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1

Combining Quantitative Genetic Footprinting and Trait Enrichment Analysis to Identify Fitness Determinants of a Bacterial Pathogen  

PubMed Central

Strains of Extraintestinal Pathogenic Escherichia coli (ExPEC) exhibit an array of virulence strategies and are a major cause of urinary tract infections, sepsis and meningitis. Efforts to understand ExPEC pathogenesis are challenged by the high degree of genetic and phenotypic variation that exists among isolates. Determining which virulence traits are widespread and which are strain-specific will greatly benefit the design of more effective therapies. Towards this goal, we utilized a quantitative genetic footprinting technique known as transposon insertion sequencing (Tn-seq) in conjunction with comparative pathogenomics to functionally dissect the genetic repertoire of a reference ExPEC isolate. Using Tn-seq and high-throughput zebrafish infection models, we tracked changes in the abundance of ExPEC variants within saturated transposon mutant libraries following selection within distinct host niches. Nine hundred and seventy bacterial genes (18% of the genome) were found to promote pathogen fitness in either a niche-dependent or independent manner. To identify genes with the highest therapeutic and diagnostic potential, a novel Trait Enrichment Analysis (TEA) algorithm was developed to ascertain the phylogenetic distribution of candidate genes. TEA revealed that a significant portion of the 970 genes identified by Tn-seq have homologues more often contained within the genomes of ExPEC and other known pathogens, which, as suggested by the first axiom of molecular Koch's postulates, is considered to be a key feature of true virulence determinants. Three of these Tn-seq-derived pathogen-associated genes—a transcriptional repressor, a putative metalloendopeptidase toxin and a hypothetical DNA binding protein—were deleted and shown to independently affect ExPEC fitness in zebrafish and mouse models of infection. Together, the approaches and observations reported herein provide a resource for future pathogenomics-based research and highlight the diversity of factors required by a single ExPEC isolate to survive within varying host environments. PMID:23990803

Wiles, Travis J.; Norton, J. Paul; Russell, Colin W.; Dalley, Brian K.; Fischer, Kael F.; Mulvey, Matthew A.

2013-01-01

2

Feature Selection Methods for Identifying Genetic Determinants of Host Species in RNA Viruses  

PubMed Central

Despite environmental, social and ecological dependencies, emergence of zoonotic viruses in human populations is clearly also affected by genetic factors which determine cross-species transmission potential. RNA viruses pose an interesting case study given their mutation rates are orders of magnitude higher than any other pathogen – as reflected by the recent emergence of SARS and Influenza for example. Here, we show how feature selection techniques can be used to reliably classify viral sequences by host species, and to identify the crucial minority of host-specific sites in pathogen genomic data. The variability in alleles at those sites can be translated into prediction probabilities that a particular pathogen isolate is adapted to a given host. We illustrate the power of these methods by: 1) identifying the sites explaining SARS coronavirus differences between human, bat and palm civet samples; 2) showing how cross species jumps of rabies virus among bat populations can be readily identified; and 3) de novo identification of likely functional influenza host discriminant markers. PMID:24130470

Aguas, Ricardo; Ferguson, Neil M.

2013-01-01

3

Feature selection methods for identifying genetic determinants of host species in RNA viruses.  

PubMed

Despite environmental, social and ecological dependencies, emergence of zoonotic viruses in human populations is clearly also affected by genetic factors which determine cross-species transmission potential. RNA viruses pose an interesting case study given their mutation rates are orders of magnitude higher than any other pathogen--as reflected by the recent emergence of SARS and Influenza for example. Here, we show how feature selection techniques can be used to reliably classify viral sequences by host species, and to identify the crucial minority of host-specific sites in pathogen genomic data. The variability in alleles at those sites can be translated into prediction probabilities that a particular pathogen isolate is adapted to a given host. We illustrate the power of these methods by: 1) identifying the sites explaining SARS coronavirus differences between human, bat and palm civet samples; 2) showing how cross species jumps of rabies virus among bat populations can be readily identified; and 3) de novo identification of likely functional influenza host discriminant markers. PMID:24130470

Aguas, Ricardo; Ferguson, Neil M

2013-01-01

4

A quantitative high-resolution genetic profile rapidly identifies sequence determinants of hepatitis C viral fitness and drug sensitivity.  

PubMed

Widely used chemical genetic screens have greatly facilitated the identification of many antiviral agents. However, the regions of interaction and inhibitory mechanisms of many therapeutic candidates have yet to be elucidated. Previous chemical screens identified Daclatasvir (BMS-790052) as a potent nonstructural protein 5A (NS5A) inhibitor for Hepatitis C virus (HCV) infection with an unclear inhibitory mechanism. Here we have developed a quantitative high-resolution genetic (qHRG) approach to systematically map the drug-protein interactions between Daclatasvir and NS5A and profile genetic barriers to Daclatasvir resistance. We implemented saturation mutagenesis in combination with next-generation sequencing technology to systematically quantify the effect of every possible amino acid substitution in the drug-targeted region (domain IA of NS5A) on replication fitness and sensitivity to Daclatasvir. This enabled determination of the residues governing drug-protein interactions. The relative fitness and drug sensitivity profiles also provide a comprehensive reference of the genetic barriers for all possible single amino acid changes during viral evolution, which we utilized to predict clinical outcomes using mathematical models. We envision that this high-resolution profiling methodology will be useful for next-generation drug development to select drugs with higher fitness costs to resistance, and also for informing the rational use of drugs based on viral variant spectra from patients. PMID:24722365

Qi, Hangfei; Olson, C Anders; Wu, Nicholas C; Ke, Ruian; Loverdo, Claude; Chu, Virginia; Truong, Shawna; Remenyi, Roland; Chen, Zugen; Du, Yushen; Su, Sheng-Yao; Al-Mawsawi, Laith Q; Wu, Ting-Ting; Chen, Shu-Hua; Lin, Chung-Yen; Zhong, Weidong; Lloyd-Smith, James O; Sun, Ren

2014-04-01

5

A Quantitative High-Resolution Genetic Profile Rapidly Identifies Sequence Determinants of Hepatitis C Viral Fitness and Drug Sensitivity  

PubMed Central

Widely used chemical genetic screens have greatly facilitated the identification of many antiviral agents. However, the regions of interaction and inhibitory mechanisms of many therapeutic candidates have yet to be elucidated. Previous chemical screens identified Daclatasvir (BMS-790052) as a potent nonstructural protein 5A (NS5A) inhibitor for Hepatitis C virus (HCV) infection with an unclear inhibitory mechanism. Here we have developed a quantitative high-resolution genetic (qHRG) approach to systematically map the drug-protein interactions between Daclatasvir and NS5A and profile genetic barriers to Daclatasvir resistance. We implemented saturation mutagenesis in combination with next-generation sequencing technology to systematically quantify the effect of every possible amino acid substitution in the drug-targeted region (domain IA of NS5A) on replication fitness and sensitivity to Daclatasvir. This enabled determination of the residues governing drug-protein interactions. The relative fitness and drug sensitivity profiles also provide a comprehensive reference of the genetic barriers for all possible single amino acid changes during viral evolution, which we utilized to predict clinical outcomes using mathematical models. We envision that this high-resolution profiling methodology will be useful for next-generation drug development to select drugs with higher fitness costs to resistance, and also for informing the rational use of drugs based on viral variant spectra from patients. PMID:24722365

Qi, Hangfei; Olson, C. Anders; Wu, Nicholas C.; Ke, Ruian; Loverdo, Claude; Chu, Virginia; Truong, Shawna; Remenyi, Roland; Chen, Zugen; Du, Yushen; Su, Sheng-Yao; Al-Mawsawi, Laith Q.; Wu, Ting-Ting; Chen, Shu-Hua; Lin, Chung-Yen; Zhong, Weidong; Lloyd-Smith, James O.; Sun, Ren

2014-01-01

6

Genome-Wide Association Study to Identify the Genetic Determinants of Otitis Media Susceptibility in Childhood  

PubMed Central

Background Otitis media (OM) is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ?3 episodes of AOM in 6 months) and chronic OM with effusion (COME; MEE ?3 months) is 40–70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS) of OM has been reported. Methods and Findings Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation) were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine) Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR?=?1.90; 95%CI 1.47–2.45; Padj-PCA?=?8.3×10?7) on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR?=?1.60; 95%CI 1.29–1.99; Padj-PCA?=?2.2×10?5) observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (PGene?=?2×10?5) and BPIFA1 (PGene?=?1.07×10?4) in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (Padj-PCA<10?5) in this GWAS, with pathway analysis showing a connection between top candidates and the TGF? pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals) from the Western Australian Family Study of Otitis Media (WAFSOM). Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS. Conclusions This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as novel candidate genes which warrant further analysis in cohorts matched more precisely for clinical phenotypes. PMID:23133572

Rye, Marie S.; Warrington, Nicole M.; Scaman, Elizabeth S. H.; Vijayasekaran, Shyan; Coates, Harvey L.; Anderson, Denise; Pennell, Craig E.; Blackwell, Jenefer M.; Jamieson, Sarra E.

2012-01-01

7

Mouse Genetics: Determining gene function  

E-print Network

Mouse Genetics: Determining gene function An International Centre for Mouse Genetics Mammalian Genetics Unit #12;Determining gene function · Mutagenesis approaches · Gene-driven, phenotype for Mouse Genetics Mammalian Genetics Unit #12;An International Centre for Mouse Genetics Mammalian Genetics

Goldschmidt, Christina

8

Identifying genetic relatives without compromising privacy  

PubMed Central

The development of high-throughput genomic technologies has impacted many areas of genetic research. While many applications of these technologies focus on the discovery of genes involved in disease from population samples, applications of genomic technologies to an individual’s genome or personal genomics have recently gained much interest. One such application is the identification of relatives from genetic data. In this application, genetic information from a set of individuals is collected in a database, and each pair of individuals is compared in order to identify genetic relatives. An inherent issue that arises in the identification of relatives is privacy. In this article, we propose a method for identifying genetic relatives without compromising privacy by taking advantage of novel cryptographic techniques customized for secure and private comparison of genetic information. We demonstrate the utility of these techniques by allowing a pair of individuals to discover whether or not they are related without compromising their genetic information or revealing it to a third party. The idea is that individuals only share enough special-purpose cryptographically protected information with each other to identify whether or not they are relatives, but not enough to expose any information about their genomes. We show in HapMap and 1000 Genomes data that our method can recover first- and second-order genetic relationships and, through simulations, show that our method can identify relationships as distant as third cousins while preserving privacy. PMID:24614977

He, Dan; Furlotte, Nicholas A.; Hormozdiari, Farhad; Joo, Jong Wha J.; Wadia, Akshay; Ostrovsky, Rafail; Sahai, Amit; Eskin, Eleazar

2014-01-01

9

Eggplant and related species are promising genetic resources to dissect the plant immune response to Pseudomonas syringae and Xanthomonas euvesicatoria and to identify new resistance determinants.  

PubMed

The apparent lack of durability of many resistance (R) genes highlights the need for the constant identification of new genetic sources of resistance for the breeding of new disease-resistant crop cultivars. To this end, we screened a collection of accessions of eggplant and close relatives for resistance against Pseudomonas syringae pv. tomato (Pto) and Xanthomonas euvesicatoria (Xeu), foliar plant pathogens of many solanaceous crops. Both pathogens caused substantial disease on most genotypes of eggplant and its relatives. Promisingly, however, some of the genotypes were fully or partially resistant to either of the pathogens, suggesting the presence of effective resistance determinants in these genotypes. Segregation of resistance to the growth of Xeu following infiltration in F2 progeny from a cross of a resistant and susceptible genotype suggests that resistance to Xeu is inherited as a multigenic trait. With regard to Pto, a mutant strain lacking all 28 functional type III secreted effectors, and a Pseudomonas fluorescens strain expressing a P.?syringae type III secretion system (T3SS), both elicit a strong cell death response on most eggplant lines. Several genotypes thus appear to harbour a mechanism for the direct recognition of a component of the T3SS. Therefore, eggplant and its close relatives are promising resources to unravel novel aspects of plant immunity and to identify new candidate R genes that could be employed in other Solanaceae in which Xeu and Pto cause agriculturally relevant diseases. PMID:24684604

Clarke, Christopher R; Hayes, Byron W; Runde, Brendan J; Wicker, Emmanuel; Vinatzer, Boris A

2014-10-01

10

Genetic Marker Identified for Aggressive Bladder Cancer  

Cancer.gov

Researchers led by Ludmila Prokunina-Olsson, Ph.D., in DCEG's Laboratory of Translational Genomics, have identified the first genetic variant associated with risk of aggressive bladder cancer. The variant, rs7257330, is in the promoter region of the CCNE1 gene, which encodes for cyclin E protein, a cell cycle regulator. This result comes from a fine-mapping analysis of data from two bladder cancer genome-wide association studies and functional studies.

11

Genetic determinants of athletic performance.  

PubMed

An extraordinary revolution in medical research has taken place over the past decade, enabled by the completion of the first human genome sequence in 2001. The Human Genome Project (HGP) has resulted in the 6 billion letter reference human genome sequence and the ultra-high throughput technologies used by medical researchers to identify correlations between positions within the human genome (genotypes) and diseases or traits (phenotypes). Just as every human disease has a genetic component, so too does every human trait. The vast majority of these diseases and traits also have an environmental component that works in conjunction with the body's hardwiring to produce the resultant phenotype- termed "complex genetic traits". A derivative of the HGP has been a deeper understanding not only of diseases but of normal human variability across the population, including aspects of athleticism. The technologies also now exist for consumers to cheaply gain access to variations in the genetic code that are correlated to traits that confer aspects of longevity, memory performance, athleticism and a multitude of others there-through gaining insight into propensities. Communication of propensity to a phenotype such as athletic performance is fraught with technical, legal (e.g., patents), social and ethical issues. That being said, the information is available, has benefit in some cases, and will be utilized in the future. Given that the "genie is out of the bottle" with respect to our ability to deliver this genetic information to individuals, over the past decade our team has worked diligently to craft the appropriate testing and communication paradigms for complex traits. Here we discuss several of the major risks and benefits of this type of testing for athletic performance. It is important to understand the limitations of genetic information in determining the vast majority of traits. PMID:22827596

Stephan, Dietrich A

2012-12-01

12

Identifying Genetic Variation for Alcohol Dependence  

PubMed Central

Researchers are using various strategies to identify the genes that may be associated with alcoholism. The initial efforts primarily relied on candidate gene and linkage studies; more recently, however, modern advances in genotyping have resulted in widespread use of genome-wide association studies for alcohol dependence. The key findings of the earlier studies were that variations (i.e., polymorphisms) in the DNA sequences of the genes encoding alcohol dehydrogenase 1B (i.e., the ADH1B gene), aldehyde dehydrogenase 2 (i.e., the ALDH2 gene), and other alcohol-metabolizing enzymes mediate the risk for alcoholism; moreover, these polymorphisms also have an impact on the risk of alcohol-related cancers, such as esophageal cancer. In addition, a gene encoding one of the receptors for the neurotransmitter ?-aminobutyric acid (GABA) known as GABRA2 seems to have a role in the development of alcohol dependence. Genome-wide association studies now offer a host of emerging opportunities, as well as challenges, for discovering the genetic etiology of alcohol dependence and for unveiling new treatment strategies. PMID:23134043

Agrawal, Arpana; Bierut, Laura J.

2012-01-01

13

Genetic sex determination and extinction.  

PubMed

Genetic factors can affect the probability of extinction either by increasing the effect of detrimental variants or by decreasing the potential for future adaptive responses. In a recent paper, Zayed and Packer demonstrate that low variation at a specific locus, the complementary sex determination (csd) locus in Hymenoptera (ants, bees and wasps), can result in a sharply increased probability of extinction. Their findings illustrate situations in which there is a feedback process between decreased genetic variation at the csd locus owing to genetic drift and decreased population growth, resulting in an extreme type of extinction vortex for these ecologically important organisms. PMID:16701470

Hedrick, Philip W; Gadau, Jürgen; Page, Robert E

2006-02-01

14

PERSPECTIVES Identifying future research needs in landscape genetics  

E-print Network

PERSPECTIVES Identifying future research needs in landscape genetics: where to from here? Niko Holderegger Ă? Helene H. Wagner Ă? Participants of the Landscape Genetics Research Agenda Workshop 2007 Received+Business Media B.V. 2009 Abstract Landscape genetics is an emerging inter- disciplinary field that combines

15

Genetic determinants of human hypertension.  

PubMed Central

Hypertension is a common trait of multifactorial determination imparting an increased risk of myocardial infarction, stroke, and end-stage renal disease. The primary determinants of hypertension, as well as the factors which determine specific morbid sequelae, remain unknown in the vast majority of subjects. Knowledge that a large fraction of the interindividual variation in this trait is genetically determined motivates the application of genetic approaches to the identification of these primary determinants. Success in this effort will afford insights into pathophysiology, permit preclinical identification of subjects with specific inherited susceptibility, and provide opportunities to tailor therapy to specific underlying abnormalities. To date, mutations in three genes have been implicated in the pathogenesis of human hypertension: mutations resulting in ectopic expression of aldosterone synthase enzymatic activity cause a mendelian form of hypertension known as glucocorticoid-remediable aldosteronism; mutations in the beta subunit of the amiloride-sensitive epithelial sodium channel cause constitutive activation of this channel and the mendelian form of hypertension known as Liddle syndrome; finally, common variants at the angiotensinogen locus have been implicated in the pathogenesis of essential hypertension in Caucasian subjects, although the nature of the functional variants and their mechanism of action remain uncertain. These early findings demonstrate the feasibility and utility of the application of genetic analysis to dissection of this trait. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:7567973

Lifton, R P

1995-01-01

16

Genetic markers cannot determine Jewish descent  

PubMed Central

Humans differentiate, classify, and discriminate: social interaction is a basic property of human Darwinian evolution. Presumably inherent differential physical as well as behavioral properties have always been criteria for identifying friend or foe. Yet, biological determinism is a relatively modern term, and scientific racism is, oddly enough, largely a consequence or a product of the Age of Enlightenment and the establishment of the notion of human equality. In recent decades ever-increasing efforts and ingenuity were invested in identifying Biblical Israelite genotypic common denominators by analysing an assortment of phenotypes, like facial patterns, blood types, diseases, DNA-sequences, and more. It becomes overwhelmingly clear that although Jews maintained detectable vertical genetic continuity along generations of socio-religious-cultural relationship, also intensive horizontal genetic relations were maintained both between Jewish communities and with the gentile surrounding. Thus, in spite of considerable consanguinity, there is no Jewish genotype to identify. PMID:25653666

Falk, Raphael

2015-01-01

17

Genetic determinants of hepatic steatosis in man  

PubMed Central

Hepatic steatosis is one of the most common liver disorders in the general population. The main cause of hepatic steatosis is nonalcoholic fatty liver disease (NAFLD), representing the hepatic component of the metabolic syndrome, which is characterized by type 2 diabetes, obesity, and dyslipidemia. Insulin resistance and excess adiposity are considered to play key roles in the pathogenesis of NAFLD. Although the risk factors for NAFLD are well established, the genetic basis of hepatic steatosis is largely unknown. Here we review recent progress on genomic variants and their association with hepatic steatosis and discuss the potential impact of these genetic studies on clinical practice. Identifying the genetic determinants of hepatic steatosis will lead to a better understanding of the pathogenesis and progression of NAFLD. PMID:21245030

Hooper, Amanda J.; Adams, Leon A.; Burnett, John R.

2011-01-01

18

Newly Identified Genetic Variations May Affect Breast Cancer Risk  

Cancer.gov

Researchers have identified genetic variations in a region of DNA that may be associated with risk for breast cancer. Women with the variation have a 1.4 times greater risk of developing breast cancer compared to those without this variation.

19

Genetically determined encephalopathy: Rett syndrome.  

PubMed

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting females that has an incidence of 1:10000 female births, one of the most common genetic causes of severe mental retardation in females. Development is apparently normal for the first 6-18 months until fine and gross motor skills and social interaction are lost, and stereotypic hand movements develop. Progression and severity of the classical form of RTT are most variable, and there are a number of atypical variants, including congenital, early onset seizure, preserved speech variant, and "forme fruste." Mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) involve most of the classical RTT patients. Mutations in cyclin-dependent kinase like 5 (CDKL5) and FoxG1 genes have been identified in the early onset seizure and the congenital variants respectively. Management of RTT is mainly symptomatic and individualized. It focuses on optimizing each patient's abilities. A dynamic multidisciplinary approach is most effective, with specific attention given to epileptic and nonepileptic paroxysmal events, as well as scoliosis, osteoporosis, and the development of spasticity, which can have a major impact on mobility, and to the development of effective communication strategies for these severely disabled individuals. PMID:23622176

Bahi-Buisson, Nadia

2013-01-01

20

Genome sequencing identifies genetic and antigenic divergence of porcine picobirnaviruses.  

PubMed

The full-length genome sequence of a porcine picobirnavirus (PBV) detected in Italy in 2004 was determined. The smaller (S) genome segment was 1730 nt, coding for a putative RNA-dependent RNA polymerase. Two distinct subpopulations of larger (L) genome segment (LA and LB) were identified in the sample, with the sizes ranging from 2351 to 2666 nt. The ORF1, coding for a protein of unknown function, contained a variable number of repetitions of the ExxRxNxxxE motif. The capsid protein-coding ORF2 spanned nt 810-2447 in the LB variants and started at nt 734 in the LA variants. However, a termination codon was present only in one of all the LA segment variants. Three-dimensional modelling of the porcine PBV capsids suggested structural differences in the protruding domain, tentatively involved as antigens in the humoral immune response. Altogether, these findings suggest the simultaneous presence of two different PBV strains sharing the same S segment but displaying genetically diverse L segments. In addition, the sample probably contained a mixture of PBVs with aberrant RNA replication products. Altered structure in the L segments could be tolerated and retained in the presence of functionally integer-cognate genes and represents a mechanism of virus diversification. PMID:24584476

Bányai, Krisztián; Potgieter, Christiaan; Gellért, Ákos; Ganesh, Balasubramanian; Tempesta, Maria; Lorusso, Eleonora; Buonavoglia, Canio; Martella, Vito

2014-10-01

21

Genetics of sex determination in tilapiine species.  

PubMed

We identified DNA markers linked to sex determining genes in six closely related species of tilapiine fishes. The mode of sex determination differed among species. In Oreochromis karongae and Tilapia mariae the sex-determining locus is on linkage group (LG) 3 and the female is heterogametic (WZ-ZZ system). In O. niloticus and T. zillii the sex-determining locus is on LG1 and the male is heterogametic (XX-XY system). A more complex pattern was observed in O. aureus and O. mossambicus, in which markers on both LG1 and LG3 were associated with sex. We found evidence for sex-linked lethal effects on LG1, as well as interactions between loci in the two linkage groups. Comparison of genetic and physical maps demonstrated a broad region of recombination suppression harboring the sex-determining locus on LG3. Sex-specific recombination suppression was found in the female heterogametic sex. Sequence analysis showed the accumulation of repetitive elements in this region. Phylogenetic analysis suggests that at least two transitions in the mode of sex determination have occurred in this clade. This variation in sex determination mechanisms among closely related species makes tilapias an excellent model system for studying the evolution of sex chromosomes in vertebrates. PMID:18418034

Cnaani, A; Lee, B-Y; Zilberman, N; Ozouf-Costaz, C; Hulata, G; Ron, M; D'Hont, A; Baroiller, J-F; D'Cotta, H; Penman, D J; Tomasino, E; Coutanceau, J-P; Pepey, E; Shirak, A; Kocher, T D

2008-01-01

22

Genetic Determinants of Arterial Stiffness.  

PubMed

Stiffness of large arteries (called arteriosclerosis) is an independent predictor of cardiovascular morbidity and mortality. Although previous studies have shown that arterial stiffness is moderately heritable, genetic factors contributing to arterial stiffness are largely unknown. In this paper, we reviewed the available literature on genetic variants that are potentially related to arterial stiffness. Most variants have shown mixed depictions of their association with arterial stiffness across multiple studies. Various methods to measure arterial stiffness at different arterial sites can contribute to these inconsistent results. In addition, studies in patient populations with hypertension or atherosclerosis may overestimate the impact of genetic variants on arterial stiffness. Future studies are recommended to standardize current measures of arterial stiffness in different age groups. Studies conducted in normal healthy subjects may also provide better opportunities to find novel genetic variants of arterial stiffness. PMID:25472935

Logan, Jeongok G; Engler, Mary B; Kim, Hyungsuk

2014-12-01

23

Genetic determinants of uveal melanoma.  

PubMed

Melanoma of the uveal tract is the most common primary intraocular tumor in adults. With advances in genetic research and the open source access of genetic databases, new insights are emerging into the molecular changes of this cancer. As with most other tumors, the driving force behind such research is the hope of finding and developing new modalities for therapeutic purposes, prognosticating disease and understanding risk factors for metastasis. With advances in proteomics, cytogenetics and gene profiling, the stage is set to unearth the underlying genetic basis which can in the future be a target of therapeutic modalities. This article describes the cytogenetic, molecular pathogenesis, and prognostic factors along with the most important findings and their attribution to current and future management of uveal melanoma. PMID:25296731

Kaur, Jasbir; Malik, Manzoor Ahmad; Gulati, Rishabh; Azad, Shorya Vardhan; Goswami, Sandeep

2014-12-01

24

Genetical Genomics Identifies the Genetic Architecture for Growth and Weevil Resistance in Spruce  

PubMed Central

In plants, relationships between resistance to herbivorous insect pests and growth are typically controlled by complex interactions between genetically correlated traits. These relationships often result in tradeoffs in phenotypic expression. In this study we used genetical genomics to elucidate genetic relationships between tree growth and resistance to white pine terminal weevil (Pissodes strobi Peck.) in a pedigree population of interior spruce (Picea glauca, P. engelmannii and their hybrids) that was growing at Vernon, B.C. and segregating for weevil resistance. Genetical genomics uses genetic perturbations caused by allelic segregation in pedigrees to co-locate quantitative trait loci (QTLs) for gene expression and quantitative traits. Bark tissue of apical leaders from 188 trees was assayed for gene expression using a 21.8K spruce EST-spotted microarray; the same individuals were genotyped for 384 SNP markers for the genetic map. Many of the expression QTLs (eQTL) co-localized with resistance trait QTLs. For a composite resistance phenotype of six attack and oviposition traits, 149 positional candidate genes were identified. Resistance and growth QTLs also overlapped with eQTL hotspots along the genome suggesting that: 1) genetic pleiotropy of resistance and growth traits in interior spruce was substantial, and 2) master regulatory genes were important for weevil resistance in spruce. These results will enable future work on functional genetic studies of insect resistance in spruce, and provide valuable information about candidate genes for genetic improvement of spruce. PMID:22973444

Porth, Ilga; White, Richard; Jaquish, Barry; Alfaro, René; Ritland, Carol; Ritland, Kermit

2012-01-01

25

Genetical genomics identifies the genetic architecture for growth and weevil resistance in spruce.  

PubMed

In plants, relationships between resistance to herbivorous insect pests and growth are typically controlled by complex interactions between genetically correlated traits. These relationships often result in tradeoffs in phenotypic expression. In this study we used genetical genomics to elucidate genetic relationships between tree growth and resistance to white pine terminal weevil (Pissodes strobi Peck.) in a pedigree population of interior spruce (Picea glauca, P. engelmannii and their hybrids) that was growing at Vernon, B.C. and segregating for weevil resistance. Genetical genomics uses genetic perturbations caused by allelic segregation in pedigrees to co-locate quantitative trait loci (QTLs) for gene expression and quantitative traits. Bark tissue of apical leaders from 188 trees was assayed for gene expression using a 21.8K spruce EST-spotted microarray; the same individuals were genotyped for 384 SNP markers for the genetic map. Many of the expression QTLs (eQTL) co-localized with resistance trait QTLs. For a composite resistance phenotype of six attack and oviposition traits, 149 positional candidate genes were identified. Resistance and growth QTLs also overlapped with eQTL hotspots along the genome suggesting that: 1) genetic pleiotropy of resistance and growth traits in interior spruce was substantial, and 2) master regulatory genes were important for weevil resistance in spruce. These results will enable future work on functional genetic studies of insect resistance in spruce, and provide valuable information about candidate genes for genetic improvement of spruce. PMID:22973444

Porth, Ilga; White, Richard; Jaquish, Barry; Alfaro, René; Ritland, Carol; Ritland, Kermit

2012-01-01

26

Identifying Interacting Genetic Variations by Fish-Swarm Logic Regression  

PubMed Central

Understanding associations between genotypes and complex traits is a fundamental problem in human genetics. A major open problem in mapping phenotypes is that of identifying a set of interacting genetic variants, which might contribute to complex traits. Logic regression (LR) is a powerful multivariant association tool. Several LR-based approaches have been successfully applied to different datasets. However, these approaches are not adequate with regard to accuracy and efficiency. In this paper, we propose a new LR-based approach, called fish-swarm logic regression (FSLR), which improves the logic regression process by incorporating swarm optimization. In our approach, a school of fish agents are conducted in parallel. Each fish agent holds a regression model, while the school searches for better models through various preset behaviors. A swarm algorithm improves the accuracy and the efficiency by speeding up the convergence and preventing it from dropping into local optimums. We apply our approach on a real screening dataset and a series of simulation scenarios. Compared to three existing LR-based approaches, our approach outperforms them by having lower type I and type II error rates, being able to identify more preset causal sites, and performing at faster speeds. PMID:23984382

Yang, Aiyuan; Yan, Chunxia; Zhu, Feng; Zhao, Zhongmeng; Cao, Zhi

2013-01-01

27

New genetic variants identified in donkey's milk whey proteins.  

PubMed

Novel genetic variants for donkey milk lysozyme and beta-lactoglobulins I and II have been identified by the combined use of peptide mass mapping and sequencing by tandem mass spectrometry in association with database searching. The novel donkey lysozyme variant designated as lysozyme B (Mr 14,631 Da) differed in three amino acid exchanges, N49 --> D, Y52 --> S, and S61 --> N, from the previously published sequence. Three novel genetic variants for donkey beta-lactoglobulins were identified. One of them is a type beta-lactoglobulin I with three amino acid exchanges at E36 --> S, S97 --> T, and V150 --> I (beta-lactoglobulin I B, Mr 18,510 Da). The two others are type beta-lactoglobulins II with two amino acid exchanges at C110 --> P and M118--> T (beta-lactoglobulin II B, Mr 18,227 Da) and with three amino acid exchanges at D96 --> E, C110 --> P, and M118 -->T (beta-lactoglobulin II C, Mr 18,241 Da). All these primary structures are closely related to those of homologous proteins in horse milk (percent identity >96%). PMID:10945434

Herrouin, M; Mollé, D; Fauquant, J; Ballestra, F; Maubois, J L; Léonil, J

2000-02-01

28

Genetic Determinants of Phosphate Response in Drosophila  

PubMed Central

Phosphate is required for many important cellular processes and having too little phosphate or too much can cause disease and reduce life span in humans. However, the mechanisms underlying homeostatic control of extracellular phosphate levels and cellular effects of phosphate are poorly understood. Here, we establish Drosophila melanogaster as a model system for the study of phosphate effects. We found that Drosophila larval development depends on the availability of phosphate in the medium. Conversely, life span is reduced when adult flies are cultured on high phosphate medium or when hemolymph phosphate is increased in flies with impaired Malpighian tubules. In addition, RNAi-mediated inhibition of MAPK-signaling by knockdown of Ras85D, phl/D-Raf or Dsor1/MEK affects larval development, adult life span and hemolymph phosphate, suggesting that some in vivo effects involve activation of this signaling pathway by phosphate. To identify novel genetic determinants of phosphate responses, we used Drosophila hemocyte-like cultured cells (S2R+) to perform a genome-wide RNAi screen using MAPK activation as the readout. We identified a number of candidate genes potentially important for the cellular response to phosphate. Evaluation of 51 genes in live flies revealed some that affect larval development, adult life span and hemolymph phosphate levels. PMID:23520455

Bergwitz, Clemens; Wee, Mark J.; Sinha, Sumi; Huang, Joanne; DeRobertis, Charles; Mensah, Lawrence B.; Cohen, Jonathan; Friedman, Adam; Kulkarni, Meghana; Hu, Yanhui; Vinayagam, Arunachalam; Schnall-Levin, Michael; Berger, Bonnie; Perkins, Lizabeth A.; Mohr, Stephanie E.; Perrimon, Norbert

2013-01-01

29

Decomposing P300 to identify its genetic basis.  

