African Americans had more TP53 mutations (42.9% v 27.6%; P = .003) and fewer PIK3CA mutations (20.0% v 33.9%; P = .008). Intratumor genetic heterogeneity was greater in African American than white tumors overall by 5.1 units (95% CI, 2.4 to 7.7) and within triple-negative tumors by 4.1 units (95% CI, 1.4 to 6.8). African Americans had more basal tumors by the 50-gene set predictor using the predication analysis of microarray method (PAM50; 39.0% v 18.6%; P < .001) and fewer PAM50 luminal A tumors (17.0% v 34.7%; P < .001). Among triple-negative subtypes, African Americans had more basal-like 1 and mesenchymal stem-like tumors. African Americans had a higher risk of tumor recurrence than whites (hazard ratio, 2.22; 95% CI, 1.05 to 4.67). Racial differences in TP53 mutation, PAM50 basal subtype, and triple-negative tumor prevalence but not intratumor genetic heterogeneity influenced the magnitude and significance of the racial disparity in tumor recurrence. African Americans had greater intratumor genetic heterogeneity and more basal gene expression tumors, even within triple-negative breast cancer. This pattern suggests more aggressive tumor biology in African Americans than whites, which could contribute to racial disparity in breast cancer outcome. © 2015 by American Society of Clinical Oncology.

Differences in acute retroviral syndrome by HIV-1 subtype in a multicentre cohort study in Africa

PubMed Central

Sanders, Eduard J.; Price, Matthew A.; Karita, Etienne; Kamali, Anatoli; Kilembe, William; Bekker, Linda-Gail; Lakhi, Shabir; Inambao, Mubiana; Anzala, Omu; Fast, Patricia E.; Gilmour, Jill; Powers, Kimberly A.

2017-01-01

Objective: Symptoms of acute retroviral syndrome (ARS) may be used to identify patients with acute HIV-1 infection who seek care. ARS symptoms in African adults differ by region. We assessed whether reporting of ARS was associated with HIV-1 subtype in a multicentre African cohort study representing countries with predominant HIV-1 subtypes A, C, and D. Methods: ARS symptoms were assessed in adults enrolling at least 6 weeks after the estimated date of infection in an acute and early HIV-1 infection cohort study. HIV-1 subtype was determined by POL genotyping. We used log-binomial regression to compare ARS symptom prevalence among those with subtype A vs. C or D, adjusting for sex, time since enrolment, and enrolment viral load. Results: Among 183 volunteers ascertained within 6 weeks after estimated date of infection, 77 (42.0%) had subtype A, 83 (45.4%) subtype C, and 23 (12.6%) subtype D infection. Individuals with subtype A were 1.40 (95% confidence interval: 1.17, 1.68) times as likely as individuals with subtypes C or D to report any ARS symptoms; each individual symptom other than rash was also more prevalent in subtype A than in subtype C or D, with prevalence ratios ranging from 1.94 (1.40, 2.70) for headache to 4.92 (2.24, 10.78) for lymphadenopathy. Conclusion: Individuals with subtype A were significantly more likely than individuals with subtypes C or D to report any ARS symptoms. HIV-1 subtypes may help explain differences in ARS that have been observed across regions in Africa, and may impact the yield of symptom-based screening strategies for acute HIV infection detection. PMID:29028659

Assessing the differences in public health impact of salmonella subtypes using a bayesian microbial subtyping approach for source attribution.

PubMed

Pires, Sara M; Hald, Tine

2010-02-01

Salmonella is a major cause of human gastroenteritis worldwide. To prioritize interventions and assess the effectiveness of efforts to reduce illness, it is important to attribute salmonellosis to the responsible sources. Studies have suggested that some Salmonella subtypes have a higher health impact than others. Likewise, some food sources appear to have a higher impact than others. Knowledge of variability in the impact of subtypes and sources may provide valuable added information for research, risk management, and public health strategies. We developed a Bayesian model that attributes illness to specific sources and allows for a better estimation of the differences in the ability of Salmonella subtypes and food types to result in reported salmonellosis. The model accommodates data for multiple years and is based on the Danish Salmonella surveillance. The number of sporadic cases caused by different Salmonella subtypes is estimated as a function of the prevalence of these subtypes in the animal-food sources, the amount of food consumed, subtype-related factors, and source-related factors. Our results showed relative differences between Salmonella subtypes in their ability to cause disease. These differences presumably represent multiple factors, such as differences in survivability through the food chain and/or pathogenicity. The relative importance of the source-dependent factors varied considerably over the years, reflecting, among others, variability in the surveillance programs for the different animal sources. The presented model requires estimation of fewer parameters than a previously developed model, and thus allows for a better estimation of these factors to result in reported human disease. In addition, a comparison of the results of the same model using different sets of typing data revealed that the model can be applied to data with less discriminatory power, which is the only data available in many countries. In conclusion, the model allows for the estimation of relative differences between Salmonella subtypes and sources, providing results that will benefit future risk assessment or risk ranking purposes.

Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma.

PubMed

Moss, Tyler J; Qi, Yuan; Xi, Liu; Peng, Bo; Kim, Tae-Beom; Ezzedine, Nader E; Mosqueda, Maribel E; Guo, Charles C; Czerniak, Bogdan A; Ittmann, Michael; Wheeler, David A; Lerner, Seth P; Matin, Surena F

2017-10-01

Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer. To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses. We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis. Adjusting for batch effects, consensus mutation calls from independent pipelines identified DNA mutations, gene expression clusters using unsupervised consensus hierarchical clustering (UCHC), and protein expression levels that were correlated with relevant clinical variables, The Cancer Genome Atlas, and other published data. WES identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were the most common mutational signatures. UCHC of RNAseq data segregated samples into four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA mutations, nonsmokers, high-grade

Enhanced interlaminar excitation or reduced superficial layer inhibition in neocortex generates different spike-and-wave-like electrographic events in vitro

PubMed Central

Hall, Stephen P.; Traub, Roger D.; Adams, Natalie E.; Cunningham, Mark O.; Schofield, Ian; Jenkins, Alistair J.

2018-01-01

Acute in vitro models have revealed a great deal of information about mechanisms underlying many types of epileptiform activity. However, few examples exist that shed light on spike-and-wave (SpW) patterns of pathological activity. SpW are seen in many epilepsy syndromes, both generalized and focal, and manifest across the entire age spectrum. They are heterogeneous in terms of their severity, symptom burden, and apparent anatomical origin (thalamic, neocortical, or both), but any relationship between this heterogeneity and underlying pathology remains elusive. In this study we demonstrate that physiological delta-frequency rhythms act as an effective substrate to permit modeling of SpW of cortical origin and may help to address this issue. For a starting point of delta activity, multiple subtypes of SpW could be modeled computationally and experimentally by either enhancing the magnitude of excitatory synaptic events ascending from neocortical layer 5 to layers 2/3 or selectively modifying superficial layer GABAergic inhibition. The former generated SpW containing multiple field spikes with long interspike intervals, whereas the latter generated SpW with short-interval multiple field spikes. Both types had different laminar origins and each disrupted interlaminar cortical dynamics in a different manner. A small number of examples of human recordings from patients with different diagnoses revealed SpW subtypes with the same temporal signatures, suggesting that detailed quantification of the pattern of spikes in SpW discharges may be a useful indicator of disparate underlying epileptogenic pathologies. NEW & NOTEWORTHY Spike-and-wave-type discharges (SpW) are a common feature in many epilepsies. Their electrographic manifestation is highly varied, as are available genetic clues to associated underlying pathology. Using computational and in vitro models, we demonstrate that distinct subtypes of SpW are generated by lamina-selective disinhibition or enhanced interlaminar excitation. These subtypes could be detected in at least some noninvasive patient recordings, suggesting more detailed analysis of SpW may be useful in determining clinical pathology. PMID:28954894

Enhanced interlaminar excitation or reduced superficial layer inhibition in neocortex generates different spike-and-wave-like electrographic events in vitro.

PubMed

Hall, Stephen P; Traub, Roger D; Adams, Natalie E; Cunningham, Mark O; Schofield, Ian; Jenkins, Alistair J; Whittington, Miles A

2018-01-01

Acute in vitro models have revealed a great deal of information about mechanisms underlying many types of epileptiform activity. However, few examples exist that shed light on spike-and-wave (SpW) patterns of pathological activity. SpW are seen in many epilepsy syndromes, both generalized and focal, and manifest across the entire age spectrum. They are heterogeneous in terms of their severity, symptom burden, and apparent anatomical origin (thalamic, neocortical, or both), but any relationship between this heterogeneity and underlying pathology remains elusive. In this study we demonstrate that physiological delta-frequency rhythms act as an effective substrate to permit modeling of SpW of cortical origin and may help to address this issue. For a starting point of delta activity, multiple subtypes of SpW could be modeled computationally and experimentally by either enhancing the magnitude of excitatory synaptic events ascending from neocortical layer 5 to layers 2/3 or selectively modifying superficial layer GABAergic inhibition. The former generated SpW containing multiple field spikes with long interspike intervals, whereas the latter generated SpW with short-interval multiple field spikes. Both types had different laminar origins and each disrupted interlaminar cortical dynamics in a different manner. A small number of examples of human recordings from patients with different diagnoses revealed SpW subtypes with the same temporal signatures, suggesting that detailed quantification of the pattern of spikes in SpW discharges may be a useful indicator of disparate underlying epileptogenic pathologies. NEW & NOTEWORTHY Spike-and-wave-type discharges (SpW) are a common feature in many epilepsies. Their electrographic manifestation is highly varied, as are available genetic clues to associated underlying pathology. Using computational and in vitro models, we demonstrate that distinct subtypes of SpW are generated by lamina-selective disinhibition or enhanced interlaminar excitation. These subtypes could be detected in at least some noninvasive patient recordings, suggesting more detailed analysis of SpW may be useful in determining clinical pathology.