PubMed

In this commentary, I explore reasons why it has been difficult to associate P300 amplitude with a gene or a single nucleotide polymorphism (SNP). I suggest we decompose P300 into the factors that contribute to it to get better traction on its genetic basis. Specifically, I note that we can improve the measurement of P300 to remove state-dependent contributions by including more than one measurement occasion; we can identify and extract the neural components contributing to P300 amplitude by estimating EEG power in specific bands of the P300; we can adjust P300 for single-trial variability; we can extract single-trial variability; and we can refine the tasks to isolate the separate psychological processes that P300 reflects. In the end, each of these factors that contribute to the conglomerate P300 may be a separate endophenotype mapping onto a separate SNP or gene. PMID:25387713

Ford, Judith M

2014-12-01

30

A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity  

PubMed Central

Large interindividual variance has been observed in sensitivity to drugs. To comprehensively decipher the genetic contribution to these variations in drug susceptibility, we present a genome-wide model using human lymphoblastoid cell lines from the International HapMap consortium, of which extensive genotypic information is available, to identify genetic variants that contribute to chemotherapeutic agent-induced cytotoxicity. Our model integrated genotype, gene expression, and sensitivity of HapMap cell lines to drugs. Cell lines derived from 30 trios of European descent (Center d'Etude du Polymorphisme Humain population) and 30 trios of African descent (Yoruban population) were used. Cell growth inhibition at increasing concentrations of etoposide for 72 h was determined by using alamarBlue assay. Gene expression on 176 HapMap cell lines (87 Center d'Etude du Polymorphisme Humain population and 89 Yoruban population) was determined by using the Affymetrix GeneChip Human Exon 1.0ST Array. We evaluated associations between genotype and cytotoxicity, genotype and gene expression and correlated gene expression of the identified candidates with cytotoxicity. The analysis identified 63 genetic variants that contribute to etoposide-induced toxicity through their effect on gene expression. These include genes that may play a role in cancer (AGPAT2, IL1B, and WNT5B) and genes not yet known to be associated with sensitivity to etoposide. This unbiased method can be used to elucidate genetic variants contributing to a wide range of cellular phenotypes induced by chemotherapeutic agents. PMID:17537913

Huang, R. Stephanie; Duan, Shiwei; Bleibel, Wasim K.; Kistner, Emily O.; Zhang, Wei; Clark, Tyson A.; Chen, Tina X.; Schweitzer, Anthony C.; Blume, John E.; Cox, Nancy J.; Dolan, M. Eileen

2007-01-01

31

DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics  

PubMed Central

Background De novo loss-of-function (dnLoF) mutations are found twofold more often in autism spectrum disorder (ASD) probands than their unaffected siblings. Multiple independent dnLoF mutations in the same gene implicate the gene in risk and hence provide a systematic, albeit arduous, path forward for ASD genetics. It is likely that using additional non-genetic data will enhance the ability to identify ASD genes. Methods To accelerate the search for ASD genes, we developed a novel algorithm, DAWN, to model two kinds of data: rare variations from exome sequencing and gene co-expression in the mid-fetal prefrontal and motor-somatosensory neocortex, a critical nexus for risk. The algorithm casts the ensemble data as a hidden Markov random field in which the graph structure is determined by gene co-expression and it combines these interrelationships with node-specific observations, namely gene identity, expression, genetic data and the estimated effect on risk. Results Using currently available genetic data and a specific developmental time period for gene co-expression, DAWN identified 127 genes that plausibly affect risk, and a set of likely ASD subnetworks. Validation experiments making use of published targeted resequencing results demonstrate its efficacy in reliably predicting ASD genes. DAWN also successfully predicts known ASD genes, not included in the genetic data used to create the model. Conclusions Validation studies demonstrate that DAWN is effective in predicting ASD genes and subnetworks by leveraging genetic and gene expression data. The findings reported here implicate neurite extension and neuronal arborization as risks for ASD. Using DAWN on emerging ASD sequence data and gene expression data from other brain regions and tissues would likely identify novel ASD genes. DAWN can also be used for other complex disorders to identify genes and subnetworks in those disorders. PMID:24602502

2014-01-01

32

SLDR: a computational technique to identify novel genetic regulatory relationships.  

PubMed

We developed a new computational technique called Step-Level Differential Response (SLDR) to identify genetic regulatory relationships. Our technique takes advantages of functional genomics data for the same species under different perturbation conditions, therefore complementary to current popular computational techniques. It can particularly identify "rare" activation/inhibition relationship events that can be difficult to find in experimental results. In SLDR, we model each candidate target gene as being controlled by N binary-state regulators that lead to ?2N observable states ("step-levels") for the target. We applied SLDR to the study of the GEO microarray data set GSE25644, which consists of 158 different mutant S. cerevisiae gene expressional profiles. For each target gene t, we first clustered ordered samples into various clusters, each approximating an observable step-level of t to screen out the "de-centric" target. Then, we ordered each gene x as a candidate regulator and aligned t to x for the purpose of examining the step-level correlations between low expression set of x (Ro) and high expression set of x (Rh) from the regulator x to t, by finding max f(t, x): |Ro-Rh| over all candidate × in the genome for each t. We therefore obtained activation and inhibitions events from different combinations of Ro and Rh. Furthermore, we developed criteria for filtering out less-confident regulators, estimated the number of regulators for each target t, and evaluated identified top-ranking regulator-target relationship. Our results can be cross-validated with the Yeast Fitness database. SLDR is also computationally efficient with o(N˛) complexity. In summary, we believe SLDR can be applied to the mining of functional genomics big data for future network biology and network medicine applications. PMID:25350940

Yue, Zongliang; Wan, Ping; Huang, Hui; Xie, Zhan; Chen, Jake Y

2014-10-21

33

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.  

PubMed

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17?000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power. PMID:24916650

Versmissen, Jorie; Oosterveer, Daniëlla M; Yazdanpanah, Mojgan; Dehghan, Abbas; Hólm, Hilma; Erdman, Jeanette; Aulchenko, Yurii S; Thorleifsson, Gudmar; Schunkert, Heribert; Huijgen, Roeland; Vongpromek, Ranitha; Uitterlinden, André G; Defesche, Joep C; van Duijn, Cornelia M; Mulder, Monique; Dadd, Tony; Karlsson, Hróbjartur D; Ordovas, Jose; Kindt, Iris; Jarman, Amelia; Hofman, Albert; van Vark-van der Zee, Leonie; Blommesteijn-Touw, Adriana C; Kwekkeboom, Jaap; Liem, Anho H; van der Ouderaa, Frans J; Calandra, Sebastiano; Bertolini, Stefano; Averna, Maurizio; Langslet, Gisle; Ose, Leiv; Ros, Emilio; Almagro, Fátima; de Leeuw, Peter W; Civeira, Fernando; Masana, Luis; Pintó, Xavier; Simoons, Maarten L; Schinkel, Arend Fl; Green, Martin R; Zwinderman, Aeilko H; Johnson, Keith J; Schaefer, Arne; Neil, Andrew; Witteman, Jacqueline Cm; Humphries, Steve E; Kastelein, John Jp; Sijbrands, Eric Jg

2015-03-01

34

Identifying Families with Likely Genetic Protective Factors against Alzheimer Disease  

Microsoft Academic Search

Summary Elderly individuals who lived beyond the age of 90 years without dementia were hypothesized to have increased concentrations of genetic protective factors against Alz- heimer disease (AD), conferring a reduced liability for this disease relative to less-aged nondemented elderly. However, testing this hypothesis is complicated by hav- ing to distinguish such a group from those who may lack genetic

Jeremy M. Silverman; Christopher J. Smith; Deborah B. Marin; Sandra Birstein; Marlene Mare; Richard C. Mohs; Kenneth L. Davis

1999-01-01

35

Genetic determinants of blood pressure regulation.  

PubMed

Hypertension is a multifactorial disorder that probably results from the inheritance of a number of susceptibility genes and involves multiple environmental determinants. Existing evidence suggests that the genetic contribution to blood pressure variation is about 30-50%. Although a number of candidate genes have been studied in different ethnic populations, results from genetic analysis are still inconsistent and specific causes of hypertension remain unclear. Furthermore, the abundance of data in the literature makes it difficult to piece together the puzzle of hypertension and to define candidate genes involved in the dynamic of blood pressure regulation. In this review, we attempt to highlight the genetic basis of hypertension pathogenesis, focusing on the most important existing genetic variations of candidate genes and their potential role in the development of this disease. Our objective is to review current knowledge and discuss limitations to clinical applications of genotypic information in the diagnosis, evaluation and treatment of hypertension. Finally, some principles of pharmacogenomics are presented here along with future perspectives of hypertension. PMID:16269952

Marteau, Jean-Brice; Zaiou, Mohamed; Siest, Gérard; Visvikis-Siest, Sophie

2005-12-01

36

Alphaviruses: Population genetics and determinants of emergence  

PubMed Central

Alphaviruses are responsible for several medically important emerging diseases and are also significant veterinary pathogens. Due to the aerosol infectivity of some alphaviruses and their ability to cause severe, sometimes fatal neurologic diseases, they are also of biodefense importance. This review discusses the ecology, epidemiology and molecular virology of the alphaviruses, then focuses on three of the most important members of the genus: Venezuelan and eastern equine encephalitis and chikungunya viruses, with emphasis on their genetics and emergence mechanisms, and how current knowledge as well as gaps influence our ability to detect and determine the source of both natural outbreaks and potential use for bioterrorism. This article is one of a series in Antiviral Research on the genetic diversity of emerging viruses. PMID:22522323

Weaver, Scott C.; Winegar, Richard; Manger, Ian D.; Forrester, Naomi L.

2013-01-01

37

Barriers to Access: Results from Focus Groups to Identify Genetic Service Needs in the Community  

Microsoft Academic Search

Objective: In efforts to prepare for implications of genomic advances, a needs assessment was undertaken from 2000 to 2002 by the Michigan Department of Community Health to develop a comprehensive state plan for genetic services. This paper reports on the access barriers to genetic services identified from focus groups conducted with members of the community and genetic service providers. Methods:

Rosalyn Y. Beene-Harris; Catharine Wang; Janice V. Bach

2007-01-01

38

New application of intelligent agents in sporadic amyotrophic lateral sclerosis identifies unexpected specific genetic background  

Microsoft Academic Search

BACKGROUND: Few genetic factors predisposing to the sporadic form of amyotrophic lateral sclerosis (ALS) have been identified, but the pathology itself seems to be a true multifactorial disease in which complex interactions between environmental and genetic susceptibility factors take place. The purpose of this study was to approach genetic data with an innovative statistical method such as artificial neural networks

Silvana Penco; Massimo Buscema; Maria Cristina Patrosso; Alessandro Marocchi; Enzo Grossi

2008-01-01

39

Comparative Genetics: Synergizing Human and NOD Mouse Studies for Identifying Genetic Causation of Type 1 Diabetes  

PubMed Central

Although once widely anticipated to unlock how human type 1 diabetes (T1D) develops, extensive study of the nonobese diabetic (NOD) mouse has failed to yield effective treatments for patients with the disease. This has led many to question the usefulness of this animal model. While criticism about the differences between NOD and human T1D is legitimate, in many cases disease in both species results from perturbations modulated by the same genes or different genes that function within the same biological pathways. Like in humans, unusual polymorphisms within an MHC class II molecule contributes the most T1D risk in NOD mice. This insight supports the validity of this model and suggests the NOD has been improperly utilized to study how to cure or prevent disease in patients. Indeed, clinical trials are far from administering T1D therapeutics to humans at the same concentration ranges and pathological states that inhibit disease in NOD mice. Until these obstacles are overcome it is premature to label the NOD mouse a poor surrogate to test agents that cure or prevent T1D. An additional criticism of the NOD mouse is the past difficulty in identifying genes underlying T1D using conventional mapping studies. However, most of the few diabetogenic alleles identified to date appear relevant to the human disorder. This suggests that rather than abandoning genetic studies in NOD mice, future efforts should focus on improving the efficiency with which diabetes susceptibility genes are detected. The current review highlights why the NOD mouse remains a relevant and valuable tool to understand the genes and their interactions that promote autoimmune diabetes and therapeutics that inhibit this disease. It also describes a new range of technologies that will likely transform how the NOD mouse is used to uncover the genetic causes of T1D for years to come. PMID:23804259

Driver, John P.; Chen, Yi-Guang; Mathews, Clayton E.

2012-01-01

40

Identifying the genetic components underlying the pathophysiology of movement disorders  

PubMed Central

Movement disorders are a heterogeneous group of neurological conditions, few of which have been classically described as bona fide hereditary illnesses (Huntington’s chorea, for instance). Most are considered to be either sporadic or to feature varying degrees of familial aggregation (parkinsonism and dystonia). In the late twentieth century, Mendelian monogenic mutations were found for movement disorders with a clear and consistent family history. Although important, these findings apply only to very rare forms of movement disorders. Already in the twenty-first century, and taking advantage of the modern developments in genetics and molecular biology, growing attention is being paid to the complex genetics of movement disorders. The search for risk genetic variants (polymorphisms) in large cohorts and the identification of different risk variants across different populations and ethnic groups are under way, with the most relevant findings to date corresponding to recent genome wide association studies in Parkinson’s disease. These new approaches focusing on risk variants may enable the design of screening tests for early or even preclinical disease, and the identification of likely therapeutic targets. PMID:23776369

Ezquerra, Mario; Compta, Yaroslau; Marti, Maria J

2011-01-01

41

Using Random Sequence Primers in the Polymerase Chain Reaction to identify Gender-Specific Genetic Markers in House Wrens  

Microsoft Academic Search

In order to fully understand the biology of asexually reproducing organism, it is essential that one is able to distinguish the males from the females. In determining the gender of monomorphic birds, standard techniques including visual identification, surgery, and karyotyping are impossible or impractical for large-scale studies. A reliable gender identification method that uses genetic markers identified within the DNA

Jeremy J. Kirchman

1994-01-01

42

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.  

PubMed

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies. PMID:22425996

Chen, Zhao; Cheng, Katherine; Walton, Zandra; Wang, Yuchuan; Ebi, Hiromichi; Shimamura, Takeshi; Liu, Yan; Tupper, Tanya; Ouyang, Jing; Li, Jie; Gao, Peng; Woo, Michele S; Xu, Chunxiao; Yanagita, Masahiko; Altabef, Abigail; Wang, Shumei; Lee, Charles; Nakada, Yuji; Peńa, Christopher G; Sun, Yanping; Franchetti, Yoko; Yao, Catherine; Saur, Amy; Cameron, Michael D; Nishino, Mizuki; Hayes, D Neil; Wilkerson, Matthew D; Roberts, Patrick J; Lee, Carrie B; Bardeesy, Nabeel; Butaney, Mohit; Chirieac, Lucian R; Costa, Daniel B; Jackman, David; Sharpless, Norman E; Castrillon, Diego H; Demetri, George D; Jänne, Pasi A; Pandolfi, Pier Paolo; Cantley, Lewis C; Kung, Andrew L; Engelman, Jeffrey A; Wong, Kwok-Kin

2012-03-29

43

Representing genetic variation as continuous surfaces: an approach for identifying spatial dependency in landscape genetic studies  

E-print Network

, migration, effective population size) and used ancestry (q) values from STRUCTURE to interpolate a genetic surface. Using a spatially adjusted Pearson's correlation coefficient to test the significance of testing landscape influence on genetic structure. Finally, we apply genetic surfacing to analyze

Storfer, Andrew

44

AbsIDconvert: An absolute approach for converting genetic identifiers at different granularities  

PubMed Central

Background High-throughput molecular biology techniques yield vast amounts of data, often by detecting small portions of ribonucleotides corresponding to specific identifiers. Existing bioinformatic methodologies categorize and compare these elements using inferred descriptive annotation given this sequence information irrespective of the fact that it may not be representative of the identifier as a whole. Results All annotations, no matter the granularity, can be aligned to genomic sequences and therefore annotated by genomic intervals. We have developed AbsIDconvert, a methodology for converting between genomic identifiers by first mapping them onto a common universal coordinate system using an interval tree which is subsequently queried for overlapping identifiers. AbsIDconvert has many potential uses, including gene identifier conversion, identification of features within a genomic region, and cross-species comparisons. The utility is demonstrated in three case studies: 1) comparative genomic study mapping plasmodium gene sequences to corresponding human and mosquito transcriptional regions; 2) cross-species study of Incyte clone sequences; and 3) analysis of human Ensembl transcripts mapped by Affymetrix®; and Agilent microarray probes. AbsIDconvert currently supports ID conversion of 53 species for a given list of input identifiers, genomic sequence, or genome intervals. Conclusion AbsIDconvert provides an efficient and reliable mechanism for conversion between identifier domains of interest. The flexibility of this tool allows for custom definition identifier domains contingent upon the availability and determination of a genomic mapping interval. As the genomes and the sequences for genetic elements are further refined, this tool will become increasingly useful and accurate. AbsIDconvert is freely available as a web application or downloadable as a virtual machine at: http://bioinformatics.louisville.edu/abid/. PMID:22967011

2012-01-01

45

A Yeast Chemical Genetic Screen Identifies Inhibitors of Human Telomerase  

PubMed Central

Summary Telomerase comprises a reverse transcriptase and an internal RNA template that maintains telomeres in many eukaryotes, and it is a well-validated cancer target. However, there is a dearth of small molecules with efficacy against human telomerase in vivo. We developed a surrogate yeast high-throughput assay to identify human telomerase inhibitors. The reversibility of growth arrest induced by active human telomerase was assessed against a library of 678 compounds preselected for bioactivity in S. cerevisiae. Four of eight compounds identified reproducibly restored growth to strains expressing active human telomerase, and three of these four compounds also specifically inhibited purified human telomerase in vitro. These compounds represent probes for human telomerase function, and potential entry points for development of lead compounds against telomerase-positive cancers. PMID:23521791

Wong, Lai Hong; Unciti-Broceta, Asier; Spitzer, Michaela; White, Rachel; Tyers, Mike; Harrington, Lea

2013-01-01

46

A yeast chemical genetic screen identifies inhibitors of human telomerase.  

PubMed

Telomerase comprises a reverse transcriptase and an internal RNA template that maintains telomeres in many eukaryotes, and it is a well-validated cancer target. However, there is a dearth of small molecules with efficacy against human telomerase in vivo. We developed a surrogate yeast high-throughput assay to identify human telomerase inhibitors. The reversibility of growth arrest induced by active human telomerase was assessed against a library of 678 compounds preselected for bioactivity in S. cerevisiae. Four of eight compounds identified reproducibly restored growth to strains expressing active human telomerase, and three of these four compounds also specifically inhibited purified human telomerase in vitro. These compounds represent probes for human telomerase function, and potential entry points for development of lead compounds against telomerase-positive cancers. PMID:23521791

Wong, Lai Hong; Unciti-Broceta, Asier; Spitzer, Michaela; White, Rachel; Tyers, Mike; Harrington, Lea

2013-03-21

47

Molecular evolutionary genetic analysis of emerging parvoviruses identified in pigs.  

PubMed

Parvoviruses infect a wide variety of vertebrates and arthropods and are associated with various clinical manifestations. Due to the advent of new sequence-independent PCR methods and high-throughput sequencing, several novel members of parvoviruses within the subfamily Parvovirinae were recently described. Several of these viruses do not fit in the current classification and others now have confusing or contradictory nomenclature because two or more names were used for similar or identical groups of parvoviruses or identical names were used for distinct virus groups. In this study, recently described vertebrate parvoviruses with emphasis on those identified in pigs were classified through phylogenetic analyses based on the sequences of their complete or near complete genomes, open reading frame (ORF) 1 (non-structural protein, NS1), ORF2 (capsid protein, VP1), and ORF3 (nuclear phosphoprotein, NP1) genes by using Bayesian Markov chain Monte Carlo (MCMC), Maximum Likelihood (ML) and Neighbor-Joining (NJ) methods. Among all available vertebrate parvovirus sequences, eight distinct clades were identified, corresponding to the five well established genera Parvovirus, Erythrovirus, Denpendovirus, Amdovirus and Bocavirus. Moreover, three novel clades were identified and tentatively designated as PARV4-like virus, novel clade 1 and novel clade 2. Parvoviruses in pigs were found to be distributed across four different clades including Parvovirus, Bocavirus, PARV4-like virus and the novel clade 2. All pig parvoviruses identified to date were organized based on the current analysis. The present analysis will assist to clarify the nomenclature of parvoviruses in pigs and facilitate future uniform assignment of names for new parvoviruses within the subfamily Parvovirinae. PMID:23523595

Xiao, Chao-Ting; Halbur, Patrick G; Opriessnig, Tanja

2013-06-01

48

Identifying genetic networks underlying myometrial transition to labor  

PubMed Central

Background Early transition to labor remains a major cause of infant mortality, yet the causes are largely unknown. Although several marker genes have been identified, little is known about the underlying global gene expression patterns and pathways that orchestrate these striking changes. Results We performed a detailed time-course study of over 9,000 genes in mouse myometrium at defined physiological states: non-pregnant, mid-gestation, late gestation, and postpartum. This dataset allowed us to identify distinct patterns of gene expression that correspond to phases of myometrial 'quiescence', 'term activation', and 'postpartum involution'. Using recently developed functional mapping tools (HOPACH (hierarchical ordered partitioning and collapsing hybrid) and GenMAPP 2.0), we have identified new potential transcriptional regulatory gene networks mediating the transition from quiescence to term activation. Conclusions These results implicate the myometrium as an essential regulator of endocrine hormone (cortisol and progesterone synthesis) and signaling pathways (cyclic AMP and cyclic GMP stimulation) that direct quiescence via the transcripitional upregulation of both novel and previously associated regulators. With term activation, we observe the upregulation of cytoskeletal remodeling mediators (intermediate filaments), cell junctions, transcriptional regulators, and the coordinate downregulation of negative control checkpoints of smooth muscle contractile signaling. This analysis provides new evidence of multiple parallel mechanisms of uterine contractile regulation and presents new putative targets for regulating myometrial transformation and contraction. PMID:15693941

Salomonis, Nathan; Cotte, Nathalie; Zambon, Alexander C; Pollard, Katherine S; Vranizan, Karen; Doniger, Scott W; Dolganov, Gregory; Conklin, Bruce R

2005-01-01

49

Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population  

Technology Transfer Automated Retrieval System (TEKTRAN)

Genetic variants responsible for susceptibility to obesity and its comorbidities among Hispanic children have not been identified. The VIVA LA FAMILIA Study was designed to genetically map childhood obesity and associated biological processes in the Hispanic population. A genome-wide association stu...

50

Genetic errors identified in 12 major cancer types  

Cancer.gov

Examining 12 major types of cancer, scientists at Washington University School of Medicine in St. Louis (home of the Alvin J. Siteman Cancer Center) have identified 127 repeatedly mutated genes that appear to drive the development and progression of a range of tumors in the body. The discovery sets the stage for devising new diagnostic tools and more personalized cancer treatments. The research, published Oct. 17 in Nature, shows that some of the same genes commonly mutated in certain cancers also occur in seemingly unrelated tumors.

51

Genetic Diseases and Genetic Determinism Models in French Secondary School Biology Textbooks  

ERIC Educational Resources Information Center

The presentation of genetic diseases in French secondary school biology textbooks is analysed to determine the major conceptions taught in the field of human genetics. References to genetic diseases, and the processes by which they are explained (monogeny, polygeny, chromosomal anomaly and environmental influence) are studied in recent French…

Castera, Jeremy; Bruguiere, Catherine; Clement, Pierre

2008-01-01

52

Researchers Identify Genetic Variations That May Increase Risk of Breast Cancer  

Cancer.gov

Researchers have identified new genetic variations in two regions of DNA -- located on chromosomes 1 and 14 -- that may be associated with the risk of sporadic breast cancer. This study also confirms some of the previously identified associations between specific regions in the genome and breast cancer risk.

53

A genome-wide association study to identify genetic markers associated with endometrial cancer grade  

E-print Network

MEETING ABSTRACT Open Access A genome-wide association study to identify genetic markers associated with endometrial cancer grade T O’Mara1,2, D Duffy2, DJ Thompson3, S Ahmed4, K Ferguson2, CS Healey4, ANECS2, G Montgomery2, M Shah4, J Morrison3, PP... of chemotherapeutic agents targeting aggressive disease. Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in cancer susceptibility. Presently there are lim- ited published studies using GWAS data to identify...

2012-04-12

54

Harnessing genomics to identify environmental determinants of heritable disease  

EPA Science Inventory

De novo mutation is increasingly being recognized as the cause for a range of human genetic diseases and disorders. Important examples of this include inherited genetic disorders such as autism, schizophrenia, mental retardation, epilepsy, and a broad range of adverse reproductiv...

55

The Next Challenge for Psychiatric Genetics: Characterizing the Risk Associated with Identified Genes  

PubMed Central

Background As advances in genetics further our ability to identify genes influencing psychiatric disorders, the next challenge facing psychiatric genetics is to characterize the risk associated with specific genetic variants in order to better understand how these susceptibility genes are involved in the pathways leading to illness. Methods To further this goal, findings from behavior genetic analyses about how genetic influences act can be used to guide hypothesis testing about the effects associated with specific genes. Results Using the phenotype of alcohol dependence as an example, this paper provides an overview of how the integration of behavioral and statistical genetics can advance our knowledge about the genetics of psychiatric disorders. Areas currently being investigated in behavior genetics include careful delineation of phenotypes, to examine the heritability of various aspects of normal and abnormal behavior; developmental changes in the nature and magnitude of genetic and environmental effects; the extent to which different behaviors are influenced by common genes; and different forms of gene-environment correlation and interaction. Conclusions Understanding how specific genes are involved in these processes has the potential to significantly enhance our understanding of the development of psychiatric disorders. PMID:17162621

Dick, Danielle M.; Rose, Richard J.; Kaprio, Jaakko

2006-01-01

56

Identifying Sequence Determinants of Reduction Potentials of Metalloproteins  

PubMed Central

The reduction potential of an electron transfer protein is one of its most important functional characteristics. While the type of redox site and the protein fold are the major determinants of the reduction potential of a redox active protein, its amino acid sequence may tune the reduction potential as well. Thus, homologous proteins can often be divided into different classes, with each class characterized by a biological function and a reduction potential. Site-specific mutagenesis of the sequence determinants of the differences in the reduction potential between classes should change the reduction potential of a protein in one class to that of the other class. Here, a procedure is presented that combines energetic and bioinformatics analysis of homologous proteins for identifying sequence determinants that are also good candidates for site-specific mutations, using the [4Fe-4S]-ferredoxins and the [4Fe-4S]-HiPIPs as examples. This procedure is designed to guide site-specific mutations or more computationally expensive studies, such as molecular dynamics simulations. To make the procedure more accessible to the general scientific community, it is being implemented into CHARMMing, a web-based portal, with a library of density functional theory results for the redox site that used in the set up of Poisson-Boltzmann continuum electrostatics calculations for the protein energetics. PMID:23690205

Perrin, Bradley Scott; Ichiye, Toshiko

2013-01-01

57

Penn Medicine researchers identify four new genetic risk factors for testicular cancer  

Cancer.gov

A new study looking at the genomes of more than 13,000 men identified four new genetic variants associated with an increased risk of testicular cancer, the most commonly diagnosed type in young men today. The findings from this first-of-its-kind meta-analysis were reported online May 12 in Nature Genetics by researchers at the Perelman School of Medicine at the University of Pennsylvania, home of the Abramson Cancer Center.

58

Sphingolipids and Membrane Biology as Determined from Genetic Models  

PubMed Central

The importance of sphingolipids in membrane biology was appreciated early in the twentieth century when several human inborn errors of metabolism were linked to defects in sphingolipid degradation. The past two decades have seen an explosion of information linking sphingolipids with cellular processes. Studies have unraveled mechanistic details of the sphingolipid metabolic pathways, and these findings are being exploited in the development of novel therapies, some now in clinical trials. Pioneering work in yeast has laid the foundation for identifying genes encoding the enzymes of the pathways. The advent of the era of genomics and bioinformatics has led to the identification of homologous genes in other species and the subsequent creation of animal knock-out lines for these genes. Discoveries from these efforts have re-kindled interest in the role of sphingolipids in membrane biology. This review highlights some of the recent advances in understanding sphingolipids’ roles in membrane biology as determined from genetic models. PMID:18035569

Rao, Raghavendra Pralhada; Acharya, Jairaj K

2008-01-01

59

Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women  

PubMed Central

STUDY QUESTION Do genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry? SUMMARY ANSWER Many genetic variants influencing age at menarche in European populations appear to impact Chinese populations in a similar manner. WHAT IS KNOWN AND WHAT THIS PAPER ADDS Prior genome-wide association studies have uncovered 42 SNPs associated with age at menarche in European populations. This study is the first to demonstrate that many of the genetic determinants of age at menarche are shared between European and Chinese women. PARTICIPANTS AND SETTING We evaluated 37 of 42 SNPs identified as associated with age at menarche from a recent, large meta-analysis, consisting primarily of women of European ancestry, in a population of 6929 Chinese women from Shanghai, China. We also constructed weighted genetic risk scores (GRSs) combining the number of effect variants for all 37 SNPs, or only the SNPs associated with age at menarche among our study population, to evaluate their joint influence on age at menarche. MAIN RESULTS For 32 of the 37 evaluated variants, the direction of the allele associations were the same between women of European ancestry and women of Chinese ancestry (P = 3.71 × 10?6, binomial sign test); 9 of these were statistically significant. Subjects in the highest quintile of GRSs began menarche ?5 months later than those in the lowest quintile. BIAS, LIMITATIONS AND GENERALIZABILITY TO OTHER POPULATIONS Age at menarche was obtained by self-report, which can be subject to recall errors. The current analysis was restricted to loci which met or approached GWAS significance thresholds and did not evaluate loci which may act predominantly or exclusively in the Chinese population. The smaller sample size for our meta-analysis compared with meta-analyses conducted in European populations reduced the power to detect significant results. STUDY FUNDING/COMPETING INTERESTS This study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. There are no competing interests to declare. PMID:23406970

Delahanty, R.J.; Beeghly-Fadiel, A.; Long, J.R.; Gao, Y.T.; Lu, W.; Xiang, Y.B.; Zheng, Y.; Ji, B.T.; Wen, W.Q.; Cai, Q.Y.; Zheng, W.; Shu, X.O.

2013-01-01

60

INNER EAR EMBRYOGENESIS: GENETIC AND ENVIRONMENTAL DETERMINANTS  

EPA Science Inventory

The anatomy and developmental molecular genetics of the inner ear from establishment of the otic placode to formation of the definitive cochlea and vestibular apparatus will be reviewed and the complex 3-D structural changes that shape the developing inner ear will be illustrated...

61

Unique genetic loci identified for emotional behavior in control and chronic stress conditions  

PubMed Central

An individual's genetic background affects their emotional behavior and response to stress. Although studies have been conducted to identify genetic predictors for emotional behavior or stress response, it remains unknown how prior stress history alters the interaction between an individual's genome and their emotional behavior. Therefore, the purpose of this study is to identify chromosomal regions that affect emotional behavior and are sensitive to stress exposure. We utilized the BXD behavioral genetics mouse model to identify chromosomal regions that predict fear learning and emotional behavior following exposure to a control or chronic stress environment. 62 BXD recombinant inbred strains and C57BL/6 and DBA/2 parental strains underwent behavioral testing including a classical fear conditioning paradigm and the elevated plus maze. Distinct quantitative trait loci (QTLs) were identified for emotional learning, anxiety and locomotion in control and chronic stress populations. Candidate genes, including those with already known functions in learning and stress were found to reside within the identified QTLs. Our data suggest that chronic stress history reveals novel genetic predictors of emotional behavior. PMID:25374516

Carhuatanta, Kimberly A. K.; Shea, Chloe J. A.; Herman, James P.; Jankord, Ryan

2014-01-01

62

Deep sequencing identifies genetic heterogeneity and recurrent convergent evolution in chronic lymphocytic leukemia.  

PubMed

Recent high-throughput sequencing and microarray studies have characterized the genetic landscape and clonal complexity of chronic lymphocytic leukemia (CLL). Here, we performed a longitudinal study in a homogeneously treated cohort of 12 patients, with sequential samples obtained at comparable stages of disease. We identified clonal competition between 2 or more genetic subclones in 70% of the patients with relapse, and stable clonal dynamics in the remaining 30%. By deep sequencing, we identified a high reservoir of genetic heterogeneity in the form of several driver genes mutated in small subclones underlying the disease course. Furthermore, in 2 patients, we identified convergent evolution, characterized by the combination of genetic lesions affecting the same genes or copy number abnormality in different subclones. The phenomenon affects multiple CLL putative driver abnormalities, including mutations in NOTCH1, SF3B1, DDX3X, and del(11q23). This is the first report documenting convergent evolution as a recurrent event in the CLL genome. Furthermore, this finding suggests the selective advantage of specific combinations of genetic lesions for CLL pathogenesis in a subset of patients. PMID:25377784

Ojha, Juhi; Ayres, Jackline; Secreto, Charla; Tschumper, Renee; Rabe, Kari; Van Dyke, Daniel; Slager, Susan; Shanafelt, Tait; Fonseca, Rafael; Kay, Neil E; Braggio, Esteban

2015-01-15

63

Genetic risk factors for the development of allergic disease identified by genome-wide association.  

PubMed

An increasing proportion of the worldwide population is affected by allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and allergic asthma and improved treatment options are needed particularly for severe, refractory disease. Allergic diseases are complex and development involves both environmental and genetic factors. Although the existence of a genetic component for allergy was first described almost 100 years ago, progress in gene identification has been hindered by lack of high throughput technologies to investigate genetic variation in large numbers of subjects. The development of Genome-Wide Association Studies (GWAS), a hypothesis-free method of interrogating large numbers of common variants spanning the entire genome in disease and non-disease subjects has revolutionised our understanding of the genetics of allergic disease. Susceptibility genes for asthma, AR and AD have now been identified with confidence, suggesting there are common and distinct genetic loci associated with these diseases, providing novel insights into potential disease pathways and mechanisms. Genes involved in both adaptive and innate immune mechanisms have been identified, notably including multiple genes involved in epithelial function/secretion, suggesting that the airway epithelium may be particularly important in asthma. Interestingly, concordance/discordance between the genetic factors driving allergic traits such as IgE levels and disease states such as asthma have further supported the accumulating evidence for heterogeneity in these diseases. While GWAS have been useful and continue to identify novel genes for allergic diseases through increased sample sizes and phenotype refinement, future approaches will integrate analyses of rare variants, epigenetic mechanisms and eQTL approaches, leading to greater insight into the genetic basis of these diseases. Gene identification will improve our understanding of disease mechanisms and generate potential therapeutic opportunities. PMID:24766371

Portelli, M A; Hodge, E; Sayers, I

2015-01-01

64

Genetic risk factors for the development of allergic disease identified by genome-wide association  

PubMed Central

An increasing proportion of the worldwide population is affected by allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and allergic asthma and improved treatment options are needed particularly for severe, refractory disease. Allergic diseases are complex and development involves both environmental and genetic factors. Although the existence of a genetic component for allergy was first described almost 100 years ago, progress in gene identification has been hindered by lack of high throughput technologies to investigate genetic variation in large numbers of subjects. The development of Genome-Wide Association Studies (GWAS), a hypothesis-free method of interrogating large numbers of common variants spanning the entire genome in disease and non-disease subjects has revolutionised our understanding of the genetics of allergic disease. Susceptibility genes for asthma, AR and AD have now been identified with confidence, suggesting there are common and distinct genetic loci associated with these diseases, providing novel insights into potential disease pathways and mechanisms. Genes involved in both adaptive and innate immune mechanisms have been identified, notably including multiple genes involved in epithelial function/secretion, suggesting that the airway epithelium may be particularly important in asthma. Interestingly, concordance/discordance between the genetic factors driving allergic traits such as IgE levels and disease states such as asthma have further supported the accumulating evidence for heterogeneity in these diseases. While GWAS have been useful and continue to identify novel genes for allergic diseases through increased sample sizes and phenotype refinement, future approaches will integrate analyses of rare variants, epigenetic mechanisms and eQTL approaches, leading to greater insight into the genetic basis of these diseases. Gene identification will improve our understanding of disease mechanisms and generate potential therapeutic opportunities. PMID:24766371

Portelli, M A; Hodge, E; Sayers, I

2015-01-01

65

Masonic Cancer Center researchers identify genetic variation behind acute myeloid leukemia treatment success  

Cancer.gov

Researchers from the College of Pharmacy and Medical School working within the Masonic Cancer Center, University of Minnesota, have partnered to identify genetic variations that may help signal which acute myeloid leukemia (AML) patients will benefit or not benefit from one of the newest antileukemic agents.

66

Huntsman Cancer Institute scientists discover new method to identify cancer-causing rearrangements of genetic material  

Cancer.gov

Researchers from Huntsman Cancer Institute at the University of Utah report they have discovered a method to identify cancer-causing rearrangements of genetic material called chromosomal translocations quickly, accurately, and inexpensively. A description of the method and the research results appear online in this month's issue of the EMBO Molecular Medicine journal.

67

Metabolic and cardiovascular traits: an abundance of recently identified common genetic variants  

E-print Network

alleles and genes. INTRODUCTION Metabolic and cardiovascular diseases (CVD) are common, complex traitsMetabolic and cardiovascular traits: an abundance of recently identified common genetic variants have been strongly associated with meta- bolic and cardiovascular traits. Several of these loci have

Abecasis, Goncalo

68

Scientists Identify Genetic Cause of Previously Undefined Primary Immune Deficiency Disease  

Cancer.gov

NIH researchers have identified a genetic mutation that accounts for a perplexing condition found in people with an inherited immunodeficiency. The disorder, called combined immunodeficiency, is characterized by a constellation of severe health problems, including persistent bacterial and viral skin infections, severe eczema, acute allergies and asthma, and cancer.

69

USC study identifies genetic basis for aggressive breast cancer in women of African ancestry:  

Cancer.gov

Researchers at the Keck School of Medicine of USC, together with other scientists, have identified the location of a genetic risk factor for a type of breast cancer that disproportionately affects women of African descent and carries a worse prognosis than other forms of the disease.

70

Pooled Segregant Sequencing Reveals Genetic Determinants of Yeast Pseudohyphal Growth  

PubMed Central

The pseudohyphal growth response is a dramatic morphological transition and presumed foraging mechanism wherein yeast cells form invasive and surface-spread multicellular filaments. Pseudohyphal growth has been studied extensively as a model of conserved signaling pathways controlling stress responses, cell morphogenesis, and fungal virulence in pathogenic fungi. The genetic contribution to pseudohyphal growth is extensive, with at least 500 genes required for filamentation; as such, pseudohyphal growth is a complex trait, and linkage analysis is a classical means to dissect the genetic basis of a complex phenotype. Here, we implemented linkage analysis by crossing each of two filamentous strains of Saccharomyces cerevisiae (?1278b and SK1) with an S288C-derived non-filamentous strain. We then assayed meiotic progeny for filamentation and mapped allelic linkage in pooled segregants by whole-genome sequencing. This analysis identified linkage in a cohort of genes, including the negative regulator SFL1, which we find contains a premature stop codon in the invasive SK1 background. The S288C allele of the polarity gene PEA2, encoding Leu409 rather than Met, is linked with non-invasion. In ?1278b, the pea2-M409L mutation results in decreased invasive filamentation and elongation, diminished activity of a Kss1p MAPK pathway reporter, decreased unipolar budding, and diminished binding of the polarisome protein Spa2p. Variation between SK1 and S288C in the mitochondrial inner membrane protein Mdm32p at residues 182 and 262 impacts invasive growth and mitochondrial network structure. Collectively, this work identifies new determinants of pseudohyphal growth, while highlighting the coevolution of protein complexes and organelle structures within a given genome in specifying complex phenotypes. PMID:25144783

Song, Qingxuan; Johnson, Cole; Wilson, Thomas E.; Kumar, Anuj

2014-01-01

71

A genetic evaluation of morphology used to identify harvested Canada geese  

USGS Publications Warehouse

Using maximum likelihood estimators (in genetic stock identification), we used genetic markers to evaluate the utility of 2 morphological measures (culmen length and plumage color) to correctly identify groups of hunter-harvested dusky (Branta canadensis occidentalis) and dusky-like Canada geese on the wintering grounds within the Pacific Flyway. Significant levels of genetic differentiation were observed across all sampled breeding sites for both nuclear microsatellite loci and mtDNA when analyzed at the sequence level. The ability to discriminate among geese from these sites using genetic markers was further demonstrated using computer simulations. We estimated contributions from the Copper River Delta, the primary breeding area of dusky Canada geese, to groups of hunter-harvested geese classified as dusky Canada geese on the basis of morphology as 50.6 ?? 10.1(SE)% for females and 50.3 ?? 13.0% for males. We also estimated that 16 ?? 8.1% of females classified as dusky Canada geese on the basis of morphology originated from Middleton Island, Alaska; a locale currently managed as a subpopulation of dusky Canada geese, even though the majority of geese from this area possess a unique mtdna haplotype not found on the Copper River Delta. The use of culmen length and plumage color to identify the origin of breeding populations in the harvest provides conservative criteria for management of dusky Canada geese as individuals of other breeding populations are misassigned as dusky Canada geese and birds of the lighter-plumaged dusky-like group did not appear to originate from, breeding sites of the dusky Canada goose. Our analyses demonstrate that genetic markers can accurately estimate the proportion of genetically differentiated areas that comprise an admixed group, but they also raise questions about the management scale of Pacific Flyway Canada geese (e.g., at the subspecies or breeding population level) and the use of morphological and genetic characteristics to monitor the harvest of different populations within admixed wintering flocks.

Pearce, J.M.; Pierson, B. J.; Talbot, S.L.; Derksen, D.V.; Kraege, Donald K.; Scribner, K.T.

2000-01-01

72

Radiogenomics: Using Genetics to Identify Cancer Patients at Risk for Development of Adverse Effects Following Radiotherapy  

PubMed Central

Normal tissue adverse effects following radiotherapy are common and significantly affect quality of life. These effects cannot be accounted for by dosimetric, treatment or demographic factors alone, and evidence suggests that common genetic variants are associated with radiotherapy adverse effects. The field of radiogenomics has evolved to identify such genetic risk factors. Radiogenomics has two goals: 1) develop an assay to predict which cancer patients are most likely to develop radiation injuries resulting from radiotherapy, and 2) obtain information about the molecular pathways responsible for radiation-induced normal tissue toxicities. This review summarizes the history of the field and current research. PMID:24441285

Kerns, Sarah L; Ostrer, Harry; Rosenstein, Barry S

2013-01-01

73

Unique among unique. Is it genetically determined?  

PubMed

The cross-country world championship is one of the best models to study characteristics needed to achieve top-level endurance athletic capacity. We report the genotype combination of a recent cross-country champion (12 km race) in polymorphisms of seven genes that are candidates to influence endurance phenotype traits (ACTN3, ACE, PPARGC1A, AMPD1, CKMM, GDF8 (myostatin) and HFE). His data were compared with those of eight other runners (world-class but not world champions). The only athlete with the genotype theoretically more suited to attaining world-class endurance running performance was the case study subject. A favourable genetic endowment, together with exceptional environmental factors (years of altitude living and training in this case), seems to be necessary to attain the highest possible level of running endurance performance. PMID:18662936

Gonzalez-Freire, M; Santiago, C; Verde, Z; Lao, J I; Oiivan, J; Gómez-Gallego, F; Lucia, A

2009-04-01

74

DETERMINING GENETIC DIVERSITY AMONG LINES OF VIGNA UNGUICULATA SUBSPECIES BY AFLP AND SSR MARKERS  

Technology Transfer Automated Retrieval System (TEKTRAN)

AFLP and SSR markers were utilized to determine the genetic diversity among Vigna unguiculata subspecies. The three AFLP primer sets and the 10 SSR primer sets successfully identified very closely related accessions and a lack of homogeneity in some accessions. The AFLP methodology was successful f...

75

Tilapia sex determination: Where temperature and genetics meet  

Microsoft Academic Search

This review deals with the complex sex determining system of Nile tilapia, Oreochromis niloticus, governed by the interactions between a genetic determination and the influence of temperature, shown in both domestic and wild populations. Naturally sex reversed individuals are strongly suggested in two wild populations. This can be due to the masculinising temperatures which some fry encounter during their sex

J. F. Baroiller; H. D'Cotta; E. Bezault; S. Wessels; G. Hoerstgen-Schwark

2009-01-01

76

Identifying dynamical modules from genetic regulatory systems: applications to the segment polarity network  

PubMed Central

Background It is widely accepted that genetic regulatory systems are 'modular', in that the whole system is made up of smaller 'subsystems' corresponding to specific biological functions. Most attempts to identify modules in genetic regulatory systems have relied on the topology of the underlying network. However, it is the temporal activity (dynamics) of genes and proteins that corresponds to biological functions, and hence it is dynamics that we focus on here for identifying subsystems. Results Using Boolean network models as an exemplar, we present a new technique to identify subsystems, based on their dynamical properties. The main part of the method depends only on the stable dynamics (attractors) of the system, thus requiring no prior knowledge of the underlying network. However, knowledge of the logical relationships between the network components can be used to describe how each subsystem is regulated. To demonstrate its applicability to genetic regulatory systems, we apply the method to a model of the Drosophila segment polarity network, providing a detailed breakdown of the system. Conclusion We have designed a technique for decomposing any set of discrete-state, discrete-time attractors into subsystems. Having a suitable mathematical model also allows us to describe how each subsystem is regulated and how robust each subsystem is against perturbations. However, since the subsystems are found directly from the attractors, a mathematical model or underlying network topology is not necessarily required to identify them, potentially allowing the method to be applied directly to experimental expression data. PMID:17961242

Irons, David J; Monk, Nicholas AM

2007-01-01

77

Genetic Determinants of Pubertal Timing in the General Population  

PubMed Central

Puberty is an important developmental stage during which reproductive capacity is attained. The timing of puberty varies greatly among healthy individuals in the general population and is influenced by both genetic and environmental factors. Although genetic variation is known to influence the normal spectrum of pubertal timing, the specific genes involved remain largely unknown. Genetic analyses have identified a number of genes responsible for rare disorders of pubertal timing such as hypogonadotropic hypogonadism and Kallmann syndrome. Recently, the first loci with common variation reproducibly associated with population variation in the timing of puberty were identified at 6q21 in or near LIN28B and at 9q31.2. However, these two loci explain only a small fraction of the genetic contribution to population variation in pubertal timing, suggesting the need to continue to consider other loci and other types of variants. Here we provide an update of the genes implicated in disorders of puberty, discuss genes and pathways that may be involved in the timing of normal puberty, and suggest additional avenues of investigation to identify genetic regulators of puberty in the general population. PMID:20144687

Gajdos, Zofia K.Z.; Henderson, Katherine D.; Hirschhorn, Joel N.

2010-01-01

78

A Classifier-based approach to identify genetic similarities between diseases  

PubMed Central

Motivation: Genome-wide association studies are commonly used to identify possible associations between genetic variations and diseases. These studies mainly focus on identifying individual single nucleotide polymorphisms (SNPs) potentially linked with one disease of interest. In this work, we introduce a novel methodology that identifies similarities between diseases using information from a large number of SNPs. We separate the diseases for which we have individual genotype data into one reference disease and several query diseases. We train a classifier that distinguishes between individuals that have the reference disease and a set of control individuals. This classifier is then used to classify the individuals that have the query diseases. We can then rank query diseases according to the average classification of the individuals in each disease set, and identify which of the query diseases are more similar to the reference disease. We repeat these classification and comparison steps so that each disease is used once as reference disease. Results: We apply this approach using a decision tree classifier to the genotype data of seven common diseases and two shared control sets provided by the Wellcome Trust Case Control Consortium. We show that this approach identifies the known genetic similarity between type 1 diabetes and rheumatoid arthritis, and identifies a new putative similarity between bipolar disease and hypertension. Contact: serafim@cs.stanford.edu PMID:19477990

Schaub, Marc A.; Kaplow, Irene M.; Sirota, Marina; Do, Chuong B.; Butte, Atul J.; Batzoglou, Serafim

2009-01-01

79

New de novo genetic mutations in schizophrenia identified -Mental Wellness Today http://www.mentalwellnesstoday.com/...hizophrenia/schizophrenia-articles/16-shizophrenia-research/194-new-de-novo-genetic-mutations-in-schizophrenia-identified[10/10/2012 4:3  

E-print Network

New de novo genetic mutations in schizophrenia identified - Mental Wellness Today http://www.mentalwellnesstoday.com/...hizophrenia/schizophrenia-articles/16-shizophrenia-research/194-new-de-novo-genetic-mutations-in-schizophrenia-identified[10/10/2012 4 Articles Heart attack more likely in those with schizophrenia: Study Faith Can Help Mental Health Outcomes

80

Genetic Determinants of Responses to Selenium Supplementation  

Technology Transfer Automated Retrieval System (TEKTRAN)

In a cohort of healthy adults (106 M, 155 W) in eastern North Dakota, we determined the relationships of five biomarkers of selenium (Se) status (plasma Se, serum selenoprotein P [SePP], plasma glutathione peroxidase [GPX3] activity, buccal cell Se, urine Se) to genotype for four selenoproteins (cyt...

81

Regional Heritability Mapping to identify loci underlying genetic variation of complex traits  

PubMed Central

Background Genome-wide association studies can have limited power to identify QTL, partly due to the stringent correction for multiple testing and low linkage-disequilibrium between SNPs and QTL. Regional Heritability Mapping (RHM) has been advanced as an alternative approach to capture underlying genetic effects. In this study, RHM was used to identify loci underlying variation in the 16th QTLMAS workshop simulated traits. Methods The method was implemented by fitting a mixed model where a genomic region and the overall genetic background were added as random effects. Heritabilities for the genetic regional effects were estimated, and the presence of a QTL in the region was tested using a likelihood ratio test (LRT). Several region sizes were considered (100, 50 and 20 adjacent SNPs). Bonferroni correction was used to calculate the LRT thresholds for genome-wide (p < 0.05) and suggestive (i.e., one false positive per genome scan) significance. Results Genomic heritabilities (0.31, 0.32 and 0.48, respectively) and genetic correlations (0.80, -0.42 and 0.19, between trait-pairs 1&2, 1&3 and 2&3) were similar to the simulated ones. RHM identified 7 QTL (4 at genome-wide and 3 at suggestive level) for Trait1; 4 (2 genome-wide and 2 suggestive) for Trait2; and 7 (6 genome-wide and 1 suggestive) for Trait3. Only one of the identified suggestive QTL was a false-positive. The position of these QTL tended to coincide with the position where the largest QTL (or several of them) were simulated. Several signals were detected for the simulated QTL with smaller effect. A combined analysis including all significant regions showed that they explain more than half of the total genetic variance of the traits. However, this might be overestimated, due to Beavis effect. All QTL affecting traits 1&2 and 2&3 had positive correlations, following the trend of the overall correlation of both trait-pairs. All but one QTL affecting traits 1&3 were negatively correlated, in agreement with the simulated situation. Moreover, RHM identified extra loci that were not found by association and linkage analysis, highlighting the improved power of this approach. Conclusions RHM identified the largest QTL among the simulated ones, with some signals for the ones with small effect. Moreover, RHM performed better than association and linkage analysis, in terms of both power and resolution. PMID:25519517

2014-01-01

82

Competitive Metagenomic DNA Hybridization Identifies Host-Specific Microbial Genetic Markers in Cow Fecal Samples†  

PubMed Central

Several PCR methods have recently been developed to identify fecal contamination in surface waters. In all cases, researchers have relied on one gene or one microorganism for selection of host-specific markers. Here we describe the application of a genome fragment enrichment (GFE) method to identify host-specific genetic markers from fecal microbial community DNA. As a proof of concept, bovine fecal DNA was challenged against a porcine fecal DNA background to select for bovine-specific DNA sequences. Bioinformatic analyses of 380 bovine enriched metagenomic sequences indicated a preponderance of Bacteroidales-like regions predicted to encode membrane-associated and secreted proteins. Oligonucleotide primers capable of annealing to select Bacteroidales-like bovine GFE sequences exhibited extremely high specificity (>99%) in PCR assays with total fecal DNAs from 279 different animal sources. These primers also demonstrated a broad distribution of corresponding genetic markers (81% positive) among 148 different bovine sources. These data demonstrate that direct metagenomic DNA analysis by the competitive solution hybridization approach described is an efficient method for identifying potentially useful fecal genetic markers and for characterizing differences between environmental microbial communities. PMID:16751515

Shanks, Orin C.; Santo Domingo, Jorge W.; Lamendella, Regina; Kelty, Catherine A.; Graham, James E.

2006-01-01

83

Parallel Genetic and Proteomic Screens Identify Msps as a CLASP–Abl Pathway Interactor in Drosophila  

PubMed Central

Regulation of cytoskeletal structure and dynamics is essential for multiple aspects of cellular behavior, yet there is much to learn about the molecular machinery underlying the coordination between the cytoskeleton and its effector systems. One group of proteins that regulate microtubule behavior and its interaction with other cellular components, such as actin-regulatory proteins and transport machinery, is the plus-end tracking proteins (MT+TIPs). In particular, evidence suggests that the MT+TIP, CLASP, may play a pivotal role in the coordination of microtubules with other cellular structures in multiple contexts, although the molecular mechanism by which it functions is still largely unknown. To gain deeper insight into the functional partners of CLASP, we conducted parallel genetic and proteome-wide screens for CLASP interactors in Drosophila melanogaster. We identified 36 genetic modifiers and 179 candidate physical interactors, including 13 that were identified in both data sets. Grouping interactors according to functional classifications revealed several categories, including cytoskeletal components, signaling proteins, and translation/RNA regulators. We focused our initial investigation on the MT+TIP Minispindles (Msps), identified among the cytoskeletal effectors in both genetic and proteomic screens. Here, we report that Msps is a strong modifier of CLASP and Abl in the retina. Moreover, we show that Msps functions during axon guidance and antagonizes both CLASP and Abl activity. Our data suggest a model in which CLASP and Msps converge in an antagonistic balance in the Abl signaling pathway. PMID:20498300

Lowery, L. A.; Lee, H.; Lu, C.; Murphy, R.; Obar, R. A.; Zhai, B.; Schedl, M.; Van Vactor, D.; Zhan, Y.

2010-01-01

84

Positive genetic interactors of HMG2 identify a new set of genetic perturbations for improving sesquiterpene production in Saccharomyces cerevisiae  

PubMed Central

Background Terpenoids and isoprenoids are an important class of natural products, which includes currently used drugs, high value bioactive and industrial compounds, and fuel candidates. Due to their industrial application, there is increasing interest in the development of S. cerevisiae strains capable of producing high levels of terpenoids. Results Aiming to identify new gene targets which can be manipulated to increase sesquiterpene production, a set of HMG2 positive genetic interactors were assessed as single and digenic heterozygous deletions in the presence or absence of stable HMG2(K6R) overexpression. Upon single allele deletion, most genes examined led to increased sesquiterpene production in yeast cells. Tandem heterozygous deletion of a set of three genes, the ubiquitin ligases ubc7 and ssm4/doa10, and the ER resident protein pho86, led to an 11-fold increase in caryophyllene yields (125 mg/L in shake flasks) compared to cells lacking these modifications. The effect of the heterozygous deletions appears to be due to Hmg1p and Hmg2p stabilization. Conclusion Heterozygous deletions cause significant reductions in protein levels but do not lead to growth impediments frequently seen in haploid strains. By exploiting desirable haploinsufficiencies in yeast, we identified a new set of genes that can be disrupted in tandem and cause significant stabilization of Hmgp and a substantial increase in sesquiterpene production. The approach presented here allows new genetic perturbations to be compiled on yeast cell factory strains without negatively impacting cell growth and viability. PMID:23259547

2012-01-01

85

Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and genetic pathways driving tumorigenesis  

PubMed Central

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas of Schwann cell-lineage origin that occur sporadically or in association with the inherited syndrome, Neurofibromatosis Type 1. To identify genetic drivers of MPNST development, we utilized the Sleeping Beauty (SB) transposon-based somatic mutagenesis system in mice with somatic loss of tumor protein p53 (Trp53) function and/or overexpression of epidermal growth factor receptor (EGFR). Common insertion site (CIS) analysis of 269 neurofibromas and 106 MPNSTs identified 695 and 87 sites with a statistically significant number of recurrent transposon insertions, respectively. Comparison to human data sets revealed novel and known driver genes for MPNST formation at these sites. Pairwise co-occurrence analysis of CIS-associated genes identified many cooperating mutations that are enriched for in Wnt/CTNNB1, PI3K/Akt/mTor, and growth factor receptor signaling pathways. Lastly, we identified several novel proto-oncogenes including forkhead box R2 (Foxr2), which we functionally validated as a proto-oncogene involved in MPNST maintenance. PMID:23685747

Rahrmann, Eric P; Watson, Adrienne L; Keng, Vincent W; Choi, Kwangmin; Moriarity, Branden S; Beckmann, Dominic A; Wolf, Natalie; Sarver, Aaron; Collins, Margaret H; Moertel, Christopher L; Wallace, Margaret R; Gel, Bernat; Serra, Eduard; Ratner, Nancy; Largaespada, David A

2013-01-01

86

Linkage Mapping Identifies the Sex Determining Region as a Single Locus in the Pennate Diatom Seminavis robusta  

PubMed Central

The pennate diatom Seminavis robusta, characterized by an archetypical diatom life cycle including a heterothallic mating system, is emerging as a model system for studying the molecular regulation of the diatom cell and life cycle. One of its main advantages compared with other diatom model systems is that sexual crosses can be made routinely, offering unprecedented possibilities for forward genetics. To date, nothing is known about the genetic basis of sex determination in diatoms. Here, we report on the construction of mating type-specific linkage maps for S. robusta, and use them to identify a single locus sex determination system in this diatom. We identified 13 mating type plus and 15 mating type minus linkage groups obtained from the analysis of 463 AFLP markers segregating in a full-sib family, covering 963.7 and 972.2 cM, respectively. Five linkage group pairs could be identified as putative homologues. The mating type phenotype mapped as a monogenic trait, disclosing the mating type plus as the heterogametic sex. This study provides the first evidence for a genetic sex determining mechanism in a diatom. PMID:23527302

Vanstechelman, Ives; Sabbe, Koen; Vyverman, Wim; Vanormelingen, Pieter; Vuylsteke, Marnik

2013-01-01

87

A cellular genetics approach identifies gene-drug interactions and pinpoints drug toxicity pathway nodes  

PubMed Central

New approaches to toxicity testing have incorporated high-throughput screening across a broad-range of in vitro assays to identify potential key events in response to chemical or drug treatment. To date, these approaches have primarily utilized repurposed drug discovery assays. In this study, we describe an approach that combines in vitro screening with genetic approaches for the experimental identification of genes and pathways involved in chemical or drug toxicity. Primary embryonic fibroblasts isolated from 32 genetically-characterized inbred mouse strains were treated in concentration-response format with 65 compounds, including pharmaceutical drugs, environmental chemicals, and compounds with known modes-of-action. Integrated cellular responses were measured at 24 and 72 h using high-content imaging and included cell loss, membrane permeability, mitochondrial function, and apoptosis. Genetic association analysis of cross-strain differences in the cellular responses resulted in a collection of candidate loci potentially underlying the variable strain response to each chemical. As a demonstration of the approach, one candidate gene involved in rotenone sensitivity, Cybb, was experimentally validated in vitro and in vivo. Pathway analysis on the combined list of candidate loci across all chemicals identified a number of over-connected nodes that may serve as core regulatory points in toxicity pathways. PMID:25221565

Suzuki, Oscar T.; Frick, Amber; Parks, Bethany B.; Trask, O. Joseph; Butz, Natasha; Steffy, Brian; Chan, Emmanuel; Scoville, David K.; Healy, Eric; Benton, Cristina; McQuaid, Patricia E.; Thomas, Russell S.; Wiltshire, Tim

2014-01-01

88

INTRODUCTION Fragile X syndrome (FXS), the most common genetic determinant  

E-print Network

INTRODUCTION Fragile X syndrome (FXS), the most common genetic determinant of cognitive impairment disability, among other behavioral impairments (Einfeld et al., 1991; Elia et al., 2000; Hagerman et al This is an Open Access article distributed under the terms of the Creative Commons Attribution Non

Broadie, Kendal S.

89

Genetic and Environmental Determinants of Bitter Perception and Sweet Preferences  

Microsoft Academic Search

ABSTRACT. Objective. Flavor is the primary dimen- sion by which young children determine food accep- tance. However, children are not merely miniature adults because sensory systems mature postnatally and their responses to certain tastes differ markedly from adults. Among these differences are heightened preferences for sweet-tasting and greater rejection of bitter-tasting foods. The present study tests the hypothesis that genetic

Julie A. Mennella; M. Yanina Pepino; Danielle R. Reed

90

ORIGINAL RESEARCH Genetic determinants of swimming motility in the squid  

E-print Network

ORIGINAL RESEARCH Genetic determinants of swimming motility in the squid light-organ symbiont for the colo- nization of the light-emitting organ of the Hawaiian bobtail squid, Euprymna scolopes are able to colonize a subset of juvenile squid to light-producing levels. Thirty-three genes required

McFall-Ngai, Margaret

91

Disease Risk Factors Identified through Shared Genetic Architecture and Electronic Medical Records  

PubMed Central

Genome-Wide Association Studies (GWAS) have identified genetic variants for thousands of diseases and traits. In this study, we evaluated the relationships between specific risk factors (for example, blood cholesterol level) and diseases on the basis of their shared genetic architecture in a comprehensive human disease-SNP association database (VARIMED), analyzing the findings from 8,962 published association studies. Similarity between traits and diseases was statistically evaluated based on their association with shared gene variants. We identified 120 disease-trait pairs that were statistically similar, and of these we tested and validated five previously unknown disease-trait associations by searching electronic medical records (EMR) from 3 independent medical centers for evidence of the trait appearing in patients within one year of first diagnosis of the disease. We validated that mean corpuscular volume is elevated before diagnosis of acute lymphoblastic leukemia; both have associated variants in the gene IKZF1. Platelet count is decreased before diagnosis of alcohol dependence; both are associated with variants in the gene C12orf51. Alkaline phosphatase level is elevated in patients with venous thromboembolism; both share variants in ABO. Similarly, we found prostate specific antigen and serum magnesium levels were altered before the diagnosis of lung cancer and gastric cancer, respectively. Disease-trait associations identifies traits that can potentially serve a prognostic function clinically; validating disease-trait associations through EMR can whether these candidates are risk factors for complex diseases. PMID:24786325

Li, Li; Ruau, David J.; Patel, Chirag J.; Weber, Susan C.; Chen, Rong; Tatonetti, Nicholas P.; Dudley, Joel T.; Butte, Atul J.

2015-01-01

92

A Genetic Screening Strategy Identifies Novel Regulators of the Proteostasis Network  

PubMed Central

A hallmark of diseases of protein conformation and aging is the appearance of protein aggregates associated with cellular toxicity. We posit that the functional properties of the proteostasis network (PN) protect the proteome from misfolding and combat the proteotoxic events leading to cellular pathology. In this study, we have identified new components of the proteostasis network that can suppress aggregation and proteotoxicity, by performing RNA interference (RNAi) genetic screens for multiple unrelated conformationally challenged cytoplasmic proteins expressed in Caenorhabditis elegans. We identified 88 suppressors of polyglutamine (polyQ) aggregation, of which 63 modifiers also suppressed aggregation of mutant SOD1G93A. Of these, only 23 gene-modifiers suppressed aggregation and restored animal motility, revealing that aggregation and toxicity can be genetically uncoupled. Nine of these modifiers were shown to be effective in restoring the folding and function of multiple endogenous temperature-sensitive (TS) mutant proteins, of which five improved folding in a HSF-1–dependent manner, by inducing cytoplasmic chaperones. This triage screening strategy also identified a novel set of PN regulatory components that, by altering metabolic and RNA processing functions, establish alternate cellular environments not generally dependent on stress response activation and that are broadly protective against misfolded and aggregation-prone proteins. PMID:22242008

Silva, M. Catarina; Fox, Susan; Beam, Monica; Thakkar, Happy; Amaral, Margarida D.; Morimoto, Richard I.

2011-01-01

93

A screening method to identify genetic variation in root growth response to a salinity gradient.  

PubMed

Salinity as well as drought are increasing problems in agriculture. Durum wheat (Triticum turgidum L. ssp. durum Desf.) is relatively salt sensitive compared with bread wheat (Triticum aestivum L.), and yields poorly on saline soil. Field studies indicate that roots of durum wheat do not proliferate as extensively as bread wheat in saline soil. In order to look for genetic diversity in root growth within durum wheat, a screening method was developed to identify genetic variation in rates of root growth in a saline solution gradient similar to that found in many saline fields. Seedlings were grown in rolls of germination paper in plastic tubes 37 cm tall, with a gradient of salt concentration increasing towards the bottom of the tubes which contained from 50-200 mM NaCl with complete nutrients. Seedlings were grown in the light to the two leaf stage, and transpiration and evaporation were minimized so that the salinity gradient was maintained. An NaCl concentration of 150 mM at the bottom was found suitable to identify genetic variation. This corresponds to a level of salinity in the field that reduces shoot growth by 50% or more. The screen inhibited seminal axile root length more than branch root length in three out of four genotypes, highlighting changes in root system architecture caused by a saline gradient that is genotype dependent. This method can be extended to other species to identify variation in root elongation in response to gradients in salt, nutrients, or toxic elements. PMID:21118825

Rahnama, Afrasyab; Munns, Rana; Poustini, Kazem; Watt, Michelle

2011-01-01

94

IndividualizedPath: identifying genetic alterations contributing to the dysfunctional pathways in glioblastoma individuals.  

PubMed

Due to the extensive complexity and high genetic heterogeneity of genetic alterations in cancer, comprehensively depicting the molecular mechanisms of cancer remains difficult. Characterizing personalized pathogenesis in cancer individuals can help to reveal new details of the complex mechanisms. In this study, we proposed an integrative method called IndividualizedPath to identify genetic alterations and their downstream risk pathways from the perspective of individuals through combining the DNA copy number, gene expression data and topological structures of biological pathways. By applying the method to TCGA glioblastoma multiforme (GBM) samples, we identified 394 gene-pathway pairs in 252 GBM individuals. We found that genes with copy number alterations showed high heterogeneity across GBM individuals, whereas they affected relatively consistent biological pathways. A global landscape of gene-pathway pairs showed that EGFR linked with multiple cancer-related biological pathways confers the highest risk of GBM. GBM individuals with MET-pathway pairs showed significantly shorter survival times than those with only MET amplification. Importantly, we found that the same risk pathways were affected by different genes in distinct groups of GBM individuals with a significant pattern of mutual exclusivity. Similarly, GBM subtype analysis revealed some subtype-specific gene-pathway pairs. In addition, we found that some rare copy number alterations had a large effect on contribution to numerous cancer-related pathways. In summary, our method offers the possibility to identify personalized cancer mechanisms, which can be applied to other types of cancer through the web server (http://bioinfo.hrbmu.edu.cn/IndividualizedPath/). PMID:24911613

Ping, Yanyan; Zhang, Hongyi; Deng, Yulan; Wang, Li; Zhao, Hongying; Pang, Lin; Fan, Huihui; Xu, Chaohan; Li, Feng; Zhang, Yong; Gong, Yonghui; Xiao, Yun; Li, Xia

2014-08-01

95

Genome-wide screen for modifiers of Na + /K + ATPase alleles identifies critical genetic loci.  