Comparative quantification of diverse serotypes of HIV-1 in plasma from a diverse population of patients.

PubMed

Clarke, J R; Galpin, S; Braganza, R; Ashraf, A; Russell, R; Churchill, D R; Weber, J N; McClure, M O

2000-12-01

HIV-1 is characterised by extensive genetic variability encompassing at least 10 different phylogenetically related clades within the major group of HIV-1 subtypes. Most commercially available HIV-1 RNA plasma viral load assays have been optimised with clade B viruses and may yield misleadingly low RNA levels for nonclade B viruses that are increasingly found in Europe. In this study we compare the most recent versions of the Roche Amplicor HIV Monitor and the Chiron Quantiplex for ability to detect viraemia in a population of patients infected with a range of HIV-1 subtypes. EDTA-treated plasma was obtained from 206 patients. The Amplicor and Quantiplex assays were carried out in accordance with manufacturers' instructions. Results from 53/206 (25.7%) samples differed by >0.4 log between Amplicor 1.5 and Quantiplex 3.0. A >0.5 log and 1.0 log difference was detected between Amplicor 1.5 and Quantiplex 3.0 in 37/206 (17.9%) and 7/206 (3.4%) of samples, respectively. Overall, Amplicor 1.5 gave a median value of 0.22 log higher than Quantiplex 3.0. Discordant results were detected in 53 out of 206 (25.7%) samples. Of these 22 out of 123 (17.9%) samples were of UK origin, 18 out of 43 (41.9%) African, 1 out of 8 (12.5%) South American, 1 out of 6 (16.7%) North American, 4 out of 9 (44.4%) North European, 3 out of 11 (23.7%) South European and 3 out of 7 (42.3%) Asian samples, respectively. Serotyping revealed that discordant viral load results between Amplicor 1.5 and Quantiplex 3.0 occurred within samples from all subtypes (A-E). Despite the improvements made to both the Roche Amplicor and the Chiron Quantiplex assays discordant results were detected between the two assays in 25.7% of cases. In a substantial minority of patients there were major discrepancies between the two assays that were not explained by HIV subtype differences. Copyright 2000 Wiley-Liss, Inc.

Feline immudeficiency virus subtypes B and A in cats from São Luis, Maranhão, Brazil.

PubMed

Martins, Nathálya Dos S; Rodrigues, Ana Paula de S; da Luz, Luciana A; Dos Reis, Luana da L; de Oliveira, Renata M; de Oliveira, Rudson A; Abreu-Silva, Ana Lucia; Dos Reis, Jenner Karlisson P; Melo, Ferdinan A

2018-02-01

Feline immunodeficiency virus (FIV) is a retrovirus of the genus Lentivirus that is distributed worldwide, with prevalence rates varying between 2.5% and 44%. FIV causes immunosuppression, with depletion of TCD4 + lymphocytes, with the majority of clinical signs caused by secondary and opportunistic infections. Blood samples were collected from nine domestic cats (Felis catus domesticus) from the city of São Luís, Maranhão State, Brazil. All samples were positive in a rapid immunochromatographic test (SNAP® Combo FeLV Ag/FIV Antibody Test) and in a polymerase chain reaction (PCR) assay. Phylogenetic analysis showed that six samples clustered within subtype B, one within subtype A, and two did not cluster with any known subtype. Five unique haplotypes (Hap-1, Hap-2, Hap-3, Hap-5 and Hap-6) and a shared haplotype (Hap-4) were found, this last one being the most frequent. This is the first report on the genetic diversity of FIV in the city of São Luís and the first report of subtype A in Brazil. New variations of the virus are also reported.

Subtype B was the dominant strain among HIV type 1 infections except for the population of men who have sex with men in Harbin City, China.