PubMed

BackgroundMutations affecting the Na + / K + ATPase (a.k.a. the sodium-potassium pump) genes cause conditional locomotor phenotypes in flies and three distinct complex neurological diseases in humans. More than 50 mutations have been identified affecting the human ATP1A2 and ATP1A3 genes that are known to cause rapid-onset Dystonia Parkinsonism, familial hemiplegic migraine, alternating hemiplegia of childhood, and variants of familial hemiplegic migraine with neurological complications including seizures and various mood disorders. In flies, mutations affecting the ATPalpha gene have dramatic phenotypes including altered longevity, neural dysfunction, neurodegeneration, myodegeneration, and striking locomotor impairment. Locomotor defects can manifest as conditional bang-sensitive (BS) or temperature-sensitive (TS) paralysis: phenotypes well-suited for genetic screening.ResultsWe performed a genome-wide deficiency screen using three distinct missense alleles of ATPalpha and conditional locomotor function assays to identify novel modifier loci. A secondary screen confirmed allele-specificity of the interactions and many of the interactions were mapped to single genes and subsequently validated. We successfully identified 64 modifier loci and used classical mutations and RNAi to confirm 50 single gene interactions. The genes identified include those with known function, several with unknown function or that were otherwise uncharacterized, and many loci with no described association with locomotor or Na+/ K+ ATPase function.ConclusionsWe used an unbiased genome-wide screen to find regions of the genome containing elements important for genetic modulation of ATPalpha dysfunction. We have identified many critical regions and narrowed several of these to single genes. These data demonstrate there are many loci capable of modifying ATPalpha dysfunction, which may provide the basis for modifying migraine, locomotor and seizure dysfunction in animals. PMID:25476251

Talsma, Aaron D; Chaves, John F; LaMonaca, Alexandra; Wieczorek, Emily D; Palladino, Michael J

2014-12-01

96

New genetic risk variants identified in multiethnic analysis of prostate cancer  

Cancer.gov

Researchers have newly identified 23 common genetic variants—one-letter changes in DNA known as single-nucleotide polymorphisms or SNPs—that are associated with risk of prostate cancer. These results come from an analysis of more than 10 million SNPs in data pooled from studies that included over 43,000 men with prostate cancer and nearly 44,000 men without the disease. Study participants were from Australia, Ghana, Japan, the United Kingdom, and the United States and were of diverse ancestry.

97

Identifying flavor preference subgroups. Genetic basis and related eating behavior traits.  

PubMed

Subgroups based on flavor preferences were identified and their genetic and behavior related characteristics investigated using extensive data from 331 Finnish twins (21-25years, 146 men) including 47 monozygotic (MZ) and 93 dizygotic (DZ) pairs, and 51 twin individuals. The subgroup identification (hierarchical and K-means clustering) was based on liking responses to food names representing sour, umami, and spicy flavor qualities. Furthermore, sensory tests were conducted, a questionnaire on food likes completed, and various eating behavior related traits measured with validated scales. Sensory data included intensity ratings of PROP (6-n-propylthiouracil-impregnated filter paper), hedonic and intensity responses to sourness (orange juice with and without added citric acid, 0.42%), pungency (strawberry jelly with and without added capsaicin 0.00013%) and umami ('mouthfeel flavor' taste solution). Ratings of liking of 41 general food names were categorized into salty-and-fatty, sweet-and-fatty, fruits and vegetables and fish foods. Subgroup differences (complex samples procedure) and the genetics underlying the subgroups (structural equation modeling) were investigated. Of the resulting two groups (basic, n=140, adventurous n=152; non-grouped n=39), the adventurous expressed higher liking for sour and spicy foods, and had more tolerance for capsaicin burn in the sensory-hedonic test. The adventurous were also less food neophobic (25.9±9.1 vs. 32.5±10.6, respectively) and expressed higher liking for fruits and vegetables compared to the basic group. Genetic effects were shown to underlie the subgroups (heritability 72%, CI: 36-92%). Linkage analysis for 27 candidate gene regions revealed suggestively that being adventurous is linked to TAS1R1 and PKD1L3 genes. These results indicate that food neophobia and genetic differences may form a barrier through which individual flavor preferences are generated. PMID:24361469

Törnwall, Outi; Silventoinen, Karri; Hiekkalinna, Tero; Perola, Markus; Tuorila, Hely; Kaprio, Jaakko

2014-04-01

98

Novel Genetic Loci Identified for the Pathophysiology of Childhood Obesity in the Hispanic Population  

PubMed Central

Genetic variants responsible for susceptibility to obesity and its comorbidities among Hispanic children have not been identified. The VIVA LA FAMILIA Study was designed to genetically map childhood obesity and associated biological processes in the Hispanic population. A genome-wide association study (GWAS) entailed genotyping 1.1 million single nucleotide polymorphisms (SNPs) using the Illumina Infinium technology in 815 children. Measured genotype analysis was performed between genetic markers and obesity-related traits i.e., anthropometry, body composition, growth, metabolites, hormones, inflammation, diet, energy expenditure, substrate utilization and physical activity. Identified genome-wide significant loci: 1) corroborated genes implicated in other studies (MTNR1B, ZNF259/APOA5, XPA/FOXE1 (TTF-2), DARC, CCR3, ABO); 2) localized novel genes in plausible biological pathways (PCSK2, ARHGAP11A, CHRNA3); and 3) revealed novel genes with unknown function in obesity pathogenesis (MATK, COL4A1). Salient findings include a nonsynonymous SNP (rs1056513) in INADL (p?=?1.2E-07) for weight; an intronic variant in MTNR1B associated with fasting glucose (p?=?3.7E-08); variants in the APOA5-ZNF259 region associated with triglycerides (p?=?2.5-4.8E-08); an intronic variant in PCSK2 associated with total antioxidants (p?=?7.6E-08); a block of 23 SNPs in XPA/FOXE1 (TTF-2) associated with serum TSH (p?=?5.5E-08 to 1.0E-09); a nonsynonymous SNP (p?=?1.3E-21), an intronic SNP (p?=?3.6E-13) in DARC identified for MCP-1; an intronic variant in ARHGAP11A associated with sleep duration (p?=?5.0E-08); and, after adjusting for body weight, variants in MATK for total energy expenditure (p?=?2.7E-08) and in CHRNA3 for sleeping energy expenditure (p?=?6.0E-08). Unprecedented phenotyping and high-density SNP genotyping enabled localization of novel genetic loci associated with the pathophysiology of childhood obesity. PMID:23251661

Comuzzie, Anthony G.; Cole, Shelley A.; Laston, Sandra L.; Voruganti, V. Saroja; Haack, Karin; Gibbs, Richard A.; Butte, Nancy F.

2012-01-01

99

Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population.  

PubMed

Genetic variants responsible for susceptibility to obesity and its comorbidities among Hispanic children have not been identified. The VIVA LA FAMILIA Study was designed to genetically map childhood obesity and associated biological processes in the Hispanic population. A genome-wide association study (GWAS) entailed genotyping 1.1 million single nucleotide polymorphisms (SNPs) using the Illumina Infinium technology in 815 children. Measured genotype analysis was performed between genetic markers and obesity-related traits i.e., anthropometry, body composition, growth, metabolites, hormones, inflammation, diet, energy expenditure, substrate utilization and physical activity. Identified genome-wide significant loci: 1) corroborated genes implicated in other studies (MTNR1B, ZNF259/APOA5, XPA/FOXE1 (TTF-2), DARC, CCR3, ABO); 2) localized novel genes in plausible biological pathways (PCSK2, ARHGAP11A, CHRNA3); and 3) revealed novel genes with unknown function in obesity pathogenesis (MATK, COL4A1). Salient findings include a nonsynonymous SNP (rs1056513) in INADL (p = 1.2E-07) for weight; an intronic variant in MTNR1B associated with fasting glucose (p = 3.7E-08); variants in the APOA5-ZNF259 region associated with triglycerides (p = 2.5-4.8E-08); an intronic variant in PCSK2 associated with total antioxidants (p = 7.6E-08); a block of 23 SNPs in XPA/FOXE1 (TTF-2) associated with serum TSH (p = 5.5E-08 to 1.0E-09); a nonsynonymous SNP (p = 1.3E-21), an intronic SNP (p = 3.6E-13) in DARC identified for MCP-1; an intronic variant in ARHGAP11A associated with sleep duration (p = 5.0E-08); and, after adjusting for body weight, variants in MATK for total energy expenditure (p = 2.7E-08) and in CHRNA3 for sleeping energy expenditure (p = 6.0E-08). Unprecedented phenotyping and high-density SNP genotyping enabled localization of novel genetic loci associated with the pathophysiology of childhood obesity. PMID:23251661

Comuzzie, Anthony G; Cole, Shelley A; Laston, Sandra L; Voruganti, V Saroja; Haack, Karin; Gibbs, Richard A; Butte, Nancy F

2012-01-01

100

A genetic approach for the identification of exosporium assembly determinants of Bacillus anthracis  

PubMed Central

The exosporium is the outermost layer of spores of the zoonotic pathogen Bacillus anthracis. The composition of the exosporium and its functions are only partly understood. Because this outer spore layer is refractive to traditional biochemical analysis, a genetic approach is needed in order to define the proteins which comprise this important spore layer and its assembly pathway. We have created a novel genetic screening system for the identification and isolation of mutants with defects in exosporium assembly during B. anthracis spore maturation. The system is based on the targeting sequence of the BclA exosporium nap layer glycoprotein and a fluorescent reporter. By utilizing this screening system and gene inactivation with Tn916, several novel putative exosporium-associated determinants were identified. A sampling of the mutants obtained was further characterized, confirming their exosporium defect and validating the utility of this screen to identify novel spore determinants in the genome of this pathogen. PMID:23411372

Spreng, Krista A.; Thompson, Brian M.; Stewart, George C.

2013-01-01

101

Genetic determinants of disease progression in Alzheimer’s disease  

PubMed Central

There is a strong genetic basis for late-onset of Alzheimer’s disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer’s Disease Research Center. Patients were classified as “rapid progressors” if the MMSE changed ?3 points in 12 months and “slow progressors” if the MMSE changed ?2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between SNPs and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p=0.94) or APOE*2 (p=0.33) with AD progression, we found multiple nominally significant associations (p<0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2 and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ and ADAM19) at p<1E-05. Our data suggest that short-term clinical disease progression in AD has genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies. PMID:25114068

Wang, Xingbin; Lopez, Oscar L.; Sweet, Robert A.; Becker, James .T; DeKosky, Steven T.; Barmada, Mahmud M.; Demirci, F. Yesim; Kamboh, M. Ilyas.

2014-01-01

102

Genetic determinants of disease progression in Alzheimer's disease.  

PubMed

There is a strong genetic basis for late-onset Alzheimer's disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer's Disease Research Center. Patients were classified as "rapid progressors" if the Mini-Mental State Examination (MMSE) changed ?3 points in 12 months and "slow progressors" if the MMSE changed ?2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between single nucleotide polymorphisms (SNPs) and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p = 0.94) or APOE*2 (p = 0.33) with AD progression, we found multiple nominally significant associations (p < 0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2, and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ, and ADAM19) at p < 1E-05. Our data suggest that short-term clinical disease progression in AD has a genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies. PMID:25114068

Wang, Xingbin; Lopez, Oscar L; Sweet, Robert A; Becker, James T; DeKosky, Steven T; Barmada, Mahmud M; Demirci, F Yesim; Kamboh, M Ilyas

2015-01-01

103

5?RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy  

PubMed Central

The transcriptome is subject to multiple changes during pathogenesis, including the use of alternate 5? start-sites that can affect transcription levels and output. Current RNA sequencing techniques can assess mRNA levels, but do not robustly detect changes in 5? start-site use. Here, we developed a transcriptome sequencing strategy that detects genome-wide changes in start-site usage (5?RNA-Seq) and applied this methodology to identify regulatory events that occur in hypertrophic cardiomyopathy (HCM). Compared with transcripts from WT mice, 92 genes had altered start-site usage in a mouse model of HCM, including four-and-a-half LIM domains protein 1 (Fhl1). HCM-induced altered transcriptional regulation of Fhl1 resulted in robust myocyte expression of a distinct protein isoform, a response that was conserved in humans with genetic or acquired cardiomyopathies. Genetic ablation of Fhl1 in HCM mice was deleterious, which suggests that Fhl1 transcriptional changes provide salutary effects on stressed myocytes in this disease. Because Fhl1 is a chromosome X–encoded gene, stress-induced changes in its transcription may contribute to gender differences in the clinical severity of HCM. Our findings indicate that 5?RNA-Seq has the potential to identify genome-wide changes in 5? start-site usage that are associated with pathogenic phenotypes. PMID:24509080

Christodoulou, Danos C.; Wakimoto, Hiroko; Onoue, Kenji; Eminaga, Seda; Gorham, Joshua M.; DePalma, Steve R.; Herman, Daniel S.; Teekakirikul, Polakit; Conner, David A.; McKean, David M.; Domenighetti, Andrea A.; Aboukhalil, Anton; Chang, Stephen; Srivastava, Gyan; McDonough, Barbara; De Jager, Philip L.; Chen, Ju; Bulyk, Martha L.; Muehlschlegel, Jochen D.; Seidman, Christine E.; Seidman, J.G.

2014-01-01

104

May genetic factors in fibromyalgia help to identify patients with differentially altered frequencies of immune cells?  

PubMed Central

There is common agreement that fibromyalgia (FM) is an extremely heterogeneous entity. Patients differ in their clinical symptoms, endocrine and immune parameters. In this study we evaluated endocrine and immunological features of distinct subsets of FM patients. In contrast to previous attempts to identify subsets of FM patients, based solely on their psychological and cognitive features, herein we propose to separate FM patients by genetic features. Allelic expression of the polymorphic promoter region of the serotonin transporter (5-HTTLPR) was analysed as a relevant genetic factor for FM. Seventy-five patients meeting the American College of Rheumatology criteria and 27 healthy age-matched controls participated in this study. All controls and FM patients were submitted to genotyping of 5-HTTLPR. Twenty-seven FM patients, who were able to discontinue hypnotic, sedative or psychotropic prescription medications for at least 2 weeks, were then subdivided into L (homozygote LL) or S groups (genotypes LS and SS). They were evaluated for salivary cortisol levels, absolute number of leucocyte subpopulations, including natural killer (NK) cells and activated T and B lymphocytes. Both groups presented decreased cortisol levels, more intense in the L group, increased all B lymphocytes subsets and reduced CD4+CD25high T lymphocytes. The L group had increased CD4+CD25low activated T lymphocytes, while the S group displayed elevated CD4+human leucocyte antigen D-related (HLA-DR)+ activated T lymphocytes and decreased NK cells. We demonstrate that genetic factors may help to identify FM individuals with differentially altered frequencies of immune cells. PMID:19037919

Carvalho, L S C; Correa, H; Silva, G C; Campos, F S; Baiăo, F R; Ribeiro, L S; Faria, A M; d'Avila Reis, D

2008-01-01

105

Non-Genetic Determinants of Mosquito Competence for Malaria Parasites  

PubMed Central

Understanding how mosquito vectors and malaria parasites interact is of fundamental interest, and it also offers novel perspectives for disease control. Both the genetic and environmental contexts are known to affect the ability of mosquitoes to support malaria development and transmission, i.e., vector competence. Although the role of environment has long been recognized, much work has focused on host and parasite genetic effects. However, the last few years have seen a surge of studies revealing a great diversity of ways in which non-genetic factors can interfere with mosquito-Plasmodium interactions. Here, we review the current evidence for such environmentally mediated effects, including ambient temperature, mosquito diet, microbial gut flora, and infection history, and we identify additional factors previously overlooked in mosquito-Plasmodium interactions. We also discuss epidemiological implications, and the evolutionary consequences for vector immunity and parasite transmission strategies. Finally, we propose directions for further research and argue that an improved knowledge of non-genetic influences on mosquito-Plasmodium interactions could aid in implementing conventional malaria control measures and contribute to the design of novel strategies. PMID:23818841

Lefčvre, Thierry; Vantaux, Amélie; Dabiré, Kounbobr R.; Mouline, Karine; Cohuet, Anna

2013-01-01

106

Dana-Farber Cancer Institute researchers identify genetic mutation responsible for most cases of a rare lymphoma:  

Cancer.gov

Scientists at Dana-Farber Cancer Institute have identified a gene mutation that underlies the vast majority of cases of Waldenström's macroglobulinemia, a rare form of lymphoma that has eluded all previous efforts to find a genetic cause.

107

A microfluidic-based genetic screen to identify microbial virulence factors that inhibit dendritic cell migration.  

PubMed

Microbial pathogens are able to modulate host cells and evade the immune system by multiple mechanisms. For example, Salmonella injects effector proteins into host cells and evades the host immune system in part by inhibiting dendritic cell (DC) migration. The identification of microbial factors that modulate normal host functions should lead to the development of new classes of therapeutics that target these pathways. Current screening methods to identify either host or pathogen genes involved in modulating migration towards a chemical signal are limited because they do not employ stable, precisely controlled chemical gradients. Here, we develop a positive selection microfluidic-based genetic screen that allows us to identify Salmonella virulence factors that manipulate DC migration within stable, linear chemokine gradients. Our screen identified 7 Salmonella effectors (SseF, SifA, SspH2, SlrP, PipB2, SpiC and SseI) that inhibit DC chemotaxis toward CCL19. This method is widely applicable for identifying novel microbial factors that influence normal host cell chemotaxis as well as revealing new mammalian genes involved in directed cell migration. PMID:24599496

McLaughlin, Laura M; Xu, Hui; Carden, Sarah E; Fisher, Samantha; Reyes, Monique; Heilshorn, Sarah C; Monack, Denise M

2014-04-01

108

Targeted approach to identify genetic loci associated with evolved dioxin tolerance in Atlantic Killifish (Fundulus heteroclitus)  

PubMed Central

Background The most toxic aromatic hydrocarbon pollutants are categorized as dioxin-like compounds (DLCs) to which extreme tolerance has evolved independently and contemporaneously in (at least) four populations of Atlantic killifish (Fundulus heteroclitus). Surprisingly, the magnitude and phenotype of DLC tolerance is similar among these killifish populations that have adapted to varied, but highly aromatic hydrocarbon-contaminated urban/industrialized estuaries of the US Atlantic coast. Multiple tolerant and neighboring sensitive killifish populations were compared with the expectation that genetic loci associated with DLC tolerance would be revealed. Results Since the aryl hydrocarbon receptor (AHR) pathway partly or fully mediates DLC toxicity in vertebrates, single nucleotide polymorphisms (SNPs) from 42 genes associated with the AHR pathway were identified to serve as targeted markers. Wild fish (N?=?36/37) from four highly tolerant killifish populations and four nearby sensitive populations were genotyped using 59 SNP markers. Similar to other killifish population genetic analyses, strong genetic differentiation among populations was detected, consistent with isolation by distance models. When DLC-sensitive populations were pooled and compared to pooled DLC-tolerant populations, multi-locus analyses did not distinguish the two groups. However, pairwise comparisons of nearby tolerant and sensitive populations revealed high differentiation among sensitive and tolerant populations at these specific loci: AHR 1 and 2, cathepsin Z, the cytochrome P450s (CYP1A and 3A30), and the NADH dehydrogenase subunits. In addition, significant shifts in minor allele frequency were observed at AHR2 and CYP1A loci across most sensitive/tolerant pairs, but only AHR2 exhibited shifts in the same direction across all pairs. Conclusions The observed differences in allelic composition at the AHR2 and CYP1A SNP loci were identified as significant among paired sensitive/tolerant populations of Atlantic killifish with multiple statistical tests. The genetic patterns reported here lend support to the argument that AHR2 and CYP1A play a role in the adaptive response to extreme DLC contamination. Additional functional assays are required to isolate the exact mechanism of DLC tolerance. PMID:24422627

2014-01-01

109

Transgenerational inheritance of non-genetically determined phenotypes.  

PubMed

Inheritance of non-genetic factors permits ancestral environmental history to inform the development of subsequent generations. This form of soft inheritance has been shown in mammals, yet the molecular underpinnings of this phenomenon are poorly understood. In the present article, we focus on gametic inheritance of non-genetic factors, utilizing examples of paternal transmission to explore the core issues that need to be addressed in order to gain greater insight into the molecular mechanisms. Three essential processes are identified: (i) how the environment affects the germline to establish an altered molecular milieu, (ii) the molecular nature of the inherited mark, and (iii) how this affects genome function in the developing embryo to elicit an alternative developmental outcome. PMID:23697936

Holland, Michelle L; Rakyan, Vardhman K

2013-06-01

110

Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer  

PubMed Central

Background Genetic predisposition is the primary risk factor for familial breast cancer. For the majority of familial breast cancer, however, the genetic predispositions remain unknown. All newly identified predispositions occur rarely in disease population, and the unknown genetic predispositions are estimated to reach up to total thousands. Family unit is the basic structure of genetics. Because it is an autosomal dominant disease, individuals with a history of familial breast cancer must carry the same genetic predisposition across generations. Therefore, focusing on the cases in lineages of familial breast cancer, rather than pooled cases in disease population, is expected to provide high probability to identify the genetic predisposition for each family. Methods In this study, we tested genetic predispositions by analyzing the family-specific variants in familial breast cancer. Using exome sequencing, we analyzed three families and 22 probands with BRCAx (BRCA-negative) familial breast cancer. Results We observed the presence of family-specific, novel, deleterious germline variants in each family. Of the germline variants identified, many were shared between the disease-affected family members of the same family but not found in different families, which have their own specific variants. Certain variants are putative deleterious genetic predispositions damaging functionally important genes involved in DNA replication and damaging repair, tumor suppression, signal transduction, and phosphorylation. Conclusions Our study demonstrates that the predispositions for many BRCAx familial breast cancer families can lie in each disease family. The application of a family-focused approach has the potential to detect many new predispositions. PMID:24969172

2014-01-01

111

Genetical Toxicogenomics in Drosophila Identifies Master Modulatory Loci that are Regulated by Developmental Exposure to Lead  

PubMed Central

The genetics of gene expression in recombinant inbred lines (RILs) can be mapped as expression quantitative trait loci (eQTLs). So-called “genetical genomics” studies have identified locally-acting eQTLs (cis-eQTLs) for genes that show differences in steady state RNA levels. These studies have also identified distantly-acting master-modulatory trans-eQTLs that regulate tens or hundreds of transcripts (hotspots or transbands). We expand on these studies by performing genetical genomics experiments in two environments in order to identify trans-eQTL that might be regulated by developmental exposure to the neurotoxin lead. Flies from each of 75 RIL were raised from eggs to adults on either control food (made with 250 µM sodium acetate), or lead-treated food (made with 250 µM lead acetate, PbAc). RNA expression analyses of whole adult male flies (5–10 days old) were performed with Affymetrix DrosII whole genome arrays (18,952 probesets). Among the 1,389 genes with cis-eQTL, there were 405 genes unique to control flies and 544 genes unique to lead-treated ones (440 genes had the same cis-eQTLs in both samples). There are 2,396 genes with trans-eQTL which mapped to 12 major transbands with greater than 95 genes. Permutation analyses of the strain labels but not the expression data suggests that the total number of eQTL and the number of transbands are more important criteria for validation than the size of the transband. Two transbands, one located on the 2nd chromosome and one on the 3rd chromosome, co-regulate 33 lead-induced genes, many of which are involved in neurodevelopmental processes. For these 33 genes, rather than allelic variation at one locus exerting differential effects in two environments, we found that variation at two different loci are required for optimal effects on lead-induced expression. PMID:19737576

Ruden, Douglas M.; Chen, Lang; Possidente, Debra; Possidente, Bernard; Rasouli, Parsa; Wang, Luan; Lu, Xiangyi; Garfinkel, Mark D.; Hirsch, Helmut V. B.; Page, Grier P.

2009-01-01

112

Integrative genomic analysis identifies epigenetic marks that mediate genetic risk for epithelial ovarian cancer  

PubMed Central

Background Both genetic and epigenetic factors influence the development and progression of epithelial ovarian cancer (EOC). However, there is an incomplete understanding of the interrelationship between these factors and the extent to which they interact to impact disease risk. In the present study, we aimed to gain insight into this relationship by identifying DNA methylation marks that are candidate mediators of ovarian cancer genetic risk. Methods We used 214 cases and 214 age-matched controls from the Mayo Clinic Ovarian Cancer Study. Pretreatment, blood-derived DNA was profiled for genome-wide methylation (Illumina Infinium HumanMethylation27 BeadArray) and single nucleotide polymorphisms (SNPs, Illumina Infinium HD Human610-Quad BeadArray). The Causal Inference Test (CIT) was implemented to distinguish CpG sites that mediate genetic risk, from those that are consequential or independently acted on by genotype. Results Controlling for the estimated distribution of immune cells and other key covariates, our initial epigenome-wide association analysis revealed 1,993 significantly differentially methylated CpGs that between cases and controls (FDR, q?

2014-01-01

113

Genetic caste determination in Pogonomyrmex harvester ants imposes costs during colony founding  

E-print Network

Genetic caste determination in Pogonomyrmex harvester ants imposes costs during colony founding T with marked morphological differences between the queen and worker castes. These differences usually result). However, genetically determined caste differentiation has been recently discovered in two populations

Alvarez, Nadir

114

75 FR 8299 - Draft Environmental Impact Statement; Determination of Regulated Status of Alfalfa Genetically...  

Federal Register 2010, 2011, 2012, 2013, 2014

...connection with making a determination on the status of the Monsanto Company and Forage Genetics International alfalfa lines designated...connection with making a determination on the status of the Monsanto Company and Forage Genetics International alfalfa lines...

2010-02-24

115

Genetical and comparative genomics of Brassica under altered Ca supply identifies Arabidopsis Ca-transporter orthologs.  

PubMed

Although Ca transport in plants is highly complex, the overexpression of vacuolar Ca(2+) transporters in crops is a promising new technology to improve dietary Ca supplies through biofortification. Here, we sought to identify novel targets for increasing plant Ca accumulation using genetical and comparative genomics. Expression quantitative trait locus (eQTL) mapping to 1895 cis- and 8015 trans-loci were identified in shoots of an inbred mapping population of Brassica rapa (IMB211 × R500); 23 cis- and 948 trans-eQTLs responded specifically to altered Ca supply. eQTLs were screened for functional significance using a large database of shoot Ca concentration phenotypes of Arabidopsis thaliana. From 31 Arabidopsis gene identifiers tagged to robust shoot Ca concentration phenotypes, 21 mapped to 27 B. rapa eQTLs, including orthologs of the Ca(2+) transporters At-CAX1 and At-ACA8. Two of three independent missense mutants of BraA.cax1a, isolated previously by targeting induced local lesions in genomes, have allele-specific shoot Ca concentration phenotypes compared with their segregating wild types. BraA.CAX1a is a promising target for altering the Ca composition of Brassica, consistent with prior knowledge from Arabidopsis. We conclude that multiple-environment eQTL analysis of complex crop genomes combined with comparative genomics is a powerful technique for novel gene identification/prioritization. PMID:25082855

Graham, Neil S; Hammond, John P; Lysenko, Artem; Mayes, Sean; O Lochlainn, Seosamh; Blasco, Bego; Bowen, Helen C; Rawlings, Chris J; Rios, Juan J; Welham, Susan; Carion, Pierre W C; Dupuy, Lionel X; King, Graham J; White, Philip J; Broadley, Martin R

2014-07-01

116

Rapid in vivo forward genetic approach for identifying axon death genes in Drosophila  

PubMed Central

Axons damaged by acute injury, toxic insults, or neurodegenerative diseases execute a poorly defined autodestruction signaling pathway leading to widespread fragmentation and functional loss. Here, we describe an approach to study Wallerian degeneration in the Drosophila L1 wing vein that allows for analysis of axon degenerative phenotypes with single-axon resolution in vivo. This method allows for the axotomy of specific subsets of axons followed by examination of progressive axonal degeneration and debris clearance alongside uninjured control axons. We developed new Flippase (FLP) reagents using proneural gene promoters to drive FLP expression very early in neural lineages. These tools allow for the production of mosaic clone populations with high efficiency in sensory neurons in the wing. We describe a collection of lines optimized for forward genetic mosaic screens using MARCM (mosaic analysis with a repressible cell marker; i.e., GFP-labeled, homozygous mutant) on all major autosomal arms (?95% of the fly genome). Finally, as a proof of principle we screened the X chromosome and identified a collection eight recessive and two dominant alleles of highwire, a ubiquitin E3 ligase required for axon degeneration. Similar unbiased forward genetic screens should help rapidly delineate axon death genes, thereby providing novel potential drug targets for therapeutic intervention to prevent axonal and synaptic loss. PMID:24958874

Neukomm, Lukas J.; Burdett, Thomas C.; Gonzalez, Michael A.; Züchner, Stephan; Freeman, Marc R.

2014-01-01

117

Rapid in vivo forward genetic approach for identifying axon death genes in Drosophila.  

PubMed

Axons damaged by acute injury, toxic insults, or neurodegenerative diseases execute a poorly defined autodestruction signaling pathway leading to widespread fragmentation and functional loss. Here, we describe an approach to study Wallerian degeneration in the Drosophila L1 wing vein that allows for analysis of axon degenerative phenotypes with single-axon resolution in vivo. This method allows for the axotomy of specific subsets of axons followed by examination of progressive axonal degeneration and debris clearance alongside uninjured control axons. We developed new Flippase (FLP) reagents using proneural gene promoters to drive FLP expression very early in neural lineages. These tools allow for the production of mosaic clone populations with high efficiency in sensory neurons in the wing. We describe a collection of lines optimized for forward genetic mosaic screens using MARCM (mosaic analysis with a repressible cell marker; i.e., GFP-labeled, homozygous mutant) on all major autosomal arms (?95% of the fly genome). Finally, as a proof of principle we screened the X chromosome and identified a collection eight recessive and two dominant alleles of highwire, a ubiquitin E3 ligase required for axon degeneration. Similar unbiased forward genetic screens should help rapidly delineate axon death genes, thereby providing novel potential drug targets for therapeutic intervention to prevent axonal and synaptic loss. PMID:24958874

Neukomm, Lukas J; Burdett, Thomas C; Gonzalez, Michael A; Züchner, Stephan; Freeman, Marc R

2014-07-01

118

Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas.  

PubMed

The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs. PMID:23583981

Zhang, Jinghui; Wu, Gang; Miller, Claudia P; Tatevossian, Ruth G; Dalton, James D; Tang, Bo; Orisme, Wilda; Punchihewa, Chandanamali; Parker, Matthew; Qaddoumi, Ibrahim; Boop, Fredrick A; Lu, Charles; Kandoth, Cyriac; Ding, Li; Lee, Ryan; Huether, Robert; Chen, Xiang; Hedlund, Erin; Nagahawatte, Panduka; Rusch, Michael; Boggs, Kristy; Cheng, Jinjun; Becksfort, Jared; Ma, Jing; Song, Guangchun; Li, Yongjin; Wei, Lei; Wang, Jianmin; Shurtleff, Sheila; Easton, John; Zhao, David; Fulton, Robert S; Fulton, Lucinda L; Dooling, David J; Vadodaria, Bhavin; Mulder, Heather L; Tang, Chunlao; Ochoa, Kerri; Mullighan, Charles G; Gajjar, Amar; Kriwacki, Richard; Sheer, Denise; Gilbertson, Richard J; Mardis, Elaine R; Wilson, Richard K; Downing, James R; Baker, Suzanne J; Ellison, David W

2013-06-01

119

Can novel genetic analyses help to identify low-dispersal marine invasive species?  

PubMed Central

Genetic methods can be a powerful tool to resolve the native versus introduced status of populations whose taxonomy and biogeography are poorly understood. The genetic study of introduced species is presently dominated by analyses that identify signatures of recent colonization by means of summary statistics. Unfortunately, such approaches cannot be used in low-dispersal species, in which recently established populations originating from elsewhere in the species' native range also experience periods of low population size because they are founded by few individuals. We tested whether coalescent-based molecular analyses that provide detailed information about demographic history supported the hypothesis that a sea squirt whose distribution is centered on Tasmania was recently introduced to mainland Australia and New Zealand through human activities. Methods comparing trends in population size (Bayesian Skyline Plots and Approximate Bayesian Computation) were no more informative than summary statistics, likely because of recent intra-Tasmanian dispersal. However, IMa2 estimates of divergence between putatively native and introduced populations provided information at a temporal scale suitable to differentiate between recent (potentially anthropogenic) introductions and ancient divergence, and indicated that all three non-Tasmanian populations were founded during the period of European settlement. While this approach can be affected by inaccurate molecular dating, it has considerable (albeit largely unexplored) potential to corroborate nongenetic information in species with limited dispersal capabilities. PMID:25165524

Teske, Peter R; Sandoval-Castillo, Jonathan; Waters, Jonathan M; Beheregaray, Luciano B

2014-01-01

120

Criteria for Identifying and Evaluating Candidate Sites for Open-Field Trials of Genetically Engineered Mosquitoes  

PubMed Central

Abstract Recent laboratory successes in the development of genetically engineered mosquitoes for controlling pathogen transmission have fostered the need for standardized procedures for advancing the technical achievements to practical tools. It is incumbent in many cases for the same scientists doing the in-laboratory discovery research to also take on the initial challenges of developing the pathway that will move the technologies to the field. One of these challenges is having a set of criteria for selecting collaborators and sites for efficacy and safety field trials that combine rigorous science with good ethical and legal practices. Specific site-selection criteria were developed in four categories—Scientific, Regulatory, Community Engagement, and Resources—in anticipation of open-field releases of a transgenic mosquito strain designed to suppress populations of the dengue vector mosquito, Aedes aegypti. The criteria are derived from previous published material, discussions, and personal experiences with the expectation of providing guidance to laboratory scientists for addressing the conceptual and operational considerations for identifying partner researchers and countries with whom to collaborate. These criteria are not intended to be prescriptive nor can they be applied to every circumstance where genetic approaches are proposed for deployment. However, we encourage those involved in the discovery phase of research to consider each criterion during project planning activities, and where appropriate, incorporate them into a “go/no-go” decision-making process for further development and testing of the technologies. PMID:24689963

Brown, David M.; Alphey, Luke S.; McKemey, Andrew; Beech, Camilla

2014-01-01

121

Can novel genetic analyses help to identify low-dispersal marine invasive species?  