PubMed

Shao, Bing; Li, Wen-Jing; Liu, Ting; Li, Qing-Hai; Li, Hang; Chang, Man-Li; Huang, Chao-Qun; Wang, Fu-Xiang; Wang, Bin-You

2013-09-01

We sought to identify the prevalent subtypes and study the genetic variation of HIV-1 circulating in HIV infections in Harbin City, China. Forty-seven samples from the env V3-V4 region were successfully sequenced and analyzed, which involved thirty-one men who have sex with men (MSM), eight heterosexuals, seven former plasma donors (FPD)/blood transfusion recipients (BT), and one injection drug user (IDU). In all, 46.8% of CRF01_AE, 40.4% of subtype B, and 12.8% of CRF07_BC were identified. CRF01_AE (64.5%) was the dominant strain in MSM, and subtype B (81.2%) was the chief strain in other infected subjects except for the MSM population. Among all the genotypes, the B subtype possesses greater diversity of the tetramer on the tip of V3 loop than CRF07_BC and CRF01_AE, in which the peculiar GWGR was commonly found. Because nationwide there is a trend toward the increasing presence of CRF01_AE, a consecutive surveillance campaign was necessary among all HIV vulnerable populations in this locality.

A comprehensive strategy for the subtyping of patients with Fanconi anaemia: conclusions from the Spanish Fanconi Anemia Research Network

PubMed Central

Casado, José Antonio; Callén, Elsa; Jacome, Ariana; Río, Paula; Castella, Maria; Lobitz, Stephan; Ferro, Teresa; Muñoz, Arturo; Sevilla, Julián; Cantalejo, Ángeles; Cela, Elena; Cervera, José; Sánchez‐Calero, Jesús; Badell, Isabel; Estella, Jesús; Dasí, Ángeles; Olivé, Teresa; Ortega, Juan José; Rodriguez‐Villa, Antonia; Tapia, María; Molinés, Antonio; Madero, Luis; Segovia, José C; Neveling, Kornelia; Kalb, Reinhard; Schindler, Detlev; Hanenberg, Helmut; Surrallés, Jordi; Bueren, Juan A

2007-01-01

Background Fanconi anaemia is a heterogeneous genetic disease, where 12 complementation groups have been already described. Identifying the complementation group in patients with Fanconi anaemia constitutes a direct procedure to confirm the diagnosis of the disease and is required for the recruitment of these patients in gene therapy trials. Objective To determine the subtype of Fanconi anaemia patients in Spain, a Mediterranean country with a relatively high population (23%) of Fanconi anaemia patients belonging to the gypsy race. Methods Most patients could be subtyped by retroviral complementation approaches in peripheral blood T cells, although some mosaic patients were subtyped in cultured skin fibroblasts. Other approaches, mainly based on western blot analysis and generation of nuclear RAD51 and FANCJ foci, were required for the subtyping of a minor number of patients. Results and conclusions From a total of 125 patients included in the Registry of Fanconi Anaemia, samples from 102 patients were available for subtyping analyses. In 89 cases the subtype could be determined and in 8 cases exclusions of common complementation groups were made. Compared with other international studies, a skewed distribution of complementation groups was observed in Spain, where 80% of the families belonged to the Fanconi anaemia group A (FA‐A) complementation group. The high proportion of gypsy patients, all of them FA‐A, and the absence of patients with FA‐C account for this characteristic distribution of complementation groups. PMID:17105750

Identification of Nine Novel Loci Associated with White Blood Cell Subtypes in a Japanese Population

PubMed Central

Okada, Yukinori; Hirota, Tomomitsu; Kamatani, Yoichiro; Takahashi, Atsushi; Ohmiya, Hiroko; Kumasaka, Natsuhiko; Higasa, Koichiro; Yamaguchi-Kabata, Yumi; Hosono, Naoya; Nalls, Michael A.; Chen, Ming Huei; van Rooij, Frank J. A.; Smith, Albert V.; Tanaka, Toshiko; Couper, David J.; Zakai, Neil A.; Ferrucci, Luigi; Longo, Dan L.; Hernandez, Dena G.; Witteman, Jacqueline C. M.; Harris, Tamara B.; O'Donnell, Christopher J.; Ganesh, Santhi K.; Matsuda, Koichi; Tsunoda, Tatsuhiko; Tanaka, Toshihiro; Kubo, Michiaki; Nakamura, Yusuke; Tamari, Mayumi; Yamamoto, Kazuhiko; Kamatani, Naoyuki

2011-01-01

White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P<5.0×10−8, of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITGA4, MLZE, STXBP6 loci, and the MHC region for the monocyte count; the SLC45A3-NUCKS1, GATA2, NAALAD2, ERG loci for the basophil count). We further evaluated associations in the identified loci using 15,600 subjects from Caucasian populations. These WBC subtype-related loci demonstrated a variety of patterns of pleiotropic associations within the WBC subtypes, or with total WBC count, platelet count, or red blood cell-related traits (n = 30,454), which suggests unique and common functional roles of these loci in the processes of hematopoiesis. This study should contribute to the understanding of the genetic backgrounds of the WBC subtypes and hematological traits. PMID:21738478

An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients.