PubMed

Genetic methods can be a powerful tool to resolve the native versus introduced status of populations whose taxonomy and biogeography are poorly understood. The genetic study of introduced species is presently dominated by analyses that identify signatures of recent colonization by means of summary statistics. Unfortunately, such approaches cannot be used in low-dispersal species, in which recently established populations originating from elsewhere in the species' native range also experience periods of low population size because they are founded by few individuals. We tested whether coalescent-based molecular analyses that provide detailed information about demographic history supported the hypothesis that a sea squirt whose distribution is centered on Tasmania was recently introduced to mainland Australia and New Zealand through human activities. Methods comparing trends in population size (Bayesian Skyline Plots and Approximate Bayesian Computation) were no more informative than summary statistics, likely because of recent intra-Tasmanian dispersal. However, IMa2 estimates of divergence between putatively native and introduced populations provided information at a temporal scale suitable to differentiate between recent (potentially anthropogenic) introductions and ancient divergence, and indicated that all three non-Tasmanian populations were founded during the period of European settlement. While this approach can be affected by inaccurate molecular dating, it has considerable (albeit largely unexplored) potential to corroborate nongenetic information in species with limited dispersal capabilities. PMID:25165524

Teske, Peter R; Sandoval-Castillo, Jonathan; Waters, Jonathan M; Beheregaray, Luciano B

2014-07-01

122

Identifying genetic variants for heart rate variability in the acetylcholine pathway.  

PubMed

Heart rate variability is an important risk factor for cardiovascular disease and all-cause mortality. The acetylcholine pathway plays a key role in explaining heart rate variability in humans. We assessed whether 443 genotyped and imputed common genetic variants in eight key genes (CHAT, SLC18A3, SLC5A7, CHRNB4, CHRNA3, CHRNA, CHRM2 and ACHE) of the acetylcholine pathway were associated with variation in an established measure of heart rate variability reflecting parasympathetic control of the heart rhythm, the root mean square of successive differences (RMSSD) of normal RR intervals. The association was studied in a two stage design in individuals of European descent. First, analyses were performed in a discovery sample of four cohorts (n?=?3429, discovery stage). Second, findings were replicated in three independent cohorts (n?=?3311, replication stage), and finally the two stages were combined in a meta-analysis (n?=?6740). RMSSD data were obtained under resting conditions. After correction for multiple testing, none of the SNPs showed an association with RMSSD. In conclusion, no common genetic variants for heart rate variability were identified in the largest and most comprehensive candidate gene study on the acetylcholine pathway to date. Future gene finding efforts for RMSSD may want to focus on hypothesis free approaches such as the genome-wide association study. PMID:25384021

Riese, Harriëtte; Muńoz, Loretto M; Hartman, Catharina A; Ding, Xiuhua; Su, Shaoyong; Oldehinkel, Albertine J; van Roon, Arie M; van der Most, Peter J; Lefrandt, Joop; Gansevoort, Ron T; van der Harst, Pim; Verweij, Niek; Licht, Carmilla M M; Boomsma, Dorret I; Hottenga, Jouke-Jan; Willemsen, Gonneke; Penninx, Brenda W J H; Nolte, Ilja M; de Geus, Eco J C; Wang, Xiaoling; Snieder, Harold

2014-01-01

123

Population genetic analysis identifies source-sink dynamics for two sympatric garter snake species ( Thamnophis elegans and Thamnophis sirtalis )  

Microsoft Academic Search

Population genetic structure can be shaped by multiple ecological and evolutionary factors, but the genetic consequences of these factors for multiple species inhabiting the same envi- ronment remain unexplored. We used microsatellite markers to examine the population structures of two coexisting species of garter snake, Thamnophis elegans and Thamnophis sirtalis , to determine if shared landscape and biology imposed similar

MOLLIE K. M ANIER; STEVAN J. A RNOLD

124

Multifactor dimensionality reduction analysis identifies specific nucleotide patterns promoting genetic polymorphisms  

PubMed Central

Background The fidelity of DNA replication serves as the nidus for both genetic evolution and genomic instability fostering disease. Single nucleotide polymorphisms (SNPs) constitute greater than 80% of the genetic variation between individuals. A new theory regarding DNA replication fidelity has emerged in which selectivity is governed by base-pair geometry through interactions between the selected nucleotide, the complementary strand, and the polymerase active site. We hypothesize that specific nucleotide combinations in the flanking regions of SNP fragments are associated with mutation. Results We modeled the relationship between DNA sequence and observed polymorphisms using the novel multifactor dimensionality reduction (MDR) approach. MDR was originally developed to detect synergistic interactions between multiple SNPs that are predictive of disease susceptibility. We initially assembled data from the Broad Institute as a pilot test for the hypothesis that flanking region patterns associate with mutagenesis (n = 2194). We then confirmed and expanded our inquiry with human SNPs within coding regions and their flanking sequences collected from the National Center for Biotechnology Information (NCBI) database (n = 29967) and a control set of sequences (coding region) not associated with SNP sites randomly selected from the NCBI database (n = 29967). We discovered seven flanking region pattern associations in the Broad dataset which reached a minimum significance level of p ? 0.05. Significant models (p << 0.001) were detected for each SNP type examined in the larger NCBI dataset. Importantly, the flanking region models were elongated or truncated depending on the nucleotide change. Additionally, nucleotide distributions differed significantly at motif sites relative to the type of variation observed. The MDR approach effectively discerned specific sites within the flanking regions of observed SNPs and their respective identities, supporting the collective contribution of these sites to SNP genesis. Conclusion The present study represents the first use of this computational methodology for modeling nonlinear patterns in molecular genetics. MDR was able to identify distinct nucleotide patterning around sites of mutations dependent upon the observed nucleotide change. We discovered one flanking region set that included five nucleotides clustered around a specific type of SNP site. Based on the strongly associated patterns identified in this study, it may become possible to scan genomic databases for such clustering of nucleotides in order to predict likely sites of future SNPs, and even the type of polymorphism most likely to occur. PMID:19331672

Arehart, Eric; Gleim, Scott; White, Bill; Hwa, John; Moore, Jason H

2009-01-01

125

Genetic determinants of metabolism in health and disease: from biochemical genetics to genome-wide associations.  

PubMed

Increasingly sophisticated measurement technologies have allowed the fields of metabolomics and genomics to identify, in parallel, risk factors of disease; predict drug metabolism; and study metabolic and genetic diversity in large human populations. Yet the complementarity of these fields and the utility of studying genes and metabolites together is belied by the frequent separate, parallel applications of genomic and metabolomic analysis. Early attempts at identifying co-variation and interaction between genetic variants and downstream metabolic changes, including metabolic profiling of human Mendelian diseases and quantitative trait locus mapping of individual metabolite concentrations, have recently been extended by new experimental designs that search for a large number of gene-metabolite associations. These approaches, including metabolomic quantitiative trait locus mapping and metabolomic genome-wide association studies, involve the concurrent collection of both genomic and metabolomic data and a subsequent search for statistical associations between genetic polymorphisms and metabolite concentrations across a broad range of genes and metabolites. These new data-fusion techniques will have important consequences in functional genomics, microbial metagenomics and disease modeling, the early results and implications of which are reviewed. PMID:22546284

Robinette, Steven L; Holmes, Elaine; Nicholson, Jeremy K; Dumas, Marc E

2012-01-01

126

Genetic determinants of metabolism in health and disease: from biochemical genetics to genome-wide associations  

PubMed Central

Increasingly sophisticated measurement technologies have allowed the fields of metabolomics and genomics to identify, in parallel, risk factors of disease; predict drug metabolism; and study metabolic and genetic diversity in large human populations. Yet the complementarity of these fields and the utility of studying genes and metabolites together is belied by the frequent separate, parallel applications of genomic and metabolomic analysis. Early attempts at identifying co-variation and interaction between genetic variants and downstream metabolic changes, including metabolic profiling of human Mendelian diseases and quantitative trait locus mapping of individual metabolite concentrations, have recently been extended by new experimental designs that search for a large number of gene-metabolite associations. These approaches, including metabolomic quantitiative trait locus mapping and metabolomic genome-wide association studies, involve the concurrent collection of both genomic and metabolomic data and a subsequent search for statistical associations between genetic polymorphisms and metabolite concentrations across a broad range of genes and metabolites. These new data-fusion techniques will have important consequences in functional genomics, microbial metagenomics and disease modeling, the early results and implications of which are reviewed. PMID:22546284

2012-01-01

127

Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density  

PubMed Central

Patient bone mineral density (BMD) predicts the likelihood of osteoporotic fracture. While substantial progress has been made toward elucidating the genetic determinants of BMD, our understanding of the factors involved remains incomplete. Here, using a systems genetics approach in the mouse, we predicted that bicaudal C homolog 1 (Bicc1), which encodes an RNA-binding protein, is responsible for a BMD quantitative trait locus (QTL) located on murine chromosome 10. Consistent with this prediction, mice heterozygous for a null allele of Bicc1 had low BMD. We used a coexpression network–based approach to determine how Bicc1 influences BMD. Based on this analysis, we inferred that Bicc1 was involved in osteoblast differentiation and that polycystic kidney disease 2 (Pkd2) was a downstream target of Bicc1. Knock down of Bicc1 and Pkd2 impaired osteoblastogenesis, and Bicc1 deficiency–dependent osteoblast defects were rescued by Pkd2 overexpression. Last, in 2 human BMD genome-wide association (GWAS) meta-analyses, we identified SNPs in BICC1 and PKD2 that were associated with BMD. These results, in both mice and humans, identify Bicc1 as a genetic determinant of osteoblastogenesis and BMD and suggest that it does so by regulating Pkd2 transcript levels. PMID:24789909

Mesner, Larry D.; Ray, Brianne; Hsu, Yi-Hsiang; Manichaikul, Ani; Lum, Eric; Bryda, Elizabeth C.; Rich, Stephen S.; Rosen, Clifford J.; Criqui, Michael H.; Allison, Matthew; Budoff, Matthew J.; Clemens, Thomas L.; Farber, Charles R.

2014-01-01

128

Genetic determinants of glucose-6-phosphate dehydrogenase activity in Kenya  

PubMed Central

Background The relationship between glucose-6-phosphate dehydrogenase (G6PD) deficiency and clinical phenomena such as primaquine-sensitivity and protection from severe malaria remains poorly defined, with past association studies yielding inconsistent and conflicting results. One possibility is that examination of a single genetic variant might underestimate the presence of true effects in the presence of unrecognized functional allelic diversity. Methods We systematically examined this possibility in Kenya, conducting a fine-mapping association study of erythrocyte G6PD activity in 1828 Kenyan children across 30 polymorphisms at or around the G6PD locus. Results We demonstrate a strong functional role for c.202G>A (rs1050828), which accounts for the majority of variance in enzyme activity observed (P=1.5×10?200, additive model). Additionally, we identify other common variants that exert smaller, intercorrelated effects independent of c.202G>A, and haplotype analyses suggest that each variant tags one of two haplotype motifs that are opposite in sequence identity and effect direction. We posit that these effects are of biological and possible clinical significance, specifically noting that c.376A>G (rs1050829) augments 202AG heterozygote risk for deficiency trait by two-fold (OR = 2.11 [1.12 - 3.84], P=0.014). Conclusions Our results suggest that c.202G>A is responsible for the majority of the observed prevalence of G6PD deficiency trait in Kenya, but also identify a novel role for c.376A>G as a genetic modifier which marks a common haplotype that augments the risk conferred to 202AG heterozygotes, suggesting that variation at both loci merits consideration in genetic association studies probing G6PD deficiency-associated clinical phenotypes. PMID:25201310

2014-01-01

129

Genetic Differences in Transcript Responses to Low-Dose Ionizing Radiation Identify Tissue Functions Associated with Breast Cancer Susceptibility  

PubMed Central

High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, <10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGF?-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p?=?0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly influenced by genotype. Our findings suggest that the biological assumptions concerning the mechanisms by which LD radiation is translated into breast cancer risk should be reexamined and suggest a new strategy to identify genetic features that predispose or protect individuals from LD-induced breast cancer. PMID:23077491

Snijders, Antoine M.; Marchetti, Francesco; Bhatnagar, Sandhya; Duru, Nadire; Han, Ju; Hu, Zhi; Mao, Jian-Hua; Gray, Joe W.; Wyrobek, Andrew J.

2012-01-01

130

GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.  

PubMed

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ? 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ?2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics. PMID:23722424

Rietveld, Cornelius A; Medland, Sarah E; Derringer, Jaime; Yang, Jian; Esko, Tőnu; Martin, Nicolas W; Westra, Harm-Jan; Shakhbazov, Konstantin; Abdellaoui, Abdel; Agrawal, Arpana; Albrecht, Eva; Alizadeh, Behrooz Z; Amin, Najaf; Barnard, John; Baumeister, Sebastian E; Benke, Kelly S; Bielak, Lawrence F; Boatman, Jeffrey A; Boyle, Patricia A; Davies, Gail; de Leeuw, Christiaan; Eklund, Niina; Evans, Daniel S; Ferhmann, Rudolf; Fischer, Krista; Gieger, Christian; Gjessing, Hĺkon K; Hägg, Sara; Harris, Jennifer R; Hayward, Caroline; Holzapfel, Christina; Ibrahim-Verbaas, Carla A; Ingelsson, Erik; Jacobsson, Bo; Joshi, Peter K; Jugessur, Astanand; Kaakinen, Marika; Kanoni, Stavroula; Karjalainen, Juha; Kolcic, Ivana; Kristiansson, Kati; Kutalik, Zoltán; Lahti, Jari; Lee, Sang H; Lin, Peng; Lind, Penelope A; Liu, Yongmei; Lohman, Kurt; Loitfelder, Marisa; McMahon, George; Vidal, Pedro Marques; Meirelles, Osorio; Milani, Lili; Myhre, Ronny; Nuotio, Marja-Liisa; Oldmeadow, Christopher J; Petrovic, Katja E; Peyrot, Wouter J; Polasek, Ozren; Quaye, Lydia; Reinmaa, Eva; Rice, John P; Rizzi, Thais S; Schmidt, Helena; Schmidt, Reinhold; Smith, Albert V; Smith, Jennifer A; Tanaka, Toshiko; Terracciano, Antonio; van der Loos, Matthijs J H M; Vitart, Veronique; Völzke, Henry; Wellmann, Jürgen; Yu, Lei; Zhao, Wei; Allik, Jüri; Attia, John R; Bandinelli, Stefania; Bastardot, François; Beauchamp, Jonathan; Bennett, David A; Berger, Klaus; Bierut, Laura J; Boomsma, Dorret I; Bültmann, Ute; Campbell, Harry; Chabris, Christopher F; Cherkas, Lynn; Chung, Mina K; Cucca, Francesco; de Andrade, Mariza; De Jager, Philip L; De Neve, Jan-Emmanuel; Deary, Ian J; Dedoussis, George V; Deloukas, Panos; Dimitriou, Maria; Eiríksdóttir, Guđny; Elderson, Martin F; Eriksson, Johan G; Evans, David M; Faul, Jessica D; Ferrucci, Luigi; Garcia, Melissa E; Grönberg, Henrik; Guđnason, Vilmundur; Hall, Per; Harris, Juliette M; Harris, Tamara B; Hastie, Nicholas D; Heath, Andrew C; Hernandez, Dena G; Hoffmann, Wolfgang; Hofman, Adriaan; Holle, Rolf; Holliday, Elizabeth G; Hottenga, Jouke-Jan; Iacono, William G; Illig, Thomas; Järvelin, Marjo-Riitta; Kähönen, Mika; Kaprio, Jaakko; Kirkpatrick, Robert M; Kowgier, Matthew; Latvala, Antti; Launer, Lenore J; Lawlor, Debbie A; Lehtimäki, Terho; Li, Jingmei; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C; Madden, Pamela A; Magnusson, Patrik K E; Mäkinen, Tomi E; Masala, Marco; McGue, Matt; Metspalu, Andres; Mielck, Andreas; Miller, Michael B; Montgomery, Grant W; Mukherjee, Sutapa; Nyholt, Dale R; Oostra, Ben A; Palmer, Lyle J; Palotie, Aarno; Penninx, Brenda W J H; Perola, Markus; Peyser, Patricia A; Preisig, Martin; Räikkönen, Katri; Raitakari, Olli T; Realo, Anu; Ring, Susan M; Ripatti, Samuli; Rivadeneira, Fernando; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sarin, Antti-Pekka; Schlessinger, David; Scott, Rodney J; Snieder, Harold; St Pourcain, Beate; Starr, John M; Sul, Jae Hoon; Surakka, Ida; Svento, Rauli; Teumer, Alexander; Tiemeier, Henning; van Rooij, Frank J A; Van Wagoner, David R; Vartiainen, Erkki; Viikari, Jorma; Vollenweider, Peter; Vonk, Judith M; Waeber, Gérard; Weir, David R; Wichmann, H-Erich; Widen, Elisabeth; Willemsen, Gonneke; Wilson, James F; Wright, Alan F; Conley, Dalton; Davey-Smith, George; Franke, Lude; Groenen, Patrick J F; Hofman, Albert; Johannesson, Magnus; Kardia, Sharon L R; Krueger, Robert F; Laibson, David; Martin, Nicholas G; Meyer, Michelle N; Posthuma, Danielle; Thurik, A Roy; Timpson, Nicholas J; Uitterlinden, André G; van Duijn, Cornelia M; Visscher, Peter M; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D

2013-06-21

131

Inhibitory collaterals in genetically identified medium spiny neurons in mouse primary corticostriatal cultures  

PubMed Central

Inhibitory collaterals between striatal medium spiny neuron (MSN) subtypes have been shown to critically influence striatal output. However, the low rate of inhibitory collateral detection between striatal MSNs in conventional ex vivo slice recordings has made the study of these connections challenging. Furthermore, most studies on MSN collaterals have been conducted either blind or in models, in which only one MSN subtype can be distinguished. Here, we describe a dissociated culture system using striatal and cortical neurons harvested from genetically modified mice at postnatal day 0. These mice express tdTomato and enhanced green fluorescent protein (EGFP) downstream of the dopamine D1 and D2 receptor promoters, respectively, allowing for simultaneous distinction between the two major subtypes of MSNs. In vitro, these neurons develop spines, hyperpolarized resting membrane potentials and exhibit up-and-down states, while also maintaining expression of both fluorophores through time. Using paired whole-cell patch-clamp recordings from identified MSNs at 14 days in vitro, we are able to detect a much higher rate of inhibitory functional synapses than what has been previously reported in slice recordings. These collateral synapses release ?-Aminobutyric acid (GABA) and shape the firing patters of other MSNs. Although reduced in vitro models have a number of inherent limitations, the cultures described here provide a unique opportunity to study frequently observed functional collaterals between identifiable MSNs. Additionally, cultured neurons allow for control of the extracellular environment, with the potential to investigate pharmacological regulation of inhibitory MSNs collaterals. PMID:24400165

Lalchandani, Rupa R; Vicini, Stefano

2013-01-01

132

A systematic forward genetic analysis identified components of the Chlamydomonas circadian system  

PubMed Central

The molecular bases of circadian clocks have been studied in animals, fungi, bacteria, and plants, but not in eukaryotic algae. To establish a new model for molecular analysis of the circadian clock, here we identified a large number of components of the circadian system in the eukaryotic unicellular alga Chlamydomonas reinhardtii by a systematic forward genetic approach. We isolated 105 insertional mutants that exhibited defects in period, phase angle, and/or amplitude of circadian rhythms in bioluminescence derived from a luciferase reporter gene in their chloroplast genome. Simultaneous measurement of circadian rhythms in bioluminescence and growth rate revealed that some of these mutants had defects in the circadian clock itself, whereas one mutant had a defect in a specific process for the chloroplast bioluminescence rhythm. We identified 30 genes (or gene loci) that would be responsible for rhythm defects in 37 mutants. Classification of these genes revealed that various biological processes are involved in regulation of the chloroplast rhythmicity. Amino acid sequences of six genes that would have crucial roles in the circadian clock revealed features of the Chlamydomonas clock that have both partially plant-like and original components. PMID:18334618

Matsuo, Takuya; Okamoto, Kazuhisa; Onai, Kiyoshi; Niwa, Yoshimi; Shimogawara, Kosuke; Ishiura, Masahiro

2008-01-01

133

Genetic Interaction Screens Identify a Role for Hedgehog Signaling in Drosophila Border Cell Migration  

PubMed Central

Background Cell motility is essential for embryonic development and physiological processes such as the immune response, but also contributes to pathological conditions such as tumor progression and inflammation. However, our understanding of the mechanisms underlying migratory processes is incomplete. Drosophila border cells provide a powerful genetic model to identify the roles of genes that contribute to cell migration. Results Members of the Hedgehog signaling pathway were uncovered in two independent screens for interactions with the small GTPase Rac and the polarity protein Par-1 in border cell migration. Consistent with a role in migration, multiple Hh signaling components were enriched in the migratory border cells. Interference with Hh signaling by several different methods resulted in incomplete cell migration. Moreover, the polarized distribution of E-Cadherin and a marker of tyrosine kinase activity were altered when Hh signaling was disrupted. Conservation of Hh-Rac and Hh-Par-1 signaling was illustrated in the wing, in which Hh-dependent phenotypes were enhanced by loss of Rac or par-1. Conclusions We identified a pathway by which Hh signaling connects to Rac and Par-1 in cell migration. These results further highlight the importance of modifier screens in the identification of new genes that function in developmental pathways. PMID:23335293

Geisbrecht, Erika R.; Sawant, Ketki; Su, Ying; Liu, Ze (Cindy); Silver, Debra L.; Burtscher, Ashley; Wang, Xuejiao; Zhu, Alan Jian; McDonald, Jocelyn A.

2013-01-01

134

Additional records of metazoan parasites from Caribbean marine mammals, including genetically identified anisakid nematodes.  

PubMed

Studies of marine mammal parasites in the Caribbean are scarce. An assessment for marine mammal endo- and ectoparasites from Puerto Rico and the Virgin Islands, but extending to other areas of the Caribbean, was conducted between 1989 and 1994. The present study complements the latter and enhances identification of anisakid nematodes using molecular markers. Parasites were collected from 59 carcasses of stranded cetaceans and manatees from 1994 to 2006, including Globicephala macrorhynchus, Kogia breviceps, Kogia sima, Lagenodelphis hosei, Mesoplodon densirostris, Peponocephala electra, Stenella longirostris, Steno bredanensis, Trichechus manatus. Tursiops truncatus, and Ziphius cavirostris. Sixteen species of endoparasitic helminthes were morphologically identified, including two species of acanthocephalans (Bolbosoma capitatum, Bolbosoma vasculosum), nine species of nematodes (Anisakis sp., Anisakis brevispiculata, Anisakis paggiae, Anisakis simplex, Anisakis typica, Anisakis ziphidarium, Crassicauda anthonyi, Heterocheilus tunicatus, Pseudoterranova ceticola), two species of cestodes (Monorygma grimaldi, Phyllobothrium delphini), and three species of trematodes (Chiorchis groschafti, Pulmonicola cochleotrema, Monoligerum blairi). The nematodes belonging to the genus Anisakis recovered in some stranded animals were genetically identified to species level based on their sequence analysis of mitochondrial DNA (629 bp of mtDNA cox 2). A total of five new host records and six new geographic records are presented. PMID:19582477

Colón-Llavina, Marlene M; Mignucci-Giannoni, Antonio A; Mattiucci, Simonetta; Paoletti, Michela; Nascetti, Giuseppe; Williams, Ernest H

2009-10-01

135

The Real maccoyii: Identifying Tuna Sushi with DNA Barcodes – Contrasting Characteristic Attributes and Genetic Distances  

PubMed Central

Background The use of DNA barcodes for the identification of described species is one of the least controversial and most promising applications of barcoding. There is no consensus, however, as to what constitutes an appropriate identification standard and most barcoding efforts simply attempt to pair a query sequence with reference sequences and deem identification successful if it falls within the bounds of some pre-established cutoffs using genetic distance. Since the Renaissance, however, most biological classification schemes have relied on the use of diagnostic characters to identify and place species. Methodology/Principal Findings Here we developed a cytochrome c oxidase subunit I character-based key for the identification of all tuna species of the genus Thunnus, and compared its performance with distance-based measures for identification of 68 samples of tuna sushi purchased from 31 restaurants in Manhattan (New York City) and Denver, Colorado. Both the character-based key and GenBank BLAST successfully identified 100% of the tuna samples, while the Barcode of Life Database (BOLD) as well as genetic distance thresholds, and neighbor-joining phylogenetic tree building performed poorly in terms of species identification. A piece of tuna sushi has the potential to be an endangered species, a fraud, or a health hazard. All three of these cases were uncovered in this study. Nineteen restaurant establishments were unable to clarify or misrepresented what species they sold. Five out of nine samples sold as a variant of “white tuna” were not albacore (T. alalunga), but escolar (Lepidocybium flavorunneum), a gempylid species banned for sale in Italy and Japan due to health concerns. Nineteen samples were northern bluefin tuna (T. thynnus) or the critically endangered southern bluefin tuna (T. maccoyii), though nine restaurants that sold these species did not state these species on their menus. Conclusions/Significance The Convention on International Trade Endangered Species (CITES) requires that listed species must be identifiable in trade. This research fulfills this requirement for tuna, and supports the nomination of northern bluefin tuna for CITES listing in 2010. PMID:19924239

Lowenstein, Jacob H.; Amato, George; Kolokotronis, Sergios-Orestis

2009-01-01

136

The quest for genetic determinants of human longevity: challenges and insights  

PubMed Central

Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress. PMID:16708071

Christensen, Kaare; Johnson, Thomas E.; Vaupel, James W.

2009-01-01

137

Hierarchical Genetic Algorithm Approach to Determine Pulse Sequences in NMR  

E-print Network

We develop a new class of genetic algorithm that computationally determines efficient pulse sequences to implement a quantum gate U in a three-qubit system. The method is shown to be quite general, and the same algorithm can be used to derive efficient sequences for a variety of target matrices. We demonstrate this by implementing the inversion-on-equality gate efficiently when the spin-spin coupling constants $J_{12}=J_{23}=J$ and $J_{13}=0$. We also propose new pulse sequences to implement the Parity gate and Fanout gate, which are about 50% more efficient than the previous best efforts. Moreover, these sequences are shown to require significantly less RF power for their implementation. The proposed algorithm introduces several new features in the conventional genetic algorithm framework. We use matrices instead of linear chains, and the columns of these matrices have a well defined hierarchy. The algorithm is a genetic algorithm coupled to a fast local optimizer, and is hence a hybrid GA. It shows fast con...

Ajoy, Ashok

2009-01-01

138

Hierarchical Genetic Algorithm Approach to Determine Pulse Sequences in NMR  

E-print Network

We develop a new class of genetic algorithm that computationally determines efficient pulse sequences to implement a quantum gate U in a three-qubit system. The method is shown to be quite general, and the same algorithm can be used to derive efficient sequences for a variety of target matrices. We demonstrate this by implementing the inversion-on-equality gate efficiently when the spin-spin coupling constants $J_{12}=J_{23}=J$ and $J_{13}=0$. We also propose new pulse sequences to implement the Parity gate and Fanout gate, which are about 50% more efficient than the previous best efforts. Moreover, these sequences are shown to require significantly less RF power for their implementation. The proposed algorithm introduces several new features in the conventional genetic algorithm framework. We use matrices instead of linear chains, and the columns of these matrices have a well defined hierarchy. The algorithm is a genetic algorithm coupled to a fast local optimizer, and is hence a hybrid GA. It shows fast convergence, and running on a MATLAB platform takes about 20 minutes on a standard personal computer to derive efficient pulse sequences for any target 8X8 matrix $U$.

Ashok Ajoy; Anil Kumar

2009-12-04

139

Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins  

PubMed Central

Background Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase) are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category) and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium. Methods CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family. Results None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value < 0.05 in EPICOLON stage 1 [rs698 in ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive), rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive), rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant), and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive). In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1.12, 95% CI = 1.00-1.25, P-value = 0.04, log-additive 0, 1, 2 alleles) and borderline significant for rs698 and rs2102302. The rs3803185 variant was not significantly associated with CRC risk in an external cohort (MCC-Spain), but it still showed some borderline significance in the pooled analysis of both cohorts (OR = 1.08, 95% CI = 0.98-1.18, P-value = 0.09, log-additive 0, 1, 2 alleles). Conclusions ARL11, ADH1C, GALNTL2 and IL6 genetic variants may have an effect on CRC risk. Further validation and meta-analyses should be undertaken in larger CRC studies. PMID:21819567

2011-01-01

140

Low-Dose Radiation Cataract and Genetic Determinants of Radiosensitivity  

SciTech Connect

The lens of the eye is one of the most radiosensitive tissues in the body. Ocular ionizing radiation exposure results in characteristic, dose related, progressive lens changes leading to cataract formation. While initial, early stages of lens opacification may not cause visual disability, the severity of such changes progressively increases with dose until vision is impaired and cataract extraction surgery may be required. Because of the transparency of the eye, radiation induced lens changes can easily be followed non-invasively over time. Thus, the lens provides a unique model system in which to study the effects of low dose ionizing radiation exposure in a complex, highly organized tissue. Despite this observation, considerable uncertainties remain surrounding the relationship between dose and risk of developing radiation cataract. For example, a growing number of human epidemiological findings suggest significant risk among various groups of occupationally and accidentally exposed individuals and confidence intervals that include zero dose. Nevertheless, questions remain concerning the relationship between lens opacities, visual disability, clinical cataract, threshold dose and/or the role of genetics in determining radiosensitivity. Experimentally, the response of the rodent eye to radiation is quite similar to that in humans and thus animal studies are well suited to examine the relationship between radiation exposure, genetic determinants of radiosensitivity and cataractogenesis. The current work has expanded our knowledge of the low-dose effects of X-irradiation or high-LET heavy ion exposure on timing and progression of radiation cataract and has provided new information on the genetic, molecular, biochemical and cell biological features which contribute to this pathology. Furthermore, findings have indicated that single and/or multiple haploinsufficiency for various genes involved in DNA repair and cell cycle checkpoint control, such as Atm, Brca1 or Rad9, influence cataract development and thus radiosensitivity. These observations have direct applicability to various human populations including accidentally exposed individuals, interventional medical workers, astronauts and nuclear plant workers.

Kleiman, Norman Jay [Columbia University] [Columbia University

2013-11-30

141

Genetic Determinants Influencing Human Serum Metabolome among African Americans  

PubMed Central

Phenotypes proximal to gene action generally reflect larger genetic effect sizes than those that are distant. The human metabolome, a result of multiple cellular and biological processes, are functional intermediate phenotypes proximal to gene action. Here, we present a genome-wide association study of 308 untargeted metabolite levels among African Americans from the Atherosclerosis Risk in Communities (ARIC) Study. Nineteen significant common variant-metabolite associations were identified, including 13 novel loci (p<1.6×10?10). These loci were associated with 7–50% of the difference in metabolite levels per allele, and the variance explained ranged from 4% to 20%. Fourteen genes were identified within the nineteen loci, and four of them contained non-synonymous substitutions in four enzyme-encoding genes (KLKB1, SIAE, CPS1, and NAT8); the other significant loci consist of eight other enzyme-encoding genes (ACE, GATM, ACY3, ACSM2B, THEM4, ADH4, UGT1A, TREH), a transporter gene (SLC6A13) and a polycystin protein gene (PKD2L1). In addition, four potential disease-associated paths were identified, including two direct longitudinal predictive relationships: NAT8 with N-acetylornithine, N-acetyl-1-methylhistidine and incident chronic kidney disease, and TREH with trehalose and incident diabetes. These results highlight the value of using endophenotypes proximal to gene function to discover new insights into biology and disease pathology. PMID:24625756

Yu, Bing; Zheng, Yan; Alexander, Danny; Morrison, Alanna C.; Coresh, Josef; Boerwinkle, Eric

2014-01-01

142

What Determines Blood Vessel Structure? Genetic Prespecification vs. Hemodynamics  

NSDL National Science Digital Library

Vascular network remodeling, angiogenesis, and arteriogenesis play an important role in the pathophysiology of ischemic cardiovascular diseases and cancer. Based on recent studies of vascular network development in the embryo, several novel aspects to angiogenesis have been identified as crucial to generate a functional vascular network. These aspects include specification of arterial and venous identity in vessels and network patterning. In early embryogenesis, vessel identity and positioning are genetically hardwired and involve neural guidance genes expressed in the vascular system. We demonstrated that, during later stages of embryogenesis, blood flow plays a crucial role in regulating vessel identity and network remodeling. The flow-evoked remodeling process is dynamic and involves a high degree of vessel plasticity. The open question in the field is how genetically predetermined processes in vessel identity and patterning balance with the contribution of blood flow in shaping a functional vascular architecture. Although blood flow is essential, it remains unclear to what extent flow is able to act on the developing cardiovascular system. There is significant evidence that mechanical forces created by flowing blood are biologically active within the embryo and that the level of mechanical forces and the type of flow patterns present in the embryo are able to affect gene expression. Here, we highlight the pivotal role for blood flow and physical forces in shaping the cardiovascular system.

Elizabeth A. V. Jones (College de France)

2006-10-01

143

Evolution of a pathogen: a comparative genomics analysis identifies a genetic pathway to pathogenesis in Acinetobacter.  

PubMed

Acinetobacter baumannii is an emergent and global nosocomial pathogen. In addition to A. baumannii, other Acinetobacter species, especially those in the Acinetobacter calcoaceticus-baumannii (Acb) complex, have also been associated with serious human infection. Although mechanisms of attachment, persistence on abiotic surfaces, and pathogenesis in A. baumannii have been identified, the genetic mechanisms that explain the emergence of A. baumannii as the most widespread and virulent Acinetobacter species are not fully understood. Recent whole genome sequencing has provided insight into the phylogenetic structure of the genus Acinetobacter. However, a global comparison of genomic features between Acinetobacter spp. has not been described in the literature. In this study, 136 Acinetobacter genomes, including 67 sequenced in this study, were compared to identify the acquisition and loss of genes in the expansion of the Acinetobacter genus. A whole genome phylogeny confirmed that A. baumannii is a monophyletic clade and that the larger Acb complex is also a well-supported monophyletic group. The whole genome phylogeny provided the framework for a global genomic comparison based on a blast score ratio (BSR) analysis. The BSR analysis demonstrated that specific genes have been both lost and acquired in the evolution of A. baumannii. In addition, several genes associated with A. baumannii pathogenesis were found to be more conserved in the Acb complex, and especially in A. baumannii, than in other Acinetobacter genomes; until recently, a global analysis of the distribution and conservation of virulence factors across the genus was not possible. The results demonstrate that the acquisition of specific virulence factors has likely contributed to the widespread persistence and virulence of A. baumannii. The identification of novel features associated with transcriptional regulation and acquired by clades in the Acb complex presents targets for better understanding the evolution of pathogenesis and virulence in the expansion of the genus. PMID:23365658

Sahl, Jason W; Gillece, John D; Schupp, James M; Waddell, Victor G; Driebe, Elizabeth M; Engelthaler, David M; Keim, Paul

2013-01-01

144

Genetic Variants Modulating CRIPTO Serum Levels Identified by Genome-Wide Association Study in Cilento Isolates  

PubMed Central

Cripto, the founding member of the EGF-CFC genes, plays an essential role in embryo development and is involved in cancer progression. Cripto is a GPI-anchored protein that can interact with various components of multiple signaling pathways, such as TGF-?, Wnt and MAPK, driving different processes, among them epithelial-mesenchymal transition, cell proliferation, and stem cell renewal. Cripto protein can also be cleaved and released outside the cell in a soluble and still active form. Cripto is not significantly expressed in adult somatic tissues and its re-expression has been observed associated to pathological conditions, mainly cancer. Accordingly, CRIPTO has been detected at very low levels in the plasma of healthy volunteers, whereas its levels are significantly higher in patients with breast, colon or glioblastoma tumors. These data suggest that CRIPTO levels in human plasma or serum may have clinical significance. However, very little is known about the variability of serum levels of CRIPTO at a population level and the genetic contribution underlying this variability remains unknown. Here, we report the first genome-wide association study of CRIPTO serum levels in isolated populations (n = 1,054) from Cilento area in South Italy. The most associated SNPs (p-value<5*10-8) were all located on chromosome 3p22.1-3p21.3, in the CRIPTO gene region. Overall six CRIPTO associated loci were replicated in an independent sample (n = 535). Pathway analysis identified a main network including two other genes, besides CRIPTO, in the associated regions, involved in cell movement and proliferation. The replicated loci explain more than 87% of the CRIPTO variance, with 85% explained by the most associated SNP. Moreover, the functional analysis of the main associated locus identified a causal variant in the 5’UTR of CRIPTO gene which is able to strongly modulate CRIPTO expression through an AP-1-mediate transcriptional regulation. PMID:25629528

Ruggiero, Daniela; Nappo, Stefania; Nutile, Teresa; Sorice, Rossella; Talotta, Francesco; Giorgio, Emilia; Bellenguez, Celine; Leutenegger, Anne-Louise; Liguori, Giovanna L.; Ciullo, Marina

2015-01-01

145

Genome-wide association study identifies genetic loci associated with iron deficiency.  

PubMed

The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS) was performed using DNA collected from white men aged?25 y and women?50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF)?12 µg/L (cases) and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women). Regression analysis was used to examine the association between case-control status (336 cases, 343 controls) and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP) genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA) medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF) gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10(-7) for all). An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P=7.0×10(-9), corrected P=0.012) was replicated within the VA samples (observed P=0.012). Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification. PMID:21483845

McLaren, Christine E; Garner, Chad P; Constantine, Clare C; McLachlan, Stela; Vulpe, Chris D; Snively, Beverly M; Gordeuk, Victor R; Nickerson, Debbie A; Cook, James D; Leiendecker-Foster, Catherine; Beckman, Kenneth B; Eckfeldt, John H; Barcellos, Lisa F; Murray, Joseph A; Adams, Paul C; Acton, Ronald T; Killeen, Anthony A; McLaren, Gordon D

2011-01-01

146

A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence.  

PubMed

Antibacterial drug development suffers from a paucity of targets whose inhibition kills replicating and nonreplicating bacteria. The latter include phenotypically dormant cells, known as persisters, which are tolerant to many antibiotics and often contribute to failure in the treatment of chronic infections. This is nowhere more apparent than in tuberculosis caused by Mycobacterium tuberculosis, a pathogen that tolerates many antibiotics once it ceases to replicate. We developed a strategy to identify proteins that Mycobacterium tuberculosis requires to both grow and persist and whose inhibition has the potential to prevent drug tolerance and persister formation. This strategy is based on a tunable dual-control genetic switch that provides a regulatory range spanning three orders of magnitude, quickly depletes proteins in both replicating and nonreplicating mycobacteria, and exhibits increased robustness to phenotypic reversion. Using this switch, we demonstrated that depletion of the nicotinamide adenine dinucleotide synthetase (NadE) rapidly killed Mycobacterium tuberculosis under conditions of standard growth and nonreplicative persistence induced by oxygen and nutrient limitation as well as during the acute and chronic phases of infection in mice. These findings establish the dual-control switch as a robust tool with which to probe the essentiality of Mycobacterium tuberculosis proteins under different conditions, including those that induce antibiotic tolerance, and NadE as a target with the potential to shorten current tuberculosis chemotherapies. PMID:24191058

Kim, Jee-Hyun; O'Brien, Kathryn M; Sharma, Ritu; Boshoff, Helena I M; Rehren, German; Chakraborty, Sumit; Wallach, Joshua B; Monteleone, Mercedes; Wilson, Daniel J; Aldrich, Courtney C; Barry, Clifton E; Rhee, Kyu Y; Ehrt, Sabine; Schnappinger, Dirk

2013-11-19

147

Genetic modifier loci of mouse Mfrprd6 identified by quantitative trait locus analysis  

PubMed Central

The identification of genes that modify pathological ocular phenotypes in mouse models may improve our understanding of disease mechanisms and lead to new treatment strategies. Here, we identify modifier loci affecting photoreceptor cell loss in homozygous Mfrprd6 mice, which exhibit a slowly progressive photoreceptor degeneration. A cohort of 63 F2 homozygous Mfrprd6 mice from a (B6.C3Ga-Mfrprd6/J × CAST/EiJ) F1 intercross exhibited a variable number of cell bodies in the retinal outer nuclear layer at 20 weeks of age. Mice were genotyped with a panel of single nucleotide polymorphism markers, and genotypes were correlated with phenotype by quantitative trait locus (QTL) analysis to map modifier loci. A genome-wide scan revealed a statistically significant, protective candidate locus on CAST/EiJ Chromosome 1 and suggestive modifier loci on Chromosomes 6 and 11. Multiple regression analysis of a three-QTL model indicated that the modifier loci on Chromosomes 1 and 6 together account for 26% of the observed phenotypic variation, while the modifier locus on Chromosome 11 explains only an additional 4%. Our findings indicate that the severity of the Mfrprd6 retinal degenerative phenotype in mice depends on the strain genetic background and that a significant modifier locus on CAST/EiJ Chromosome 1 protects against Mfrprd6-associated photoreceptor loss. PMID:24200520

Won, Jungyeon; Charette, Jeremy R.; Philip, Vivek M.; Stearns, Timothy M.; Zhang, Weidong; Naggert, Jürgen K.; Krebs, Mark P.; Nishina, Patsy M.

2014-01-01

148

OptForce: An Optimization Procedure for Identifying All Genetic Manipulations Leading to Targeted Overproductions  

PubMed Central

Computational procedures for predicting metabolic interventions leading to the overproduction of biochemicals in microbial strains are widely in use. However, these methods rely on surrogate biological objectives (e.g., maximize growth rate or minimize metabolic adjustments) and do not make use of flux measurements often available for the wild-type strain. In this work, we introduce the OptForce procedure that identifies all possible engineering interventions by classifying reactions in the metabolic model depending upon whether their flux values must increase, decrease or become equal to zero to meet a pre-specified overproduction target. We hierarchically apply this classification rule for pairs, triples, quadruples, etc. of reactions. This leads to the identification of a sufficient and non-redundant set of fluxes that must change (i.e., MUST set) to meet a pre-specified overproduction target. Starting with this set we subsequently extract a minimal set of fluxes that must actively be forced through genetic manipulations (i.e., FORCE set) to ensure that all fluxes in the network are consistent with the overproduction objective. We demonstrate our OptForce framework for succinate production in Escherichia coli using the most recent in silico E. coli model, iAF1260. The method not only recapitulates existing engineering strategies but also reveals non-intuitive ones that boost succinate production by performing coordinated changes on pathways distant from the last steps of succinate synthesis. PMID:20419153

Ranganathan, Sridhar; Suthers, Patrick F.; Maranas, Costas D.

2010-01-01

149

Harnessing gene expression to identify the genetic basis of drug resistance  

PubMed Central

The advent of cost-effective genotyping and sequencing methods have recently made it possible to ask questions that address the genetic basis of phenotypic diversity and how natural variants interact with the environment. We developed Camelot (CAusal Modelling with Expression Linkage for cOmplex Traits), a statistical method that integrates genotype, gene expression and phenotype data to automatically build models that both predict complex quantitative phenotypes and identify genes that actively influence these traits. Camelot integrates genotype and gene expression data, both generated under a reference condition, to predict the response to entirely different conditions. We systematically applied our algorithm to data generated from a collection of yeast segregants, using genotype and gene expression data generated under drug-free conditions to predict the response to 94 drugs and experimentally confirmed 14 novel gene–drug interactions. Our approach is robust, applicable to other phenotypes and species, and has potential for applications in personalized medicine, for example, in predicting how an individual will respond to a previously unseen drug. PMID:19888205

Chen, Bo-Juen; Causton, Helen C; Mancenido, Denesy; Goddard, Noel L; Perlstein, Ethan O; Pe'er, Dana

2009-01-01

150

Sex-determining genes on mouse autosomes identified by linkage analysis of C57BL\\/6J-YPOS sex reversal  

Microsoft Academic Search

A powerful approach for identifying mammalian primary (gonadal) sex determination genes is the molecular genetic analyses of sex reversal conditions (that is, XX individuals with testicular tissue and XY individuals with ovarian tissue). Here we determined the number and chromosomal location of autosomal and X-linked genes that cause sex reversal in C57BL\\/6J (B6) mice carrying a Y chromosome of Mus

Eva M. Eicher; Linda L. Washburn; Nicholas J. Schork; Barbara K. Lee; Elaine P. Shown; Xiaoling Xu; Robert D. Dredge; M. Todeane Pringle; David C. Page

1996-01-01

151

The Genetic Architecture of Maize (Zea mays L.) Kernel Weight Determination  

PubMed Central

Individual kernel weight is an important trait for maize yield determination. We have identified genomic regions controlling this trait by using the B73xMo17 population; however, the effect of genetic background on control of this complex trait and its physiological components is not yet known. The objective of this study was to understand how genetic background affected our previous results. Two nested stable recombinant inbred line populations (N209xMo17 and R18xMo17) were designed for this purpose. A total of 408 recombinant inbred lines were genotyped and phenotyped at two environments for kernel weight and five other traits related to kernel growth and development. All traits showed very high and significant (P < 0.001) phenotypic variability and medium-to-high heritability (0.60?0.90). When N209xMo17 and R18xMo17 were analyzed separately, a total of 23 environmentally stable quantitative trait loci (QTL) and five epistatic interactions were detected for N209xMo17. For R18xMo17, 59 environmentally stable QTL and 17 epistatic interactions were detected. A joint analysis detected 14 stable QTL regardless of the genetic background. Between 57 and 83% of detected QTL were population specific, denoting medium-to-high genetic background effects. This percentage was dependent on the trait. A meta-analysis including our previous B73xMo17 results identified five relevant genomic regions deserving further characterization. In summary, our grain filling traits were dominated by small additive QTL with several epistatic and few environmental interactions and medium-to-high genetic background effects. This study demonstrates that the number of detected QTL and additive effects for different physiologically related grain filling traits need to be understood relative to the specific germplasm. PMID:25237113

Prado, Santiago Alvarez; López, César G.; Senior, M. Lynn; Borrás, Lucas

2014-01-01

152

A genetic screen identifies an LKB1/PAR1 signaling axis controlling the Hippo/YAP pathway  

PubMed Central

The Hippo/YAP pathway is an emerging signaling cascade involved in the regulation of stem cell activity and organ size. Alterations in Hippo signaling are also a common feature of human epithelial malignancies, although the molecular bases for this misregulation are unclear. As most of the current knowledge has been derived from work in the fruit fly, our understanding of mammalian Hippo/YAP signaling is still incomplete. To identify novel components of this pathway, we performed an RNAi-based kinome screen in human cells. Our screen identified several kinases not previously associated with Hippo signaling that strongly regulate the activity of the Hippo transducer YAP. Some of these kinases control processes such as response to stress, boundary formation, cell cycle and adhesion, and reflect novel inputs that may impinge on Hippo signaling and growth control. One of the hits, LKB1 (also known as Stk11), is a common tumor suppressor whose mechanism of action is only partially understood. We demonstrate that LKB1 acts through its substrates of the PAR-1 family (MARK1-4) to regulate the localization of the baso-lateral polarity complex and the activity of the core Hippo kinases. Murine and human LKB1-deficient tumors exhibit mislocalization of the basolateral determinant Scribble, reduced Hippo kinase activity, and enhanced YAP-driven transcription. Using xenograft assays and genetic analysis, we demonstrate that YAP is functionally important for the tumor suppressive effects of LKB1. Our results identify an important signaling axis that links YAP activation with LKB1 mutations, and have significant implications for the treatment of LKB1-mutant human malignancies. Additionally, our findings provide novel insight into the nature of inputs that speak to the Hippo/YAP signaling cascade. PMID:24362629

Mohseni, Morvarid; Sun, Jianlong; Lau, Allison; Curtis, Stephen; Goldsmith, Jeffrey; Fox, Victor L.; Wei, Chongjuan; Frazier, Marsha; Samson, Owen; Wong, Kwok-Kim; Kim, Carla; Camargo, Fernando D.

2014-01-01

153

Sarcolemmal phospholipid N-methylation in genetically determined hamster cardiomyopathy  

SciTech Connect

The heart sarcolemmal phosphatidylethanolamine N-methylation in UM-X7.1 strain of cardiomyopathic hamsters was examined by using 0.055, 10 and 150 microM S-adenosyl-L-(methyl-/sup 3/H) methionine as methyl donor for sites I, II and III, respectively. In comparison with control values, methylation activities at site I was increased in 40, 120 and 250 days old cardiomyopathic hamsters. On the other hand, methylation activities at sites II and III in 120 and 250 days old cardiomyopathic animals were depressed without any change in the 40 days old group. The alterations in N-methylation activities were associated with kinetic changes in apparent Vmax values without any changes in the apparent Km. These results indicate a defect in the phospholipid N-methylation process in heart sarcolemma during the development of genetically determined cardiomyopathy.

Okumura, K.; Panagia, V.; Jasmin, G.; Dhalla, N.S.

1987-02-27

154

Novel genetic algorithm search procedure for LEED surface structure determination.  

PubMed

Low Energy Electron Diffraction (LEED) is one of the most powerful experimental techniques for surface structure analysis but until now only a trial-and-error approach has been successful. So far, fitting procedures developed to optimize structural and nonstructural parameters-by minimization of the R-factor-have had a fairly small convergence radius, suitable only for local optimization. However, the identification of the global minimum among the several local minima is essential for complex surface structures. Global optimization methods have been applied to LEED structure determination, but they still require starting from structures that are relatively close to the correct one, in order to find the final structure. For complex systems, the number of trial structures and the resulting computation time increase so rapidly that the task of finding the correct model becomes impractical using the present methodologies. In this work we propose a new search method, based on Genetic Algorithms, which is able to determine the correct structural model starting from completely random structures. This method-called here NGA-LEED for Novel Genetic Algorithm for LEED-utilizes bond lengths and symmetry criteria to select reasonable trial structures before performing LEED calculations. This allows a reduction of the parameter space and, consequently of the calculation time, by several orders of magnitude. A refinement of the parameters by least squares fit of simulated annealing is performed only at some intermediate stages and in the final step. The method was successfully tested for two systems, Ag(1?1?1)(4 × 4)-O and Au(1?1?0)-(1 × 2), both in theory versus theory and in theory versus experiment comparisons. Details of the implementation as well as the results for these two systems are presented. PMID:24824047

Viana, M L; dos Reis, D D; Soares, E A; Van Hove, M A; Moritz, W; de Carvalho, V E

2014-06-01

155

Orbit determination by genetic algorithm and application to GEO observation  

NASA Astrophysics Data System (ADS)

This paper demonstrates an initial orbit determination method that solves the problem by a genetic algorithm using two well-known solutions for the Lambert's problem: universal variable method and Battin method. This paper also suggests an intuitive error evaluation method in terms of rotational angle and orbit shape by separating orbit elements into two groups. As reference orbit, mean orbit elements (original two-lines elements) and osculating orbit elements considering the J2 effect are adopted and compared. Our proposed orbit determination method has been tested with actual optical observations of a geosynchronous spacecraft. It should be noted that this demonstration of the orbit determination is limited to one test case. This observation was conducted during approximately 70 min on 2013/05/15 UT. Our method was compared with the orbit elements propagated by SGP4 using the TLE of the spacecraft. The result indicates that our proposed method had a slightly better performance on estimating orbit shape than Gauss's methods and Escobal's method by 120 km. In addition, the result of the rotational angle is closer to the osculating orbit elements than the mean orbit elements by 0.02°, which supports that the estimated orbit is valid.

Hinagawa, Hideaki; Yamaoka, Hitoshi; Hanada, Toshiya

2014-02-01

156

Corneal Antifibrotic Switch Identified in Genetic and Pharmacological Deficiency of Vimentin*  

PubMed Central

The type III intermediate filaments (IFs) are essential cytoskeletal elements of mechanosignal transduction and serve critical roles in tissue repair. Mice genetically deficient for the IF protein vimentin (Vim?/?) have impaired wound healing from deficits in myofibroblast development. We report a surprising finding made in Vim?/? mice that corneas are protected from fibrosis and instead promote regenerative healing after traumatic alkali injury. This reparative phenotype in Vim?/? corneas is strikingly recapitulated by the pharmacological agent withaferin A (WFA), a small molecule that binds to vimentin and down-regulates its injury-induced expression. Attenuation of corneal fibrosis by WFA is mediated by down-regulation of ubiquitin-conjugating E3 ligase Skp2 and up-regulation of cyclin-dependent kinase inhibitors p27Kip1 and p21Cip1. In cell culture models, WFA exerts G2/M cell cycle arrest in a p27Kip1- and Skp2-dependent manner. Finally, by developing a highly sensitive imaging method to measure corneal opacity, we identify a novel role for desmin overexpression in corneal haze. We demonstrate that desmin down-regulation by WFA via targeting the conserved WFA-ligand binding site shared among type III IFs promotes further improvement of corneal transparency without affecting cyclin-dependent kinase inhibitor levels in Vim?/? mice. This dissociates a direct role for desmin in corneal cell proliferation. Taken together, our findings illuminate a previously unappreciated pathogenic role for type III IF overexpression in corneal fibrotic conditions and also validate WFA as a powerful drug lead toward anti-fibrosis therapeutic development. PMID:22117063

Bargagna-Mohan, Paola; Paranthan, Riya R.; Hamza, Adel; Zhan, Chang-Guo; Lee, Do-Min; Kim, Kyung Bo; Lau, Daniel L.; Srinivasan, Cidambi; Nakayama, Keiko; Nakayama, Keiichi I.; Herrmann, Harald; Mohan, Royce

2012-01-01

157

Identifying Support Functions in Developmental Relationships: A Self-Determination Perspective  

ERIC Educational Resources Information Center

This study examines the content of developmental networks from the perspective of self-determination theory. We qualitatively examine 18 proteges' constellations of developmental relationships to identify specific types of developmental support functions. Our study shows that the adoption of self-determination theory leads to a theory-based…

Janssen, Suzanne; van Vuuren, Mark; de Jong, Menno D. T.

2013-01-01

158

Genetic determinants of ethanol-induced liver damage.  

PubMed Central

BACKGROUND: Although a clear correlation exists between cumulative alcohol intake and liver disease, only some of the alcohol abusers develop signs of ethanol-induced liver damage. To identify some of the genetic variations predisposing persons to alcoholic liver disease (ALD), a genetic study was performed in heavy drinkers from the cohort of the Dionysis study, a survey aimed at evaluating liver disease in the open population of two towns in Northern Italy (6917 individuals). MATERIALS AND METHODS: 158 heavy drinkers (approximately 85% of all heavy drinkers in the population; daily alcohol intake > 120 g in males and >60 g in females) were investigated by the analysis of nine polymorphic regions, mapping in exons III and IX of the alcohol-dehydrogenase (ADH)-2 gene, in exon VIII of the ADH3 gene, in intron VI, in the promoter region of the cytochrome P4502E1 (CYP2E1) gene, and in the promoter region of the tumor necrosis factor-alpha gene. RESULTS: Heavy drinkers with or without ALD significantly differed for the distribution of alleles of the cytochrome P4502E1 (CYP2E1) and alcohol-dehydrogenase-3 (ADH-3) genes. In one town, allele C2 in the promoter region of the CYP2E1 gene had a frequency of 0.06 in healthy heavy drinkers, of 0.19 in heavy drinkers with ALD (p = 0.012), and of 0.33 in heavy drinkers with cirrhosis (p = 0.033). In the other town, whose inhabitants have different genetic derivation, a prominent association between ALD and homozygosity for allele ADH3*2 of ADH3 was found, with a prevalence of 0.31 in heavy drinkers with ALD and of 0.07 in healthy heavy drinkers controls (p = 0.004). CONCLUSIONS. Both heterozygosity for allele C2 of CYP2E1 and homozygosity for allele ADH3*2 of ADH3 are independent risk factors for ALD in alcohol abusers. The relative contribution of these genotypes to ALD is dependent on their frequency in the population. Overall, heavy drinkers lacking either of these two genotypes are 3.2 and 4.3 times more protected from developing ALD and cirrhosis respectively. PMID:11471570

Monzoni, A.; Masutti, F.; Saccoccio, G.; Bellentani, S.; Tiribelli, C.; Giacca, M.

2001-01-01

159

Population genetic analysis identifies source-sink dynamics for two sympatric garter snake species (Thamnophis elegans and Thamnophis sirtalis).  

PubMed

Population genetic structure can be shaped by multiple ecological and evolutionary factors, but the genetic consequences of these factors for multiple species inhabiting the same environment remain unexplored. We used microsatellite markers to examine the population structures of two coexisting species of garter snake, Thamnophis elegans and Thamnophis sirtalis, to determine if shared landscape and biology imposed similar population genetic structures. These snakes inhabit a series of ponds, lakes and flooded meadows in northern California and tend to converge on prey type wherever they coexist. Both garter snakes had comparable effective population sizes and bidirectional migration rates (estimated using a maximum-likelihood method based on the coalescent) with low but significant levels of genetic differentiation (F(ST) = 0.024 for T. elegans and 0.035 for T. sirtalis). Asymmetrical gene flow revealed large source populations for both species as well as potential sinks, suggesting frequent extinction-recolonization and metapopulation dynamics. In addition, we found a significant correlation between their genetic structures based on both pairwise F(ST)s for shared populations (P = 0.009) and for bidirectional migration rates (P = 0.024). Possible ecological and evolutionary factors influencing similarities and differences in genetic structure for the two species are discussed. Genetic measures of effective population size and migration rates obtained in this study are also compared with estimates obtained from mark-recapture data. PMID:16262852

Manier, Mollie K; Arnold, Stevan J

2005-11-01

160

New de novo Genetic Mutations in Schizophrenia Identified | Columbia University Medical Center http://www.cumc.columbia.edu/news-room/2012/10/03/new-de-novo-genetic-mutations-in-schizophrenia-identified/#.UKJgImdNKuJ[11/13/2012 9:59:28 AM  

E-print Network

New de novo Genetic Mutations in Schizophrenia Identified | Columbia University Medical Center http://www.cumc.columbia.edu/news-room/2012/10/03/new-de-novo-genetic-mutations-in-schizophrenia-identified/#.UKJgImdNKuJ[11/13/2012 9 Profiles | Map | RSS | Giving New de novo Genetic Mutations in Schizophrenia Identified October 3, 2012 New

161

An XX\\/XY sex microchromosome system in a freshwater turtle, Chelodina longicollis (Testudines: Chelidae) with genetic sex determination  

Microsoft Academic Search

Heteromorphic sex chromosomes are rare in turtles, having been described in only four species. Like many turtle species, the\\u000a Australian freshwater turtle Chelodina longicollis has genetic sex determination, but no distinguishable (heteromorphic) sex chromosomes were identified in a previous karyotyping\\u000a study. We used comparative genomic hybridization (CGH) to show that C. longicollis has an XX\\/XY system of chromosomal sex determination,

Tariq Ezaz; Nicole Valenzuela; Frank Grützner; Ikuo Miura; Arthur Georges; Russell L. Burke; Jennifer A. Marshall Graves

2006-01-01

162

A Candidate Gene Approach Identifies an IL33 Genetic Variant as a Novel Genetic Risk Factor for GCA  

PubMed Central

Introduction Increased expression of IL-33 and its receptor ST2, encoded by the IL1RL1 gene, has been detected in the inflamed arteries of giant cell arteritis (GCA) patients. The aim of the present study was to investigate for the first time the potential influence of the IL33 and IL1RL1 loci on GCA predisposition. Methods A total of 1,363 biopsy-proven GCA patients and 3,908 healthy controls from four European cohorts (Spain, Italy, Germany and Norway) were combined in a meta-analysis. Six genetic variants: rs3939286, rs7025417 and rs7044343, within the IL33 gene, and rs2058660, rs2310173 and rs13015714, within the IL1RL1 gene, previously associated with immune-related diseases, were genotyped using predesigned TaqMan assays. Results A consistent association between the rs7025417 polymorphism and GCA was evident in the overall meta-analysis, under both allele (PMH?=?0.041, OR?=?0.88, CI 95% 0.78–0.99) and recessive (PMH?=?3.40E-03, OR?=?0.53, CI 95% 0.35–0.80) models. No statistically significant differences between allele or genotype frequencies for the other IL33 and IL1RL1 genetic variants were detected in this pooled analysis. Conclusions Our results clearly evidenced the implication of the IL33 rs7025417 polymorphism in the genetic network underlying GCA. PMID:25409453

Márquez, Ana; Solans, Roser; Hernández-Rodríguez, José; Cid, Maria C.; Castańeda, Santos; Ramentol, Marc; Rodriguez-Rodriguez, Luis; Narváez, Javier; Blanco, Ricardo; Ortego-Centeno, Norberto; Palm, Řyvind; Diamantopoulos, Andreas P.; Braun, Niko; Moosig, Frank; Witte, Torsten; Beretta, Lorenzo; Lunardi, Claudio; Cimmino, Marco A.; Vaglio, Augusto; Salvarani, Carlo; González-Gay, Miguel A.; Martín, Javier

2014-01-01

163

Variation in salamander tail regeneration is associated with genetic factors that determine tail morphology.  

PubMed

Very little is known about the factors that cause variation in regenerative potential within and between species. Here, we used a genetic approach to identify heritable genetic factors that explain variation in tail regenerative outgrowth. A hybrid ambystomatid salamander (Ambystoma mexicanum x A. andersoni) was crossed to an A. mexicanum and 217 offspring were induced to undergo metamorphosis and attain terrestrial adult morphology using thyroid hormone. Following metamorphosis, each salamander's tail tip was amputated and allowed to regenerate, and then amputated a second time and allowed to regenerate. Also, DNA was isolated from all individuals and genotypes were determined for 187 molecular markers distributed throughout the genome. The area of tissue that regenerated after the first and second amputations was highly positively correlated across males and females. Males presented wider tails and regenerated more tail tissue during both episodes of regeneration. Approximately 66-68% of the variation in regenerative outgrowth was explained by tail width, while tail length and genetic sex did not explain a significant amount of variation. A small effect QTL was identified as having a sex-independent effect on tail regeneration, but this QTL was only identified for the first episode of regeneration. Several molecular markers significantly affected regenerative outgrowth during both episodes of regeneration, but the effect sizes were small (<4%) and correlated with tail width. The results show that ambysex and minor effect QTL explain variation in adult tail morphology and importantly, tail width. In turn, tail width at the amputation plane largely determines the rate of regenerative outgrowth. Because amputations in this study were made at approximately the same position of the tail, our results resolve an outstanding question in regenerative biology: regenerative outgrowth positively co-varies as a function of tail width at the amputation site. PMID:23843997

Voss, Gareth J; Kump, D Kevin; Walker, John A; Voss, S Randal

2013-01-01

164

Variation in Salamander Tail Regeneration Is Associated with Genetic Factors That Determine Tail Morphology  

PubMed Central

Very little is known about the factors that cause variation in regenerative potential within and between species. Here, we used a genetic approach to identify heritable genetic factors that explain variation in tail regenerative outgrowth. A hybrid ambystomatid salamander (Ambystoma mexicanum x A. andersoni) was crossed to an A. mexicanum and 217 offspring were induced to undergo metamorphosis and attain terrestrial adult morphology using thyroid hormone. Following metamorphosis, each salamander’s tail tip was amputated and allowed to regenerate, and then amputated a second time and allowed to regenerate. Also, DNA was isolated from all individuals and genotypes were determined for 187 molecular markers distributed throughout the genome. The area of tissue that regenerated after the first and second amputations was highly positively correlated across males and females. Males presented wider tails and regenerated more tail tissue during both episodes of regeneration. Approximately 66–68% of the variation in regenerative outgrowth was explained by tail width, while tail length and genetic sex did not explain a significant amount of variation. A small effect QTL was identified as having a sex-independent effect on tail regeneration, but this QTL was only identified for the first episode of regeneration. Several molecular markers significantly affected regenerative outgrowth during both episodes of regeneration, but the effect sizes were small (<4%) and correlated with tail width. The results show that ambysex and minor effect QTL explain variation in adult tail morphology and importantly, tail width. In turn, tail width at the amputation plane largely determines the rate of regenerative outgrowth. Because amputations in this study were made at approximately the same position of the tail, our results resolve an outstanding question in regenerative biology: regenerative outgrowth positively co-varies as a function of tail width at the amputation site. PMID:23843997

Voss, Gareth J.; Kump, D. Kevin; Walker, John A.; Voss, S. Randal

2013-01-01

165

Chemical genetic screen identifies Toxoplasma DJ-1 as a regulator of parasite secretion, attachment, and invasion  

PubMed Central

Toxoplasma gondii is a member of the phylum Apicomplexa that includes several important human pathogens, such as Cryptosporidium and Plasmodium falciparum, the causative agent of human malaria. It is an obligate intracellular parasite that can cause severe disease in congenitally infected neonates and immunocompromised individuals. Despite the importance of attachment and invasion to the success of the parasite, little is known about the underlying mechanisms that drive these processes. Here we describe a screen to identify small molecules that block the process of host cell invasion by the T. gondii parasite. We identified a small molecule that specifically and irreversibly blocks parasite attachment and subsequent invasion of host cells. Using tandem orthogonal proteolysis–activity-based protein profiling, we determined that this compound covalently modifies a single cysteine residue in a poorly characterized protein homologous to the human protein DJ-1. Mutation of this key cysteine residue in the native gene sequence resulted in parasites that were resistant to inhibition of host cell attachment and invasion by the compound. Further analysis of the invasion phenotype confirmed that modification of Cys127 on TgDJ-1 resulted in a block of microneme secretion and motility, even in the presence of direct stimulators of calcium release. Together, our results suggest that TgDJ-1 plays an important role that is likely downstream of the calcium flux required for microneme secretion, parasite motility, and subsequent invasion of host cells. PMID:21670272

Hall, Carolyn I.; Reese, Michael L.; Weerapana, Eranthie; Child, Matthew A.; Bowyer, Paul W.; Albrow, Victoria E.; Haraldsen, Jeralyn D.; Phillips, MacDonald R.; Sandoval, Edgar Deu; Ward, Gary E.; Cravatt, Benjamin F.; Boothroyd, John C.; Bogyo, Matthew

2011-01-01

166

Rapid-Throughput Skeletal Phenotyping of 100 Knockout Mice Identifies 9 New Genes That Determine Bone Strength  

Microsoft Academic Search

Osteoporosis is a common polygenic disease and global healthcare priority but its genetic basis remains largely unknown. We report a high-throughput multi-parameter phenotype screen to identify functionally significant skeletal phenotypes in mice generated by the Wellcome Trust Sanger Institute Mouse Genetics Project and discover novel genes that may be involved in the pathogenesis of osteoporosis. The integrated use of primary

J. H. Duncan Bassett; Apostolos Gogakos; Jacqueline K. White; Holly Evans; Richard M. Jacques; Anne H. van der Spek; Edward Ryder; David Sunter; Alan Boyde; Michael J. Campbell; Peter I. Croucher; Graham R. Williams

2012-01-01

167

Determining the Pathogenicity of Genetic Variants Associated with Cardiac Channelopathies  

PubMed Central

Advancements in genetic screening have generated massive amounts of data on genetic variation; however, a lack of clear pathogenic stratification has left most variants classified as being of unknown significance. This is a critical limitation for translating genetic data into clinical practice. Genetic screening is currently recommended in the guidelines for diagnosis and treatment of cardiac channelopathies, which are major contributors to sudden cardiac death in young people. We propose to characterize the pathogenicity of genetic variants associated with cardiac channelopathies using a stratified scoring system. The development of this system was considered by using all of the tools currently available to define pathogenicity. The use of this scoring system could help clinicians to understand the limitations of genetic associations with a disease, and help them better define the role that genetics can have in their clinical routine. PMID:25608792

Campuzano, Oscar; Allegue, Catarina; Fernandez, Anna; Iglesias, Anna; Brugada, Ramon

2015-01-01

168

Whole genome sequencing to identify host genetic risk factors for severe outcomes of hepatitis a virus infection.  