PubMed

Bonnet, Crystel; Riahi, Zied; Chantot-Bastaraud, Sandra; Smagghe, Luce; Letexier, Mélanie; Marcaillou, Charles; Lefèvre, Gaëlle M; Hardelin, Jean-Pierre; El-Amraoui, Aziz; Singh-Estivalet, Amrit; Mohand-Saïd, Saddek; Kohl, Susanne; Kurtenbach, Anne; Sliesoraityte, Ieva; Zobor, Ditta; Gherbi, Souad; Testa, Francesco; Simonelli, Francesca; Banfi, Sandro; Fakin, Ana; Glavač, Damjan; Jarc-Vidmar, Martina; Zupan, Andrej; Battelino, Saba; Martorell Sampol, Loreto; Claveria, Maria Antonia; Catala Mora, Jaume; Dad, Shzeena; Møller, Lisbeth B; Rodriguez Jorge, Jesus; Hawlina, Marko; Auricchio, Alberto; Sahel, José-Alain; Marlin, Sandrine; Zrenner, Eberhart; Audo, Isabelle; Petit, Christine

2016-12-01

Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1-3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.

An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients

PubMed Central

Bonnet, Crystel; Riahi, Zied; Chantot-Bastaraud, Sandra; Smagghe, Luce; Letexier, Mélanie; Marcaillou, Charles; Lefèvre, Gaëlle M; Hardelin, Jean-Pierre; El-Amraoui, Aziz; Singh-Estivalet, Amrit; Mohand-Saïd, Saddek; Kohl, Susanne; Kurtenbach, Anne; Sliesoraityte, Ieva; Zobor, Ditta; Gherbi, Souad; Testa, Francesco; Simonelli, Francesca; Banfi, Sandro; Fakin, Ana; Glavač, Damjan; Jarc-Vidmar, Martina; Zupan, Andrej; Battelino, Saba; Martorell Sampol, Loreto; Claveria, Maria Antonia; Catala Mora, Jaume; Dad, Shzeena; Møller, Lisbeth B; Rodriguez Jorge, Jesus; Hawlina, Marko; Auricchio, Alberto; Sahel, José-Alain; Marlin, Sandrine; Zrenner, Eberhart; Audo, Isabelle; Petit, Christine

2016-01-01

Usher syndrome (USH), the most prevalent cause of hereditary deafness–blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1–3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods. PMID:27460420

Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity.

PubMed

Grünewald, Inga; Vollbrecht, Claudia; Meinrath, Jeannine; Meyer, Moritz F; Heukamp, Lukas C; Drebber, Uta; Quaas, Alexander; Beutner, Dirk; Hüttenbrink, Karl-Bernd; Wardelmann, Eva; Hartmann, Wolfgang; Büttner, Reinhard; Odenthal, Margarete; Stenner, Markus

2015-07-20

Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations.Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes.Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4.In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.

Understanding Xeroderma Pigmentosum Complementation Groups Using Gene Expression Profiling after UV-Light Exposure.

PubMed

Bowden, Nikola A; Beveridge, Natalie J; Ashton, Katie A; Baines, Katherine J; Scott, Rodney J

2015-07-14

Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live beyond 30 years. There are seven genetic subgroups of XP, which are all resultant of pathogenic mutations in genes in the nucleotide excision repair (NER) pathway and a XP variant resultant of a mutation in translesion synthesis, POLH. The clinical symptoms and severity of the disease is varied across the subgroups, which does not correlate with the functional position of the affected protein in the NER pathway. The aim of this study was to further understand the biology of XP subgroups, particularly those that manifest with neurological symptoms. Whole genome gene expression profiling of fibroblasts from each XP complementation group was assessed before and after UV-light exposure. The biological pathways with altered gene expression after UV-light exposure were distinct for each subtype and contained oncogenic related functions such as perturbation of cell cycle, apoptosis, proliferation and differentiation. Patients from the subgroups XP-B and XP-F were the only subgroups to have transcripts associated with neuronal activity altered after UV-light exposure. This study will assist in furthering our understanding of the different subtypes of XP which will lead to better diagnosis, treatment and management of the disease.

Understanding Xeroderma Pigmentosum Complementation Groups Using Gene Expression Profiling after UV-Light Exposure

PubMed Central

Bowden, Nikola A.; Beveridge, Natalie J.; Ashton, Katie A.; Baines, Katherine J.; Scott, Rodney J.

2015-01-01

Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live beyond 30 years. There are seven genetic subgroups of XP, which are all resultant of pathogenic mutations in genes in the nucleotide excision repair (NER) pathway and a XP variant resultant of a mutation in translesion synthesis, POLH. The clinical symptoms and severity of the disease is varied across the subgroups, which does not correlate with the functional position of the affected protein in the NER pathway. The aim of this study was to further understand the biology of XP subgroups, particularly those that manifest with neurological symptoms. Whole genome gene expression profiling of fibroblasts from each XP complementation group was assessed before and after UV-light exposure. The biological pathways with altered gene expression after UV-light exposure were distinct for each subtype and contained oncogenic related functions such as perturbation of cell cycle, apoptosis, proliferation and differentiation. Patients from the subgroups XP-B and XP-F were the only subgroups to have transcripts associated with neuronal activity altered after UV-light exposure. This study will assist in furthering our understanding of the different subtypes of XP which will lead to better diagnosis, treatment and management of the disease. PMID:26184184

Distinct transcriptomes define rostral and caudal serotonin neurons

PubMed Central

Wylie, Christi J.; Hendricks, Timothy J.; Zhang, Bing; Wang, Lily; Lu, Pengcheng; Leahy, Patrick; Fox, Stephanie; Maeno, Hiroshi; Deneris, Evan S.

2012-01-01

The molecular architecture of developing serotonin (5HT) neurons is poorly understood yet its determination is likely to be essential for elucidating functional heterogeneity of these cells and the contribution of serotonergic dysfunction to disease pathogenesis. Here, we describe the purification of postmitotic embryonic 5HT neurons by flow cytometry for whole genome microarray expression profiling of this unitary monoaminergic neuron type. Our studies identified significantly enriched expression of hundreds of unique genes in 5HT neurons thus providing an abundance of new serotonergic markers. Furthermore, we identified several hundred transcripts encoding homeodomain, axon guidance, cell adhesion, intracellular signaling, ion transport, and imprinted genes associated with various neurodevelopmental disorders that were differentially enriched in developing rostral and caudal 5HT neurons. These findings suggested a homeodomain code that distinguishes rostral and caudal 5HT neurons. Indeed, verification studies demonstrated that Hmx homeodomain and Hox gene expression defined an Hmx+ rostral subtype and Hox+ caudal subtype. Expression of engrailed genes in a subset of 5HT neurons in the rostral domain further distinguished two subtypes defined as Hmx+En+ and Hmx+En-. The differential enrichment of gene sets for different canonical pathways and gene ontology categories provided additional evidence for heterogeneity between rostral and caudal 5HT neurons. These findings demonstrate a deep transcriptome and biological pathway duality for neurons that give rise to the ascending and descending serotonergic subsystems. Our databases provide a rich, clinically relevant, resource for definition of 5HT neuron subtypes and elucidation of the genetic networks required for serotonergic function. PMID:20071532

Advances in the molecular genetics of gliomas - implications for classification and therapy.

PubMed

Reifenberger, Guido; Wirsching, Hans-Georg; Knobbe-Thomsen, Christiane B; Weller, Michael

2017-07-01

Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers - together with classic histological features - in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.

Diagnosis of Fanconi Anemia: Mutation Analysis by Multiplex Ligation-Dependent Probe Amplification and PCR-Based Sanger Sequencing

PubMed Central

Gille, Johan J. P.; Floor, Karijn; Kerkhoven, Lianne; Ameziane, Najim; Joenje, Hans; de Winter, Johan P.

2012-01-01

Fanconi anemia (FA) is a rare inherited disease characterized by developmental defects, short stature, bone marrow failure, and a high risk of malignancies. FA is heterogeneous: 15 genetic subtypes have been distinguished so far. A clinical diagnosis of FA needs to be confirmed by testing cells for sensitivity to cross-linking agents in a chromosomal breakage test. As a second step, DNA testing can be employed to elucidate the genetic subtype of the patient and to identify the familial mutations. This knowledge allows preimplantation genetic diagnosis (PGD) and enables prenatal DNA testing in future pregnancies. Although simultaneous testing of all FA genes by next generation sequencing will be possible in the near future, this technique will not be available immediately for all laboratories. In addition, in populations with strong founder mutations, a limited test using Sanger sequencing and MLPA will be a cost-effective alternative. We describe a strategy and optimized conditions for the screening of FANCA, FANCB, FANCC, FANCE, FANCF, and FANCG and present the results obtained in a cohort of 54 patients referred to our diagnostic service since 2008. In addition, the follow up with respect to genetic counseling and carrier screening in the families is discussed. PMID:22778927

Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer

PubMed Central

Muroni, Maria Rosaria; Sanges, Francesca; Sotgiu, Giovanni; Ena, Sara; Pira, Giovanna; Murgia, Luciano; Manca, Alessandra; Uras, Maria Gabriela; Sarobba, Maria Giuseppina; Urru, Silvana; De Miglio, Maria Rosaria

2015-01-01

Background Triple Negative Breast Cancer (TNBC) accounts for 12–24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20–40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data. Materials and Methods PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components. Results PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC. Conclusions Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies. PMID:26540293

Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer.