PubMed

Acute liver failure is a severe, but rare, outcome of hepatitis A virus infection. Unusual presentations of prevalent infections have often been attributed to pathogen-specific immune deficits that exhibit Mendelian inheritance. Genome-wide resequencing of unrelated cases has proven to be a powerful approach for identifying highly penetrant risk alleles that underlie such syndromes. Rare mutations likely to affect protein expression or function can be identified from sequence data, and their association with a similarly rare phenotype rests on their existence in multiple affected individuals. A rare or novel sequence variant that is enriched to a significant degree in a genetically diverse cohort suggests a candidate susceptibility allele. Whole genome sequencing of ten individuals from ethnically diverse backgrounds with HAV-associated acute liver failure was performed. A set of rational filtering criteria was used to identify genetic variants that are rare in the population, but enriched in this cohort. Single nucleotide polymorphisms, insertions, and deletions were considered and autosomal dominant, autosomal recessive, and polygenic models were applied. Analysis of the protein-coding exome identified no single gene with putatively deleterious mutations shared by multiple individuals, arguing against a simple Mendelian model of inheritance. A number of rare variants were significantly enriched in this cohort, consistent with a complex and genetically heterogeneous trait. Several of the variants identified in this genome-wide study lie within genes important to hepatic pathophysiology and are candidate susceptibility alleles for hepatitis A virus infection. PMID:24978929

Long, Dustin; Fix, Oren K; Deng, Xutao; Seielstad, Mark; Lauring, Adam S

2014-10-01

169

An Image-Based Genetic Assay Identifies Genes in T1D Susceptibility Loci Controlling Cellular Antiviral Immunity in Mouse  

PubMed Central

The pathogenesis of complex diseases, such as type 1 diabetes (T1D), derives from interactions between host genetics and environmental factors. Previous studies have suggested that viral infection plays a significant role in initiation of T1D in genetically predisposed individuals. T1D susceptibility loci may therefore be enriched in previously uncharacterized genes functioning in antiviral defense pathways. To identify genes involved in antiviral immunity, we performed an image-based high-throughput genetic screen using short hairpin RNAs (shRNAs) against 161 genes within T1D susceptibility loci. RAW 264.7 cells transduced with shRNAs were infected with GFP-expressing herpes simplex virus type 1 (HSV-1) and fluorescent microscopy was performed to assess the viral infectivity by fluorescence reporter activity. Of the 14 candidates identified with high confidence, two candidates were selected for further investigation, Il27 and Tagap. Administration of recombinant IL-27 during viral infection was found to act synergistically with interferon gamma (IFN-?) to activate expression of type I IFNs and proinflammatory cytokines, and to enhance the activities of interferon regulatory factor 3 (IRF3). Consistent with a role in antiviral immunity, Tagap-deficient macrophages demonstrated increased viral replication, reduced expression of proinflammatory chemokines and cytokines, and decreased production of IFN-?. Taken together, our unbiased loss-of-function genetic screen identifies genes that play a role in host antiviral immunity and delineates roles for IL-27 and Tagap in the production of antiviral cytokines. PMID:25268627

Liao, Juan; Jijon, Humberto B.; Kim, Ira R.; Goel, Gautam; Doan, Aivi; Sokol, Harry; Bauer, Hermann; Herrmann, Bernhard G.; Lassen, Kara G.; Xavier, Ramnik J.

2014-01-01

170

A modified genetic algorithm for precise determination the geometrical orbital elements of binary stars  

Microsoft Academic Search

The paper presents a modified genetic algorithm called adapted genetic algorithm with adjusting population size (AGA-POP) for precise determination the orbital elements of binary stars. The proposed approach is a simple, robust way that can be considered to be a new member in the class of self organizing genetic algorithms. The proposed AGA-POP is applied on the star ? Bootis

Abdel-Fattah Attia; Eman Mahmoud; H. I. Shahin; A. M. Osman

2009-01-01

171

Genetic Determinants of Intrinsic Colistin Tolerance in Acinetobacter baumannii  

PubMed Central

Acinetobacter baumannii is a leading cause of multidrug-resistant infections worldwide. This organism poses a particular challenge due to its ability to acquire resistance to new antibiotics through adaptation or mutation. This study was undertaken to determine the mechanisms governing the adaptability of A. baumannii to the antibiotic colistin. Screening of a transposon mutant library identified over 30 genes involved in inducible colistin resistance in A. baumannii. One of the genes identified was lpsB, which encodes a glycosyltransferase involved in lipopolysaccharide (LPS) synthesis. We demonstrate that loss of LpsB function results in increased sensitivity to both colistin and cationic antimicrobial peptides of the innate immune system. Moreover, LpsB is critical for pathogenesis in a pulmonary model of infection. Taken together, these data define bacterial processes required for intrinsic colistin tolerance in A. baumannii and underscore the importance of outer membrane structure in both antibiotic resistance and the pathogenesis of A. baumannii. PMID:23230287

Hood, M. Indriati; Becker, Kyle W.; Roux, Christelle M.; Dunman, Paul M.

2013-01-01

172

Determinants of public attitudes to genetically modified salmon.  

PubMed

The objective of this paper is to assess the attitude of Malaysian stakeholders to genetically modified (GM) salmon and to identify the factors that influence their acceptance of GM salmon using a structural equation model. A survey was carried out on 434 representatives from various stakeholder groups in the Klang Valley region of Malaysia. Public attitude towards GM salmon was measured using self-developed questionnaires with seven-point Likert scales. The findings of this study have confirmed that public attitudes towards GM salmon is a complex issue and should be seen as a multi-faceted process. The most important direct predictors for the encouragement of GM salmon are the specific application-linked perceptions about religious acceptability of GM salmon followed by perceived risks and benefits, familiarity, and general promise of modern biotechnology. Encouragement of GM salmon also involves the interplay among other factors such as general concerns of biotechnology, threatening the natural order of things, the need for labeling, the need for patenting, confidence in regulation, and societal values. The research findings can serve as a database that will be useful for understanding the social construct of public attitude towards GM foods in a developing country. PMID:24489695

Amin, Latifah; Azad, Md Abul Kalam; Gausmian, Mohd Hanafy; Zulkifli, Faizah

2014-01-01

173

Immunochip Identifies Novel, and Replicates Known, Genetic Risk Loci for Rheumatoid Arthritis in Black South Africans  

PubMed Central

The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10?5). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population. PMID:25014791

Govind, Nimmisha; Choudhury, Ananyo; Hodkinson, Bridget; Ickinger, Claudia; Frost, Jacqueline; Lee, Annette; Gregersen, Peter K; Reynolds, Richard J; Bridges, S Louis; Hazelhurst, Scott; Ramsay, Michčle; Tikly, Mohammed

2014-01-01

174

Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in black South Africans.  

PubMed

The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10(-5)). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population. PMID:25014791

Govind, Nimmisha; Choudhury, Ananyo; Hodkinson, Bridget; Ickinger, Claudia; Frost, Jacqueline; Lee, Annette; Gregersen, Peter K; Reynolds, Richard J; Bridges, S Louis; Hazelhurst, Scott; Ramsay, Michčle; Tikly, Mohammed

2014-01-01

175

Pharmacogenetics: a tool for identifying genetic factors in drug dependence and response to treatment.  

PubMed

Pharmacogenetics research looks at variations in the human genome and ways in which genetic factors might influence how individuals respond to drugs. The authors review basic principles of pharmacogenetics and cite findings from several gene-phenotype studies to illustrate possible associations between genetic variants, drug-related behaviors, and risk for drug dependence. Some gene variants affect responses to one drug; others, to various drugs. Pharmacogenetics can inform medication development and personalized treatment strategies; challenges lie along the pathway to its general use in clinical practice. PMID:22002450

Mroziewicz, Margaret; Tyndale, Rachel F

2010-12-01

176

A Co-Association Network Analysis of the Genetic Determination of Pig Conformation, Growth and Fatness  

PubMed Central

Background Several QTLs have been identified for major economically relevant traits in livestock, such as growth and meat quality, revealing the complex genetic architecture of these traits. The use of network approaches considering the interactions of multiple molecules and traits provides useful insights into the molecular underpinnings of complex traits. Here, a network based methodology, named Association Weight Matrix, was applied to study gene interactions and pathways affecting pig conformation, growth and fatness traits. Results The co-association network analysis underpinned three transcription factors, PPAR?, ELF1, and PRDM16 involved in mesoderm tissue differentiation. Fifty-four genes in the network belonged to growth-related ontologies and 46 of them were common with a similar study for growth in cattle supporting our results. The functional analysis uncovered the lipid metabolism and the corticotrophin and gonadotrophin release hormone pathways among the most important pathways influencing these traits. Our results suggest that the genes and pathways here identified are important determining either the total body weight of the animal and the fat content. For instance, a switch in the mesoderm tissue differentiation may determinate the age-related preferred pathways being in the puberty stage those related with the miogenic and osteogenic lineages; on the contrary, in the maturity stage cells may be more prone to the adipocyte fate. Hence, our results demonstrate that an integrative genomic co-association analysis is a powerful approach for identifying new connections and interactions among genes. Conclusions This work provides insights about pathways and key regulators which may be important determining the animal growth, conformation and body proportions and fatness traits. Molecular information concerning genes and pathways here described may be crucial for the improvement of genetic breeding programs applied to pork meat production. PMID:25503799

Puig-Oliveras, Anna; Ballester, Maria; Corominas, Jordi; Revilla, Manuel; Estellé, Jordi; Fernández, Ana I.; Ramayo-Caldas, Yuliaxis; Folch, Josep M.

2014-01-01

177

Identifying rare variants for genetic risk through a combined pedigree and phenotype approach: application to suicide and asthma.  

PubMed

Suicidal behavior is a complex disorder, with evidence for genetic risk independent of other genetic risk factors including psychiatric disorders. Since 1996, over 3000 DNA samples from Utah suicide decedents have been collected and banked for research use through the Utah Medical Examiner. In addition, over 12,000 Utah suicides were identified through examination of death certificates back to 1904. By linking this data with the Utah Population Database, we have identified multiple extended pedigrees with increased risk for suicide completion. A number of medical conditions co-occur with suicide, including asthma, and this study was undertaken to identify genetic risk common to asthma and suicide. This study tests the hypothesis that a particular comorbid condition may identify a more homogeneous genetic subgroup, facilitating the identification of specific genetic risk factors in that group. From pedigrees at increased risk for suicide, we identified three pedigrees also at significantly increased familial risk for asthma. Five suicide decedents from each of these pedigrees, plus an additional three decedents not from these pedigrees with diagnosed asthma, and 10 decedents with close relatives with asthma were genotyped. Results were compared with 183 publicly available unaffected control exomes from 1000 Genomes and CEPH (Centre d'etude du polymorphisme humain) samples genotyped on the same platform. A further 432 suicide decedents were also genotyped as non-asthma suicide controls. Genotyping was done using the Infinium HumanExome BeadChip. For analysis, we used the pedigree extension of Variant Annotation, Analysis and Search Tool (pVAAST) to calculate the disease burden of each gene. The Phenotype Driven Variant Ontological Re-ranking tool (Phevor) then re-ranked our pVAAST results in context of the phenotype. Using asthma as a seed phenotype, Phevor traversed biomedical ontologies and identified genes with similar biological properties to those known to result in asthma. Our top associated genes included those related to neurodevelopment or neural signaling (brain-derived neurotrophic factor (BDNF), neutral sphingomyelinase 2 (SMPD2), homeobox b2 (HOXB2), neural cell adhesion molecule (NCAM2), heterogeneous nuclear ribonucleoprotein A0 (HNRNPA0)), inflammation (free fatty acid receptor 2 (FFAR2)) and inflammation with additional evidence of neuronal involvement (oxidized low density lipoprotein receptor 1 (OLR1), toll-like receptor 3 (TLR3)). Of particular interest, BDNF has been previously implicated in both psychiatric disorders and asthma. Our results demonstrate the utility of combining pedigree and co-occurring phenotypes to identify rare variants associated with suicide risk in conjunction with specific co-occurring conditions. PMID:25335167

Darlington, T M; Pimentel, R; Smith, K; Bakian, A V; Jerominski, L; Cardon, J; Camp, N J; Callor, W B; Grey, T; Singleton, M; Yandell, M; Renshaw, P F; Yurgelun-Todd, D A; Gray, D; Coon, H

2014-01-01

178

GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics  

PubMed Central

Human perception of bitterness displays pronounced interindividual variation. This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. To better understand the effects of common genetic variations on human bitter taste perception, we conducted a genome-wide association study on a discovery panel of 504 subjects and a validation panel of 104 subjects from the general population of Săo Paulo in Brazil. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 (10.88– 11.24 Mb, build 36.1) significantly associated (best SNP: rs2708377, P = 5.31 × 10?13, r2 = 8.9%, ? = ?0.12, s.e. = 0.016) with the perceived bitterness of caffeine. This association overlaps with—but is statistically distinct from—the previously identified SNP rs10772420 influencing the perception of quinine bitterness that falls in the same bitter taste cluster. We replicated this association to quinine perception (P = 4.97 × 10?37, r2 = 23.2%, ? = 0.25, s.e. = 0.020) and additionally found the effect of this genetic locus to be concentration specific with a strong impact on the perception of low, but no impact on the perception of high concentrations of quinine. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perception. PMID:23966204

Ledda, Mirko; Kutalik, Zoltán; Souza Destito, Maria C.; Souza, Milena M.; Cirillo, Cintia A.; Zamboni, Amabilene; Martin, Nathalie; Morya, Edgard; Sameshima, Koichi; Beckmann, Jacques S.; le Coutre, Johannes; Bergmann, Sven; Genick, Ulrich K.

2014-01-01

179

Determining Relative Importance and Effective Settings for Genetic Algorithm Control Parameters.  

PubMed

Abstract Setting the control parameters of a genetic algorithm so as to obtain good results is a long-standing problem. We define an experiment design and analysis method to determine relative importance and effective settings for control parameters of any evolutionary algorithm, and we apply this method to a classic binary-encoded genetic algorithm (GA). Subsequently, as reported elsewhere, we applied the GA, with the control-parameter settings determined here, to steer a population of cloud-computing simulators toward behaviors that reveal degraded performance and system collapse. GA-steered simulators could serve as a design tool, empowering system engineers to identify and mitigate low-probability, costly failure scenarios. In the existing GA literature, we uncovered conflicting opinions and evidence regarding key GA control parameters, and effective settings to adopt. Consequently, we designed and executed an experiment to determine relative importance and effective settings for seven GA control parameters, when applied across a set of numerical optimization problems drawn from the literature. This paper describes our experiment design, analysis, and results. We found that crossover most significantly influenced GA success, followed by mutation rate and population size, and then re-randomization point and elite selection. Selection method and the precision used within the chromosome to represent numerical values had least influence. Our findings are robust over 60 numerical optimization problems. PMID:25254350

Mills, K L; Filliben, J J; Haines, A L

2014-09-25

180

A case study of "disorganized development" and its possible relevance to genetic determinants of aging.  

PubMed

In 1932, Bidder postulated that senescence results from "continued action of a (genetic) regulator (of development) after growth ceases (maturation occurs)." A 16-year-old girl who physically appears to be an infant has not been diagnosed with any known genetic syndrome or chromosomal abnormality. The subject's anthropometric measurements are that of an 11-month-old. Coordinated development of structures for swallowing/breathing has not occurred resulting in dysfunctional digestive and respiratory systems. Brain structure, proprioception and neuroendocrine functions are infantile. Dental and bone ages are pre-teen, while telomere length and telomerase inactivity suggest a cellular age at least comparable to her chronological age. Sub-telomeric microdeletions known to be responsible for developmental delay and chromosomal imbalances are not present. Findings suggest that the subject suffers from "developmental disorganization" resulting from spontaneous mutation of Bidder's putative "regulator" of development, thereby providing an opportunity to locate and identify developmental gene(s) responsible for ensuring integrated and coordinated change in form and function from conception to adulthood. If their continued expression beyond maturation erodes internal order to promote senescence then further study of her DNA and testing of homologous genes in animal models may provide clues to genetic determinants of aging and human life span. PMID:19428454

Walker, Richard F; Pakula, Lawrence C; Sutcliffe, Maxine J; Kruk, Patricia A; Graakjaer, Jesper; Shay, Jerry W

2009-05-01

181

COMBINING ISOTOPIC AND GENETIC MARKERS TO IDENTIFY BREEDING ORIGINS OF MIGRANT BIRDS  

Microsoft Academic Search

A quantitative method for linking reproductive and nonreproductive phases of migratory life cycles is fundamental to understanding the biology of migratory organisms. Here we combine genetic (mtDNA) and biochemical (stable isotope) information to examine seasonal movements in the Swainson's Thrush ( Catharus ustulatus), a Neotropical migrant. We show that when these intrinsic markers are used in concert, they can predict

Jeffrey F. Kelly; Kristen C. Ruegg; Thomas B. Smith

2005-01-01

182

Genetic variations may help identify best candidates for preventive breast cancer drugs  

Cancer.gov

Newly discovered genetic variations may help predict breast cancer risk in women who receive preventive breast cancer therapy with the selective estrogen receptor modulator drugs tamoxifen and raloxifene, a Mayo Clinic-led study has found. The study is published in the journal Cancer Discovery.

183

A Factor Graph Nested Effects Model To Identify Networks from Genetic Perturbations  

Microsoft Academic Search

Complex phenotypes such as the transformation of a normal population of cells into cancerous tissue result from a series of molecular triggers gone awry. We describe a method that searches for a genetic network consistent with expression changes observed under the knock-down of a set of genes that share a common role in the cell, such as a disease phenotype.

Charles J. Vaske; Carrie House; Truong Luu; Bryan Frank; Chen-Hsiang Yeang; Norman H. Lee; Joshua M. Stuart

2009-01-01

184

Identifying genetic loci controlling neonatal passive transfer of immunity using a hybrid genotyping strategy  

Technology Transfer Automated Retrieval System (TEKTRAN)

Colostrum intake is critical to a piglet’s survival and can be measured by precipitating out the gamma-immunoglobulins from serum with ammonium sulfate (immunocrit). Genetic analysis of immunocrits on 5,312 piglets indicated that the heritabilities (se) for direct and maternal effects were 0.13(0.06...

185

A Novel Forward Genetic Screen for Identifying Mutations Affecting Larval Neuronal Dendrite Development in Drosophila melanogaster  

PubMed Central

Vertebrate and invertebrate dendrites are information-processing compartments that can be found on both central and peripheral neurons. Elucidating the molecular underpinnings of information processing in the nervous system ultimately requires an understanding of the genetic pathways that regulate dendrite formation and maintenance. Despite the importance of dendrite development, few forward genetic approaches have been used to analyze the latest stages of dendrite development, including the formation of F-actin-rich dendritic filopodia or dendritic spines. We developed a forward genetic screen utilizing transgenic Drosophila second instar larvae expressing an actin, green fluorescent protein (GFP) fusion protein (actin?GFP) in subsets of sensory neurons. Utilizing this fluorescent transgenic reporter, we conducted a forward genetic screen of >4000 mutagenized chromosomes bearing lethal mutations that affected multiple aspects of larval dendrite development. We isolated 13 mutations on the X and second chromosomes composing 11 complementation groups affecting dendrite outgrowth/branching, dendritic filopodia formation, or actin?GFP localization within dendrites in vivo. In a fortuitous observation, we observed that the structure of dendritic arborization (da) neuron dendritic filopodia changes in response to a changing environment. PMID:16415365

Medina, Paul Mark B.; Swick, Lance L.; Andersen, Ryan; Blalock, Zachary; Brenman, Jay E.

2006-01-01

186

Integrated analysis of genetic and proteomic data identifies biomarkers associated with adverse events following smallpox vaccination  

Microsoft Academic Search

Complex clinical outcomes, such as adverse reaction to vaccination, arise from the concerted interactions among the myriad components of a biological system. Therefore, comprehensive etiological models can be developed only through the integrated study of multiple types of experimental data. In this study, we apply this paradigm to high-dimensional genetic and proteomic data collected to elucidate the mechanisms underlying the

D M Reif; A A Motsinger-Reif; B A McKinney; M T Rock; J E Crowe; J H Moore

2009-01-01

187

Application of complementation tests in identifying pathogenicity determinants of the chickpea pathogen Ascochyta rabiei  

Technology Transfer Automated Retrieval System (TEKTRAN)

The necrotrophic pathogen Ascochyta rabiei causes chickpea Ascochyta blight. Very little is known about its pathogenicity mechanisms. The objective of this research was to identify pathogenicity determinants of A. rabiei using complementation tests. The hygromycin-resistant mutant ArW519 was non-pa...

188

RNAi-based functional selection identifies novel cell migration determinants dependent on PI3K and AKT pathways.  

PubMed

Lentiviral short hairpin RNA (shRNA)-mediated genetic screening is a powerful tool for identifying loss-of-function phenotype in mammalian cells. Here, we report the identification of 91 cell migration-regulating genes using unbiased genome-wide functional genetic selection. Individual knockdown or cDNA overexpression of a set of 10 candidates reveals that most of these cell migration determinants are strongly dependent on the PI3K/PTEN/AKT pathway and on their downstream signals, such as FOXO1 and p70S6K1. ALK, one of the cell migration promoting genes, uniquely uses p55? regulatory subunit of PI3K, rather than more common p85 subunit, to trigger the activation of the PI3K-AKT pathway. Our method enables the rapid and cost-effective genome-wide selection of cell migration regulators. Our results emphasize the importance of the PI3K/PTEN/AKT pathway as a point of convergence for multiple regulators of cell migration. PMID:25347953

Seo, Minchul; Lee, Shinrye; Kim, Jong-Heon; Lee, Won-Ha; Hu, Guang; Elledge, Stephen J; Suk, Kyoungho

2014-01-01

189

Genetic Analysis of the Heterochromatin of Chromosome 3 in Drosophila Melanogaster. II. Vital Loci Identified through Ems Mutagenesis  

PubMed Central

Chromosome 3 of Drosophila melanogaster contains the last major blocks of heterochromatin in this species to be genetically analyzed. Deficiencies of heterochromatin generated through the detachment of compound-3 chromosomes revealed the presence of vital loci in the heterochromatin of chromosome 3, but an extensive complementation analysis with various combinations of lethal and nonlethal detachment products gave no evidence of tandemly repeated vital genes in this region. These findings indicate that the heterochromatin of chromosome 3 is genetically similar to that of chromosome 2. A more thorough genetic analysis of the heterochromatic regions has been carried out using the chemical mutagen ethyl methanesulfonate (EMS). Seventy-five EMS-induced lethals allelic to loci uncovered by detachment-product deficiencies were recovered and tested for complementation. In total, 12 complementation groups were identified, ten in the heterochromatin to the left of the centromere and two to the right. All but two complementation groups in the left heterochromatic block could be identified as separate loci through deficiency mapping. The interallelic complementation observed between some EMS-induced lethals, as well as the recovery of a temperature-sensitive allele for each of the two loci, provided further evidence that single-copy, transcribed vital genes reside in the heterochromatin of chromosome 3. Cytological analysis of three detachment-product deficiencies provided evidence that at least some of the genes uncovered in this study are located in the most distal segments of the heterochromatin in both arms. This study provides a detailed genetic analysis of chromosome 3 heterochromatin and offers further information on the genetic nature and heterogeneity of Drosophila heterochromatin. PMID:17246481

Marchant, G. E.; Holm, D. G.

1988-01-01

190

Seascape continuity plays an important role in determining patterns of spatial genetic structure in a coral reef fish.  

PubMed

Detecting patterns of spatial genetic structure (SGS) can help identify intrinsic and extrinsic barriers to gene flow within metapopulations. For marine organisms such as coral reef fishes, identifying these barriers is critical to predicting evolutionary dynamics and demarcating evolutionarily significant units for conservation. In this study, we adopted an alternative hypothesis-testing framework to identify the patterns and predictors of SGS in the Caribbean reef fish Elacatinus lori. First, genetic structure was estimated using nuclear microsatellites and mitochondrial cytochrome b sequences. Next, clustering and network analyses were applied to visualize patterns of SGS. Finally, logistic regressions and linear mixed models were used to identify the predictors of SGS. Both sets of markers revealed low global structure: mitochondrial ?ST=0.12, microsatellite FST=0.0056. However, there was high variability among pairwise estimates, ranging from no differentiation between sites on contiguous reef (?ST=0) to strong differentiation between sites separated by ocean expanses?20 km (maximum ?ST=0.65). Genetic clustering and statistical analyses provided additional support for the hypothesis that seascape discontinuity, represented by oceanic breaks between patches of reef habitat, is a key predictor of SGS in E. lori. Notably, the estimated patterns and predictors of SGS were consistent between both sets of markers. Combined with previous studies of dispersal in E. lori, these results suggest that the interaction between seascape continuity and the dispersal kernel plays an important role in determining genetic connectivity within metapopulations. PMID:24803419

D'Aloia, C C; Bogdanowicz, S M; Harrison, R G; Buston, P M

2014-06-01

191

Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges  

PubMed Central

Serious adverse drug reactions (SADRs) are a major cause of morbidity and mortality worldwide. Some SADRs may be predictable, based upon a drug's pharmacodynamic and pharmacokinetic properties. Many, however, appear to be idiosyncratic. Genetic factors may underlie susceptibility to SADRs and the identification of predisposing genotypes may improve patient management through the prospective selection of appropriate candidates. Here we discuss three specific SADRs with an emphasis on genetic risk factors. These SADRs, selected based on wide-sweeping clinical interest, are drug-induced liver injury, statin-induced myotoxicity and drug-induced long QT and torsades de pointes. Key challenges for the discovery of predictive risk alleles for these SADRs are also considered. PMID:17971785

Wilke, Russell A.; Lin, Debbie W.; Roden, Dan M.; Watkins, Paul B.; Flockhart, David; Zineh, Issam; Giacomini, Kathleen M.; Krauss, Ronald M.

2009-01-01

192

41 CFR 102-75.775 - Is the disposal agency required to approve a determination by FEMA that identifies surplus...  

Code of Federal Regulations, 2014 CFR

...agency required to approve a determination by FEMA that identifies surplus property for emergency...agency required to approve a determination by FEMA that identifies surplus property for emergency...determination, under § 102-75.795, by FEMA that identifies surplus property...

2014-01-01

193

41 CFR 102-75.775 - Is the disposal agency required to approve a determination by FEMA that identifies surplus...  

Code of Federal Regulations, 2012 CFR

...agency required to approve a determination by FEMA that identifies surplus property for emergency...agency required to approve a determination by FEMA that identifies surplus property for emergency...determination, under § 102-75.795, by FEMA that identifies surplus property...

2012-01-01

194

41 CFR 102-75.775 - Is the disposal agency required to approve a determination by FEMA that identifies surplus...  

Code of Federal Regulations, 2011 CFR

...agency required to approve a determination by FEMA that identifies surplus property for emergency...agency required to approve a determination by FEMA that identifies surplus property for emergency...determination, under § 102-75.795, by FEMA that identifies surplus property...

2011-01-01

195

41 CFR 102-75.775 - Is the disposal agency required to approve a determination by FEMA that identifies surplus...  

Code of Federal Regulations, 2013 CFR

...agency required to approve a determination by FEMA that identifies surplus property for emergency...agency required to approve a determination by FEMA that identifies surplus property for emergency...determination, under § 102-75.795, by FEMA that identifies surplus property...

2013-07-01

196

Mathematics Helps Determine Time Sequence of Genetic Events in Cancer | Physical Sciences in Oncology  

Cancer.gov

Cancer is inevitably a genetic disease, one characterized by multiple genetic mutations that end up transforming a healthy cell into one that grows uncontrollably. The Cancer Genome Atlas (TCGA) project, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), is in the process of identifying the many mutations that occur in several different cancers.

197

I will review the methods for identifying the genetic basis of behaviour in mice. Starting from crosses between inbred strains I will cover the methodologies that  

E-print Network

the genetic basis of common psychiatric disorders, in particular the determination of the genetic basis multiple phenotypes, opening up new possibilities for a systems level approach to complex traits. I have also investigated the genetic basis of personality traits in humans that predispose to depression

Gruen, Sonja

198

Patterns of genetic differentiation at MHC class I genes and microsatellites identify conservation units in the giant panda  

PubMed Central

Background Evaluating patterns of genetic variation is important to identify conservation units (i.e., evolutionarily significant units [ESUs], management units [MUs], and adaptive units [AUs]) in endangered species. While neutral markers could be used to infer population history, their application in the estimation of adaptive variation is limited. The capacity to adapt to various environments is vital for the long-term survival of endangered species. Hence, analysis of adaptive loci, such as the major histocompatibility complex (MHC) genes, is critical for conservation genetics studies. Here, we investigated 4 classical MHC class I genes (Aime-C, Aime-F, Aime-I, and Aime-L) and 8 microsatellites to infer patterns of genetic variation in the giant panda (Ailuropoda melanoleuca) and to further define conservation units. Results Overall, we identified 24 haplotypes (9 for Aime-C, 1 for Aime-F, 7 for Aime-I, and 7 for Aime-L) from 218 individuals obtained from 6 populations of giant panda. We found that the Xiaoxiangling population had the highest genetic variation at microsatellites among the 6 giant panda populations and higher genetic variation at Aime-MHC class I genes than other larger populations (Qinling, Qionglai, and Minshan populations). Differentiation index (FST)-based phylogenetic and Bayesian clustering analyses for Aime-MHC-I and microsatellite loci both supported that most populations were highly differentiated. The Qinling population was the most genetically differentiated. Conclusions The giant panda showed a relatively higher level of genetic diversity at MHC class I genes compared with endangered felids. Using all of the loci, we found that the 6 giant panda populations fell into 2 ESUs: Qinling and non-Qinling populations. We defined 3 MUs based on microsatellites: Qinling, Minshan-Qionglai, and Daxiangling-Xiaoxiangling-Liangshan. We also recommended 3 possible AUs based on MHC loci: Qinling, Minshan-Qionglai, and Daxiangling-Xiaoxiangling-Liangshan. Furthermore, we recommend that a captive breeding program be considered for the Qinling panda population. PMID:24144019

2013-01-01

199

Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus.  

PubMed

Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo. PMID:25615886

Johnson, Michael R; Behmoaras, Jacques; Bottolo, Leonardo; Krishnan, Michelle L; Pernhorst, Katharina; Santoscoy, Paola L Meza; Rossetti, Tiziana; Speed, Doug; Srivastava, Prashant K; Chadeau-Hyam, Marc; Hajji, Nabil; Dabrowska, Aleksandra; Rotival, Maxime; Razzaghi, Banafsheh; Kovac, Stjepana; Wanisch, Klaus; Grillo, Federico W; Slaviero, Anna; Langley, Sarah R; Shkura, Kirill; Roncon, Paolo; De, Tisham; Mattheisen, Manuel; Niehusmann, Pitt; O'Brien, Terence J; Petrovski, Slave; von Lehe, Marec; Hoffmann, Per; Eriksson, Johan; Coffey, Alison J; Cichon, Sven; Walker, Matthew; Simonato, Michele; Danis, Bénédicte; Mazzuferi, Manuela; Foerch, Patrik; Schoch, Susanne; De Paola, Vincenzo; Kaminski, Rafal M; Cunliffe, Vincent T; Becker, Albert J; Petretto, Enrico

2015-01-01

200

Genetic determinants in the development of sensitization to environmental allergens in early childhood  

PubMed Central

Sensitization to environmental allergens remains one of the strongest risk factors for asthma, and there is likely a genetic basis. We sought to identify genetic determinants for the development of allergic sensitization to environmental allergens, particularly cockroach allergen, in early childhood. A total of 631 children with the information about genotypic data on 895 single nucleotide polymorphisms (SNPs) in 179 candidate genes were selected from an existing dataset (Boston Birth Cohort). Genetic analysis was performed for allergic sensitizations among all subjects and sub-population, Black/African, respectively. Eight SNPs in seven genes showed significant association with allergic sensitization with P?identified several loci that may confer the susceptibility to allergic sensitization, and suggested that sensitization to allergens may depend on their unique loci. PMID:25505553

Tripathi, Priya; Hong, Xiumei; Caruso, Deanna; Gao, Peisong; Wang, Xiaobin

2014-01-01

201

Genetic determinants in the development of sensitization to environmental allergens in early childhood.  