PubMed

Cossu-Rocca, Paolo; Orrù, Sandra; Muroni, Maria Rosaria; Sanges, Francesca; Sotgiu, Giovanni; Ena, Sara; Pira, Giovanna; Murgia, Luciano; Manca, Alessandra; Uras, Maria Gabriela; Sarobba, Maria Giuseppina; Urru, Silvana; De Miglio, Maria Rosaria

2015-01-01

Triple Negative Breast Cancer (TNBC) accounts for 12-24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20-40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data. PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components. PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC. Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies.

Molecular Surveillance of Low Pathogenic Avian Influenza Viruses in Wild Birds across the United States: Inferences from the Hemagglutinin Gene

PubMed Central

Piaggio, Antoinette J.; Shriner, Susan A.; VanDalen, Kaci K.; Franklin, Alan B.; Anderson, Theodore D.; Kolokotronis, Sergios-Orestis

2012-01-01

A United States interagency avian influenza surveillance plan was initiated in 2006 for early detection of highly pathogenic avian influenza viruses (HPAIV) in wild birds. The plan included a variety of wild bird sampling strategies including the testing of fecal samples from aquatic areas throughout the United States from April 2006 through December 2007. Although HPAIV was not detected through this surveillance effort we were able to obtain 759 fecal samples that were positive for low pathogenic avian influenza virus (LPAIV). We used 136 DNA sequences obtained from these samples along with samples from a public influenza sequence database for a phylogenetic assessment of hemagglutinin (HA) diversity in the United States. We analyzed sequences from all HA subtypes except H5, H7, H14 and H15 to examine genetic variation, exchange between Eurasia and North America, and geographic distribution of LPAIV in wild birds in the United States. This study confirms intercontinental exchange of some HA subtypes (including a newly documented H9 exchange event), as well as identifies subtypes that do not regularly experience intercontinental gene flow but have been circulating and evolving in North America for at least the past 20 years. These HA subtypes have high levels of genetic diversity with many lineages co-circulating within the wild birds of North America. The surveillance effort that provided these samples demonstrates that such efforts, albeit labor-intensive, provide important information about the ecology of LPAIV circulating in North America. PMID:23226543

Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine.

PubMed

Kang, Peter B; Morrison, Leslie; Iannaccone, Susan T; Graham, Robert J; Bönnemann, Carsten G; Rutkowski, Anne; Hornyak, Joseph; Wang, Ching H; North, Kathryn; Oskoui, Maryam; Getchius, Thomas S D; Cox, Julie A; Hagen, Erin E; Gronseth, Gary; Griggs, Robert C

2015-03-31

To delineate optimal diagnostic and therapeutic approaches to congenital muscular dystrophy (CMD) through a systematic review and analysis of the currently available literature. Relevant, peer-reviewed research articles were identified using a literature search of the MEDLINE, EMBASE, and Scopus databases. Diagnostic and therapeutic data from these articles were extracted and analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and therapeutic studies. Recommendations were linked to the strength of the evidence, other related literature, and general principles of care. The geographic and ethnic backgrounds, clinical features, brain imaging studies, muscle imaging studies, and muscle biopsies of children with suspected CMD help predict subtype-specific diagnoses. Genetic testing can confirm some subtype-specific diagnoses, but not all causative genes for CMD have been described. Seizures and respiratory complications occur in specific subtypes. There is insufficient evidence to determine the efficacy of various treatment interventions to optimize respiratory, orthopedic, and nutritional outcomes, and more data are needed regarding complications. Multidisciplinary care by experienced teams is important for diagnosing and promoting the health of children with CMD. Accurate assessment of clinical presentations and genetic data will help in identifying the correct subtype-specific diagnosis in many cases. Multiorgan system complications occur frequently; surveillance and prompt interventions are likely to be beneficial for affected children. More research is needed to fill gaps in knowledge regarding this category of muscular dystrophies. © 2015 American Academy of Neurology.

Immunogenicity against Far Eastern and Siberian subtypes of tick-borne encephalitis (TBE) virus elicited by the currently available vaccines based on the European subtype: systematic review and meta-analysis.

PubMed

Domnich, Alexander; Panatto, Donatella; Arbuzova, Eva Klementievna; Signori, Alessio; Avio, Ulderico; Gasparini, Roberto; Amicizia, Daniela

2014-01-01

Tick-borne encephalitis (TBE) virus, which is usually divided into European, Far Eastern and Siberian subtypes, is a serious public health problem in several European and Asian countries. Vaccination is the most effective measure to prevent TBE; cross-subtype protection elicited by the TBE vaccines is biologically plausible since all TBE virus subtypes are closely related. This manuscript systematically explores available data on the cross-subtype immunogenicity elicited by the currently available Western vaccines based on the European subtype. Completed immunization course of 3 doses of both Western vaccines determined very high seroconversion/seropositivity rates against both Far Eastern and Siberian subtypes among previously flavivirus-naïve subjects. All but one study found no statistically significant difference in titers of neutralizing antibodies against strains belonging to homologous and heterologous subtypes. Pooled analysis of randomized controlled trials on head-to-head comparison of immunogenicity of Western and Russian TBE vaccines did not reveal differences in seroconversion rates against Far Eastern isolates in either hemagglutination inhibition (risk ratio = 0.98, p = 0.83) or enzyme-linked immunosorbent (risk ratio = 0.95, p = 0.44) assays after 2 vaccine doses. This suggests that, in regions where a heterogeneous TBE virus population circulates, vaccines based on the European subtype may be used alongside vaccines based on the Far Eastern subtype. Studies on the field effectiveness of TBE vaccines and investigation of vaccination failures, especially in countries where different subtypes co-circulate, will further elucidate TBE vaccination-induced cross-subtype protection.

Immunogenicity against Far Eastern and Siberian subtypes of tick-borne encephalitis (TBE) virus elicited by the currently available vaccines based on the European subtype: Systematic review and meta-analysis

PubMed Central

Domnich, Alexander; Panatto, Donatella; Arbuzova, Eva Klementievna; Signori, Alessio; Avio, Ulderico; Gasparini, Roberto; Amicizia, Daniela

2014-01-01

Tick-borne encephalitis (TBE) virus, which is usually divided into European, Far Eastern and Siberian subtypes, is a serious public health problem in several European and Asian countries. Vaccination is the most effective measure to prevent TBE; cross-subtype protection elicited by the TBE vaccines is biologically plausible since all TBE virus subtypes are closely related. This manuscript systematically explores available data on the cross-subtype immunogenicity elicited by the currently available Western vaccines based on the European subtype. Completed immunization course of 3 doses of both Western vaccines determined very high seroconversion/seropositivity rates against both Far Eastern and Siberian subtypes among previously flavivirus-naïve subjects. All but one study found no statistically significant difference in titers of neutralizing antibodies against strains belonging to homologous and heterologous subtypes. Pooled analysis of randomized controlled trials on head-to-head comparison of immunogenicity of Western and Russian TBE vaccines did not reveal differences in seroconversion rates against Far Eastern isolates in either hemagglutination inhibition (risk ratio = 0.98, p = 0.83) or enzyme-linked immunosorbent (risk ratio = 0.95, p = 0.44) assays after 2 vaccine doses. This suggests that, in regions where a heterogeneous TBE virus population circulates, vaccines based on the European subtype may be used alongside vaccines based on the Far Eastern subtype. Studies on the field effectiveness of TBE vaccines and investigation of vaccination failures, especially in countries where different subtypes co-circulate, will further elucidate TBE vaccination-induced cross-subtype protection. PMID:25483679

Genetics Home Reference: limb-girdle muscular dystrophy

MedlinePlus

... age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition ... occurs in some people with limb-girdle muscular dystrophy . Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle ...

[Subtype classification of ceftriaxone sodium and its influence on the quality of product].

PubMed

Xue, Jing; Jia, Yan-Hua; Li, Jin; Yin, Li-Hui; Hu, Chang-Qin

2014-07-01

Powder X-ray diffraction (PXRD) technology combined with cluster analysis method was used to classify 75 batches of crystalline ceftriaxone sodium into subtypes, the crystalline characteristics of each subtype were measured with scanning electron microscope (SEM). By comparing some parameters of these subtypes correlated to crystallization process of ceftriaxone sodium, such as salification rate, water content in different subtypes, as well as by studying different lattice stabilities, different compatibilities with rubber closures during accelerated stability tests, the key point to improve the quality of domestic ceftriaxone sodium was disclosed. The results of this paper indicated that the fine structure of the products could be controlled well by improving the salification and crystallization process. As a result, the subtype II of ceftriaxone sodium with high stability can be produced.