PubMed

Sensitization to environmental allergens remains one of the strongest risk factors for asthma, and there is likely a genetic basis. We sought to identify genetic determinants for the development of allergic sensitization to environmental allergens, particularly cockroach allergen, in early childhood. A total of 631 children with the information about genotypic data on 895 single nucleotide polymorphisms (SNPs) in 179 candidate genes were selected from an existing dataset (Boston Birth Cohort). Genetic analysis was performed for allergic sensitizations among all subjects and sub-population, Black/African, respectively. Eight SNPs in seven genes showed significant association with allergic sensitization with P?identified several loci that may confer the susceptibility to allergic sensitization, and suggested that sensitization to allergens may depend on their unique loci. PMID:25505553

Tripathi, Priya; Hong, Xiumei; Caruso, Deanna; Gao, Peisong; Wang, Xiaobin

2014-11-01

202

Genetic determinants of HIV-1 infection and progression to AIDS: susceptibility to HIV infection.  

PubMed

Interindividual variability in susceptibility to HIV-1 infection, its transmission, disease progression, and response to antiviral therapy has been attributed to host determinants and variability in multiple genes. Although most people exposed to the virus go on to develop full-blown disease at variable intervals, a proportion of them, labeled as long-term nonprogressors or exposed uninfected, possess 'natural resistance' to infection. A better understanding of genetic and immunologic basis of such a natural resistance to infection would bear important implications in designing therapeutic vaccine designs. The genetic variants that could influence susceptibility to HIV-1 and limit AIDS vary in different populations and among individuals. Meta-analyses of large cohort studies have identified numerous 'AIDS restriction genes' that regulate HIV cell entry (particularly chemokine coreceptors and their ligands), acquired and innate immunity (major histocompatibility complex, killer cell immunoglobulin-like receptor, and cytokines), and others [tripartite interaction motif 5 alpha (TRIM5alpha) and apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G] that influence outcome of HIV infection. Studies carried out in the Indian population with regard to genetic polymorphisms in chemokine receptors have shown that (i) the protective CCR5 Delta32 variant is rare, (ii) CCR5HHE carrying *59402A is associated with increased likelihood of infection and development of AIDS, and (iii) the Indian population generally has low CCL3L1 copy numbers (approximately 2.3). These data have implications in developing screening tests that could identify people at higher or lower risk of infection and rate of disease progression, predict vaccine responsiveness in clinical trials and understand the pathogenic mechanisms. PMID:19317737

Kaur, G; Mehra, N

2009-04-01

203

A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer.  

PubMed

Here we describe a conditional piggyBac transposition system in mice and report the discovery of large sets of new cancer genes through a pancreatic insertional mutagenesis screen. We identify Foxp1 as an oncogenic transcription factor that drives pancreatic cancer invasion and spread in a mouse model and correlates with lymph node metastasis in human patients with pancreatic cancer. The propensity of piggyBac for open chromatin also enabled genome-wide screening for cancer-relevant noncoding DNA, which pinpointed a Cdkn2a cis-regulatory region. Histologically, we observed different tumor subentities and discovered associated genetic events, including Fign insertions in hepatoid pancreatic cancer. Our studies demonstrate the power of genetic screening to discover cancer drivers that are difficult to identify by other approaches to cancer genome analysis, such as downstream targets of commonly mutated human cancer genes. These piggyBac resources are universally applicable in any tissue context and provide unique experimental access to the genetic complexity of cancer. PMID:25485836

Rad, Roland; Rad, Lena; Wang, Wei; Strong, Alexander; Ponstingl, Hannes; Bronner, Iraad F; Mayho, Matthew; Steiger, Katja; Weber, Julia; Hieber, Maren; Veltkamp, Christian; Eser, Stefan; Geumann, Ulf; Öllinger, Rupert; Zukowska, Magdalena; Barenboim, Maxim; Maresch, Roman; Cadińanos, Juan; Friedrich, Mathias; Varela, Ignacio; Constantino-Casas, Fernando; Sarver, Aaron; Ten Hoeve, Jelle; Prosser, Haydn; Seidler, Barbara; Bauer, Judith; Heikenwälder, Mathias; Metzakopian, Emmanouil; Krug, Anne; Ehmer, Ursula; Schneider, Günter; Knösel, Thomas; Rümmele, Petra; Aust, Daniela; Grützmann, Robert; Pilarsky, Christian; Ning, Zemin; Wessels, Lodewyk; Schmid, Roland M; Quail, Michael A; Vassiliou, George; Esposito, Irene; Liu, Pentao; Saur, Dieter; Bradley, Allan

2015-01-01

204

An unbiased approach to identify genes involved in development in a turtle with temperature-dependent sex determination  

PubMed Central

Background Many reptiles exhibit temperature-dependent sex determination (TSD). The initial cue in TSD is incubation temperature, unlike genotypic sex determination (GSD) where it is determined by the presence of specific alleles (or genetic loci). We used patterns of gene expression to identify candidates for genes with a role in TSD and other developmental processes without making a priori assumptions about the identity of these genes (ortholog-based approach). We identified genes with sexually dimorphic mRNA accumulation during the temperature sensitive period of development in the Red-eared slider turtle (Trachemys scripta), a turtle with TSD. Genes with differential mRNA accumulation in response to estrogen (estradiol-17?; E2) exposure and developmental stages were also identified. Results Sequencing 767 clones from three suppression-subtractive hybridization libraries yielded a total of 581 unique sequences. Screening a macroarray with a subset of those sequences revealed a total of 26 genes that exhibited differential mRNA accumulation: 16 female biased and 10 male biased. Additional analyses revealed that C16ORF62 (an unknown gene) and MALAT1 (a long noncoding RNA) exhibited increased mRNA accumulation at the male producing temperature relative to the female producing temperature during embryonic sexual development. Finally, we identified four genes (C16ORF62, CCT3, MMP2, and NFIB) that exhibited a stage effect and five genes (C16ORF62, CCT3, MMP2, NFIB and NOTCH2) showed a response to E2 exposure. Conclusions Here we report a survey of genes identified using patterns of mRNA accumulation during embryonic development in a turtle with TSD. Many previous studies have focused on examining the turtle orthologs of genes involved in mammalian development. Although valuable, the limitations of this approach are exemplified by our identification of two genes (MALAT1 and C16ORF62) that are sexually dimorphic during embryonic development. MALAT1 is a noncoding RNA that has not been implicated in sexual differentiation in other vertebrates and C16ORF62 has an unknown function. Our results revealed genes that are candidates for having roles in turtle embryonic development, including TSD, and highlight the need to expand our search parameters beyond protein-coding genes. PMID:22793670

2012-01-01

205

Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas  

PubMed Central

The commonest pediatric brain tumors are low-grade gliomas (LGGs). We utilized whole genome sequencing to discover multiple novel genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24/39 (62%) tumors. Intragenic duplications of the FGFR1 tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes containing TKD-duplicated FGFR1 into brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. TKD-duplicated FGFR1 induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs/LGGNTs. PMID:23583981

Zhang, Jinghui; Wu, Gang; Miller, Claudia P.; Tatevossian, Ruth G.; Dalton, James D.; Tang, Bo; Orisme, Wilda; Punchihewa, Chandanamali; Parker, Matthew; Qaddoumi, Ibrahim; Boop, Fredrick A.; Lu, Charles; Kandoth, Cyriac; Ding, Li; Lee, Ryan; Huether, Robert; Chen, Xiang; Hedlund, Erin; Nagahawatte, Panduka; Rusch, Michael; Boggs, Kristy; Cheng, Jinjun; Becksfort, Jared; Ma, Jing; Song, Guangchun; Li, Yongjin; Wei, Lei; Wang, Jianmin; Shurtleff, Sheila; Easton, John; Zhao, David; Fulton, Robert S.; Fulton, Lucinda L.; Dooling, David J.; Vadodaria, Bhavin; Mulder, Heather L.; Tang, Chunlao; Ochoa, Kerri; Mullighan, Charles G.; Gajjar, Amar; Kriwacki, Richard; Sheer, Denise; Gilbertson, Richard J.; Mardis, Elaine R.; Wilson, Richard K.; Downing, James R.; Baker, Suzanne J.; Ellison, David W.

2013-01-01

206

Comparative survival analysis of breast cancer microarray studies identifies important prognostic genetic pathways  

PubMed Central

Background An estimated 12% of females in the United States will develop breast cancer in their lifetime. Although, there are advances in treatment options including surgery and chemotherapy, breast cancer is still the second most lethal cancer in women. Thus, there is a clear need for better methods to predict prognosis for each breast cancer patient. With the advent of large genetic databases and the reduction in cost for the experiments, researchers are faced with choosing from a large pool of potential prognostic markers from numerous breast cancer gene expression profile studies. Methods Five microarray datasets related to breast cancer were examined using gene set analysis and the cancers were categorized into different subtypes using a scoring system based on genetic pathway activity. Results We have observed that significant genes in the individual studies show little reproducibility across the datasets. From our comparative analysis, using gene pathways with clinical variables is more reliable across studies and shows promise in assessing a patient's prognosis. Conclusions This study concludes that, in light of clinical variables, there are significant gene pathways in common across the datasets. Specifically, several pathways can further significantly stratify patients for survival. These candidate pathways should help to develop a panel of significant biomarkers for the prognosis of breast cancer patients in a clinical setting. PMID:20964848

2010-01-01

207

Genome-wide association identifies genetic variants associated with lentiform nucleus volume in N=1345 young and elderly subjects  

PubMed Central

Deficits in lentiform nucleus volume and morphometry are implicated in a number of genetically influenced disorders, including Parkinson’s disease, schizophrenia, and ADHD. Here we performed genome-wide searches to discover common genetic variants associated with differences in lentiform nucleus volume in human populations. We assessed structural MRI scans of the brain in two large genotyped samples: the Alzheimer’s Disease Neuroimaging Initiative (ADNI; N=706) and the Queensland Twin Imaging Study (QTIM; N=639). Statistics of association from each cohort were combined meta-analytically using a fixed-effects model to boost power and to reduce the prevalence of false positive findings. We identified a number of associations in and around the flavin-containing monooxygenase (FMO) gene cluster. The most highly associated SNP, rs1795240, was located in the FMO3 gene; after meta-analysis, it showed genome-wide significant evidence of association with lentiform nucleus volume (PMA=4.79×10?8). This commonly-carried genetic variant accounted for 2.68 % and 0.84 % of the trait variability in the ADNI and QTIM samples, respectively, even though the QTIM sample was on average 50 years younger. Pathway enrichment analysis revealed significant contributions of this gene to the cytochrome P450 pathway, which is involved in metabolizing numerous therapeutic drugs for pain, seizures, mania, depression, anxiety, and psychosis. The genetic variants we identified provide replicated, genome-wide significant evidence for the FMO gene cluster’s involvement in lentiform nucleus volume differences in human populations. PMID:22903471

Hibar, Derrek P.; Stein, Jason L.; Ryles, April B.; Kohannim, Omid; Jahanshad, Neda; Medland, Sarah E.; Hansell, Narelle K.; McMahon, Katie L.; de Zubicaray, Greig I.; Montgomery, Grant W.; Martin, Nicholas G.; Wright, Margaret J.; Saykin, Andrew J.; Jack, Clifford R.; Weiner, Michael W.; Toga, Arthur W.

2013-01-01

208

Interpretation of electrophoretograms of seven microsatellite loci to determine the genetic diversity of the Arabian Oryx.  

PubMed

Microsatellite markers are commonly used for examining population structure, especially inbreeding, outbreeding and gene flow. An array of microsatellite loci, preferably with multiallelic presentation, is preferable for ensuring accurate results. However, artifact peaks or stutters in the electrophoretograms significantly hamper the reliable interpretation of genotypes. We interpreted electrophoretograms of seven microsatellite loci to determine the genetic diversity of the Arabian Oryx. All the alleles of different loci exhibited good peak resolutions and hence were clearly identified. Moreover, none of the stutter peaks impaired the recognition or differentiation between homozygote and heterozygote. Our findings suggest that correct identification of alleles in the presence of co-amplified nonspecific fragments is important for reliable interpretation of microsatellite data. PMID:20198581

Arif, I A; Khan, H A; Shobrak, M; Al Homaidan, A A; Al Sadoon, M; Al Farhan, A H; Bahkali, A H

2010-01-01

209

Identification of Genetic Determinants of the Sexual Dimorphism in CNS Autoimmunity  

PubMed Central

Multiple sclerosis (MS) is a debilitating chronic inflammatory disease of the nervous system that affects approximately 2.3 million individuals worldwide, with higher prevalence in females, and a strong genetic component. While over 200 MS susceptibility loci have been identified in GWAS, the underlying mechanisms whereby they contribute to disease susceptibility remains ill-defined. Forward genetics approaches using conventional laboratory mouse strains are useful in identifying and functionally dissecting genes controlling disease-relevant phenotypes, but are hindered by the limited genetic diversity represented in such strains. To address this, we have combined the powerful chromosome substitution (consomic) strain approach with the genetic diversity of a wild-derived inbred mouse strain. Using experimental allergic encephalomyelitis (EAE), a mouse model of MS, we evaluated genetic control of disease course among a panel of 26 consomic strains of mice inheriting chromosomes from the wild-derived PWD strain on the C57BL/6J background, which models the genetic diversity seen in human populations. Nineteen linkages on 18 chromosomes were found to harbor loci controlling EAE. Of these 19 linkages, six were male-specific, four were female-specific, and nine were non-sex-specific, consistent with a differential genetic control of disease course between males and females. An MS-GWAS candidate-driven bioinformatic analysis using orthologous genes linked to EAE course identified sex-specific and non-sex-specific gene networks underlying disease pathogenesis. An analysis of sex hormone regulation of genes within these networks identified several key molecules, prominently including the MAP kinase family, known hormone-dependent regulators of sex differences in EAE course. Importantly, our results provide the framework by which consomic mouse strains with overall genome-wide genetic diversity, approximating that seen in humans, can be used as a rapid and powerful tool for modeling the genetic architecture of MS. Moreover, our data represent the first step towards mechanistic dissection of genetic control of sexual dimorphism in CNS autoimmunity. PMID:25671658

Bearoff, Frank; Case, Laure K.; Krementsov, Dimitry N.; Wall, Emma H.; Saligrama, Naresha; Blankenhorn, Elizabeth P.; Teuscher, Cory

2015-01-01

210

Identifying genetic networks in noisy and varied experimental data: The circadian clock in Arabidopsis thaliana  

NASA Astrophysics Data System (ADS)

A scheme for the optimisation of mathematical models of genetic networks has been developed and applied to the circadian clock network in the model plant Arabidopsis thaliana. Our scheme consists of constructing a cost function, which quantifies the agreement between our model and various key experimental features, an approach that may generally be preferable to direct quantitative comparisons with noisy data. We then use this to carry out an efficient search of parameter space, passing the most promising solutions on for local simulated annealing. For an example we construct a model of Arabidopsis and test this against current experimental understanding. Our study reveals the limitations of the most simple network architectures and suggests areas where additional genes might play a role.

Locke, James; Millar, Andrew J.; Turner, Matthew S.

2004-03-01

211

GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment  

PubMed Central

A genome-wide association study of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent SNPs are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (R2 ? 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ? 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics. PMID:23722424

Rietveld, Cornelius A.; Medland, Sarah E.; Derringer, Jaime; Yang, Jian; Esko, Tőnu; Martin, Nicolas W.; Westra, Harm-Jan; Shakhbazov, Konstantin; Abdellaoui, Abdel; Agrawal, Arpana; Albrecht, Eva; Alizadeh, Behrooz Z.; Amin, Najaf; Barnard, John; Baumeister, Sebastian E.; Benke, Kelly S.; Bielak, Lawrence F.; Boatman, Jeffrey A.; Boyle, Patricia A.; Davies, Gail; de Leeuw, Christiaan; Eklund, Niina; Evans, Daniel S.; Ferhmann, Rudolf; Fischer, Krista; Gieger, Christian; Gjessing, Hĺkon K.; Hägg, Sara; Harris, Jennifer R.; Hayward, Caroline; Holzapfel, Christina; Ibrahim-Verbaas, Carla A.; Ingelsson, Erik; Jacobsson, Bo; Joshi, Peter K.; Jugessur, Astanand; Kaakinen, Marika; Kanoni, Stavroula; Karjalainen, Juha; Kolcic, Ivana; Kristiansson, Kati; Kutalik, Zoltán; Lahti, Jari; Lee, Sang H.; Lin, Peng; Lind, Penelope A.; Liu, Yongmei; Lohman, Kurt; Loitfelder, Marisa; McMahon, George; Vidal, Pedro Marques; Meirelles, Osorio; Milani, Lili; Myhre, Ronny; Nuotio, Marja-Liisa; Oldmeadow, Christopher J.; Petrovic, Katja E.; Peyrot, Wouter J.; Polašek, Ozren; Quaye, Lydia; Reinmaa, Eva; Rice, John P.; Rizzi, Thais S.; Schmidt, Helena; Schmidt, Reinhold; Smith, Albert V.; Smith, Jennifer A.; Tanaka, Toshiko; Terracciano, Antonio; van der Loos, Matthijs J.H.M.; Vitart, Veronique; Völzke, Henry; Wellmann, Jürgen; Yu, Lei; Zhao, Wei; Allik, Jüri; Attia, John R.; Bandinelli, Stefania; Bastardot, François; Beauchamp, Jonathan; Bennett, David A.; Berger, Klaus; Bierut, Laura J.; Boomsma, Dorret I.; Bültmann, Ute; Campbell, Harry; Chabris, Christopher F.; Cherkas, Lynn; Chung, Mina K.; Cucca, Francesco; de Andrade, Mariza; De Jager, Philip L.; De Neve, Jan-Emmanuel; Deary, Ian J.; Dedoussis, George V.; Deloukas, Panos; Dimitriou, Maria; Eiriksdottir, Gudny; Elderson, Martin F.; Eriksson, Johan G.; Evans, David M.; Faul, Jessica D.; Ferrucci, Luigi; Garcia, Melissa E.; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Per; Harris, Juliette M.; Harris, Tamara B.; Hastie, Nicholas D.; Heath, Andrew C.; Hernandez, Dena G.; Hoffmann, Wolfgang; Hofman, Adriaan; Holle, Rolf; Holliday, Elizabeth G.; Hottenga, Jouke-Jan; Iacono, William G.; Illig, Thomas; Järvelin, Marjo-Riitta; Kähönen, Mika; Kaprio, Jaakko; Kirkpatrick, Robert M.; Kowgier, Matthew; Latvala, Antti; Launer, Lenore J.; Lawlor, Debbie A.; Lehtimäki, Terho; Li, Jingmei; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C.; Madden, Pamela A.; Magnusson, Patrik K. E.; Mäkinen, Tomi E.; Masala, Marco; McGue, Matt; Metspalu, Andres; Mielck, Andreas; Miller, Michael B.; Montgomery, Grant W.; Mukherjee, Sutapa; Nyholt, Dale R.; Oostra, Ben A.; Palmer, Lyle J.; Palotie, Aarno; Penninx, Brenda; Perola, Markus; Peyser, Patricia A.; Preisig, Martin; Räikkönen, Katri; Raitakari, Olli T.; Realo, Anu; Ring, Susan M.; Ripatti, Samuli; Rivadeneira, Fernando; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sarin, Antti-Pekka; Schlessinger, David; Scott, Rodney J.; Snieder, Harold; Pourcain, Beate St; Starr, John M.; Sul, Jae Hoon; Surakka, Ida; Svento, Rauli; Teumer, Alexander; Tiemeier, Henning; Rooij, Frank JAan; Van Wagoner, David R.; Vartiainen, Erkki; Viikari, Jorma; Vollenweider, Peter; Vonk, Judith M.; Waeber, Gérard; Weir, David R.; Wichmann, H.-Erich; Widen, Elisabeth; Willemsen, Gonneke; Wilson, James F.; Wright, Alan F.; Conley, Dalton; Davey-Smith, George; Franke, Lude; Groenen, Patrick J. F.; Hofman, Albert; Johannesson, Magnus; Kardia, Sharon L.R.; Krueger, Robert F.; Laibson, David; Martin, Nicholas G.; Meyer, Michelle N.; Posthuma, Danielle; Thurik, A. Roy; Timpson, Nicholas J.; Uitterlinden, André G.; van Duijn, Cornelia M.; Visscher, Peter M.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.

2013-01-01

212

Genetic engineering and food: what determines consumer acceptance?  

Microsoft Academic Search

Presents experimental work which attempts to understand what psychological mechanisms are likely to influence consumer acceptance of genetically engineered food, and the relationship between consumer attitudes towards the technology and consumer acceptance of its products. Discusses the relationship between consumer risk perceptions and consumer reactions; the influence of public knowledge and understanding of the technology on attitudes; media impact; ethical

Lynn J. Frewer; Chaya Howard; Richard Shepherd

1995-01-01

213

PLANT GENETIC DETERMINANTS OF ARTHROPOD COMMUNITY STRUCTURE AND DIVERSITY  

Microsoft Academic Search

To test the hypothesis that genes have extended phenotypes on the community, we quantified how genetic differences among cottonwoods affect the diversity, abundance, and composition of the dependent arthropod com- munity. Over two years, five major patterns were observed in both field and common-garden studies that focused on two species of cottonwoods and their naturally occurring F1 and backcross hybrids

Gina M. Wimp; Gregory D. Martinsen; Kevin D. Floate; Randy K. Bangert; Thomas G. Whitham

2005-01-01

214

Genetic determinism of fiber type proportion in human skeletal muscle  

Microsoft Academic Search

Skeletal muscle fiber type distribution is quite heterogeneous, with about 25% of North American Caucasian men and women having either less than 35% or more than 65% of type I fiber in their vastus lateralis muscle. To what extent human skeletal muscle fiber type proportion is under the control of genetic factors is examined in this paper. The results summarized

JEAN-AIME SIMONEAU; CLAUDE BOUCHARD

215

Integrating EMR-Linked and In Vivo Functional Genetic Data to Identify New Genotype-Phenotype Associations  

PubMed Central

The coupling of electronic medical records (EMR) with genetic data has created the potential for implementing reverse genetic approaches in humans, whereby the function of a gene is inferred from the shared pattern of morbidity among homozygotes of a genetic variant. We explored the feasibility of this approach to identify phenotypes associated with low frequency variants using Vanderbilt's EMR-based BioVU resource. We analyzed 1,658 low frequency non-synonymous SNPs (nsSNPs) with a minor allele frequency (MAF)<10% collected on 8,546 subjects. For each nsSNP, we identified diagnoses shared by at least 2 minor allele homozygotes and with an association p<0.05. The diagnoses were reviewed by a clinician to ascertain whether they may share a common mechanistic basis. While a number of biologically compelling clinical patterns of association were observed, the frequency of these associations was identical to that observed using genotype-permuted data sets, indicating that the associations were likely due to chance. To refine our analysis associations, we then restricted the analysis to 711 nsSNPs in genes with phenotypes in the On-line Mendelian Inheritance in Man (OMIM) or knock-out mouse phenotype databases. An initial comparison of the EMR diagnoses to the known in vivo functions of the gene identified 25 candidate nsSNPs, 19 of which had significant genotype-phenotype associations when tested using matched controls. Twleve of the 19 nsSNPs associations were confirmed by a detailed record review. Four of 12 nsSNP-phenotype associations were successfully replicated in an independent data set: thrombosis (F5,rs6031), seizures/convulsions (GPR98,rs13157270), macular degeneration (CNGB3,rs3735972), and GI bleeding (HGFAC,rs16844401). These analyses demonstrate the feasibility and challenges of using reverse genetics approaches to identify novel gene-phenotype associations in human subjects using low frequency variants. As increasing amounts of rare variant data are generated from modern genotyping and sequence platforms, model organism data may be an important tool to enable discovery. PMID:24949630

Mosley, Jonathan D.; Van Driest, Sara L.; Weeke, Peter E.; Delaney, Jessica T.; Wells, Quinn S.; Bastarache, Lisa; Roden, Dan M.; Denny, Josh C.

2014-01-01

216

Genetic Determinism in School Textbooks: A Comparative Study Conducted among Sixteen Countries  

ERIC Educational Resources Information Center

Genetic concepts have significantly evolved over the last ten years, and are now less connected to innate ideas and reductionism. Unique reference to genetic determinism has been replaced by the interaction between the genes and their environment (epigenetics). Our analyses relate to how current school biology textbooks present this new paradigm…

Castera, Jeremy; Clement, Pierre; Abrougui, Mondher; Nisiforou, Olympia; Valanides, Nicos; Turcinaviciene, Jurga; Sarapuu, Tago; Agorram, Boujemaa; Calado, Florbela; Bogner, Franz; Carvalho, Graca

2008-01-01

217

Evolutionary Determinants of Genetic Variation in Susceptibility to Infectious Diseases in Humans  

E-print Network

Evolutionary Determinants of Genetic Variation in Susceptibility to Infectious Diseases in Humans, USA Abstract Although genetic variation among humans in their susceptibility to infectious diseases with 40 human infectious diseases were assessed by a survey of studies on both pedigree-based quantitative

Antonovics, Janis

218

A Neural-Genetic Technique for Coastal Engineering: Determining Wave-induced  

E-print Network

. The GA's main role is numerical optimisation in- spired by natural evolution. GAs can be appliedA Neural-Genetic Technique for Coastal Engineering: Determining Wave-induced Seabed Liquefaction (ANNs) and genetic algorithms (GAs) are becoming an important alternative for solving problems

Blumenstein, Michael

219

Activity of Thalamic Reticular Neurons during Spontaneous Genetically Determined Spike and Wave Discharges  

Microsoft Academic Search

This study reports the first intracellular recordings obtained during spontaneous, genetically determined spike and wave discharges (SWDs) in nucleus reticularis thalami (NRT) neurons from the genetic absence epilepsy rats from Strasbourg (GAERS), a model that closely reproduces the typical features of childhood absence seizures. A SWD started with a large hyperpolarization, which was independent of the preceding firing, and decreased

Sean J. Slaght; Nathalie Leresche; Jean-Michel Deniau; Vincenzo Crunelli; Stephane Charpier

2002-01-01

220

Multi-locus DNA sequencing of Toxoplasma gondii isolated from Brazilian pigs identifies genetically divergent strains  

Technology Transfer Automated Retrieval System (TEKTRAN)

Five Toxoplasma gondii isolates (TgPgBr1-5) were isolated from hearts and brains of pigs freshly purchased at the market of Campos dos Goytacazes, Northern Rio de Janeiro State, Brazil. Four of the five isolates were highly pathogenic in mice. Four genotypes were identified. Multi-locus DNA sequenci...

221

High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.  

PubMed

Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations. PMID:23143596

Eyre, Steve; Bowes, John; Diogo, Dorothée; Lee, Annette; Barton, Anne; Martin, Paul; Zhernakova, Alexandra; Stahl, Eli; Viatte, Sebastien; McAllister, Kate; Amos, Christopher I; Padyukov, Leonid; Toes, Rene E M; Huizinga, Tom W J; Wijmenga, Cisca; Trynka, Gosia; Franke, Lude; Westra, Harm-Jan; Alfredsson, Lars; Hu, Xinli; Sandor, Cynthia; de Bakker, Paul I W; Davila, Sonia; Khor, Chiea Chuen; Heng, Khai Koon; Andrews, Robert; Edkins, Sarah; Hunt, Sarah E; Langford, Cordelia; Symmons, Deborah; Concannon, Pat; Onengut-Gumuscu, Suna; Rich, Stephen S; Deloukas, Panos; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Ärlsetig, Lisbeth; Martin, Javier; Rantapää-Dahlqvist, Solbritt; Plenge, Robert M; Raychaudhuri, Soumya; Klareskog, Lars; Gregersen, Peter K; Worthington, Jane

2012-12-01

222

A forward genetic screen in mice identifies mutants with abnormal cortical patterning.  

PubMed

Formation of a 6-layered cortical plate and axon tract patterning are key features of cerebral cortex development. Abnormalities of these processes may be the underlying cause for a range of functional disabilities seen in human neurodevelopmental disorders. To identify mouse mutants with defects in cortical lamination or corticofugal axon guidance, N-ethyl-N-nitrosourea (ENU) mutagenesis was performed using mice expressing LacZ reporter genes in layers II/III and V of the cortex (Rgs4-lacZ) or in corticofugal axons (TAG1-tau-lacZ). Four lines with abnormal cortical lamination have been identified. One of these was a splice site mutation in reelin (Reln) that results in a premature stop codon and the truncation of the C-terminal region (CTR) domain of reelin. Interestingly, this novel allele of Reln did not display cerebellar malformation or ataxia, and this is the first report of a Reln mutant without a cerebellar defect. Four lines with abnormal cortical axon development were also identified, one of which was found by whole-genome resequencing to carry a mutation in Lrp2. These findings demonstrated that the application of ENU mutagenesis to mice carrying transgenic reporters marking cortical anatomy is a sensitive and specific method to identify mutations that disrupt patterning of the developing brain. PMID:23968836

Ha, Seungshin; Stottmann, Rolf W; Furley, Andrew J; Beier, David R

2015-01-01

223

COMPETITIVE METAGENOMIC DNA HYBRIDIZATION IDENTIFIES HOST-SPECIFIC MICROBIAL GENETIC MARKERS IN COW FECAL SAMPLES  

EPA Science Inventory

Several PCR methods have recently been developed to identify fecal contamination in surface waters. In all cases, researchers have relied on one gene or one microorganism for selection of host specific markers. Here, we describe the application of a genome fragment enrichment met...

224

COMPETITIVE METAGENOMIC DNA HYBRIDIZATION IDENTIFIES HOST-SPECIFIC GENETIC MARKERS IN CATTLE FECAL SAMPLES - ABSTRACT  

EPA Science Inventory

Several PCR methods have recently been developed to identify fecal contamination in surface waters. In all cases, researchers have relied on one gene or one microorganism for selection of host specific markers. Here, we describe the application of a genome fragment enrichment met...

225

Cell Reports A Genetic Screen Identifies TCF3/E2A  

E-print Network

target gene CDKN1A (p21), an in- hibitor of cell-cycle progression, versus BBC3 (PUMA), a key mediator of apoptosis. Our screen identified numerous factors whose depletion cre- ates an imbalance in the p21:PUMA re- pressing PUMA across cancer cell types of multiple origins. Accordingly, TCF3/E2A depletion

226

Identifying determinants of effective complementary feeding behaviour change interventions in developing countries  

PubMed Central

As stunting moves to the forefront of the global agenda, there is substantial evidence that behaviour change interventions (BCI) can improve infant feeding practices and growth. However, this evidence has not been translated into improved outcomes on a national level because we do not know enough about what makes these interventions work, for whom, when, why, at what cost and for how long. Our objective was to examine the design and implementation of complementary feeding BCI, from the peer-reviewed literature, to identify generalisable key determinants. We identified 29 studies that evaluated BCI efficacy or effectiveness, were conducted in developing countries, and reported outcomes on infant and young children aged 6–24 months. Two potential determinants emerged: (1) effective studies used formative research to identify cultural barriers and enablers to optimal feeding practices, to shape the intervention strategy, and to formulate appropriate messages and mediums for delivery; (2) effective studies delineated the programme impact pathway to the target behaviour change and assessed intermediary behaviour changes to learn what worked. We found that BCI that used these developmental and implementation processes could be effective despite heterogeneous approaches and design components. Our analysis was constrained, however, by the limited published data on how design and implementation were carried out, perhaps because of publishing space limits. Information on cost-effectiveness, sustainability and scalability was also very limited. We suggest a more comprehensive reporting process and a more strategic research agenda to enable generalisable evidence to accumulate. PMID:24798264

Fabrizio, Cecilia S; van Liere, Marti; Pelto, Gretel

2014-01-01

227

Identifying determinants of effective complementary feeding behaviour change interventions in developing countries.  

PubMed

As stunting moves to the forefront of the global agenda, there is substantial evidence that behaviour change interventions (BCI) can improve infant feeding practices and growth. However, this evidence has not been translated into improved outcomes on a national level because we do not know enough about what makes these interventions work, for whom, when, why, at what cost and for how long. Our objective was to examine the design and implementation of complementary feeding BCI, from the peer-reviewed literature, to identify generalisable key determinants. We identified 29 studies that evaluated BCI efficacy or effectiveness, were conducted in developing countries, and reported outcomes on infant and young children aged 6-24 months. Two potential determinants emerged: (1) effective studies used formative research to identify cultural barriers and enablers to optimal feeding practices, to shape the intervention strategy, and to formulate appropriate messages and mediums for delivery; (2) effective studies delineated the programme impact pathway to the target behaviour change and assessed intermediary behaviour changes to learn what worked. We found that BCI that used these developmental and implementation processes could be effective despite heterogeneous approaches and design components. Our analysis was constrained, however, by the limited published data on how design and implementation were carried out, perhaps because of publishing space limits. Information on cost-effectiveness, sustainability and scalability was also very limited. We suggest a more comprehensive reporting process and a more strategic research agenda to enable generalisable evidence to accumulate. PMID:24798264

Fabrizio, Cecilia S; van Liere, Marti; Pelto, Gretel

2014-10-01

228

Niche Divergence versus Neutral Processes: Combined Environmental and Genetic Analyses Identify Contrasting Patterns of Differentiation in Recently Diverged Pine Species  

PubMed Central

Background and Aims Solving relationships of recently diverged taxa, poses a challenge due to shared polymorphism and weak reproductive barriers. Multiple lines of evidence are needed to identify independently evolving lineages. This is especially true of long-lived species with large effective population sizes, and slow rates of lineage sorting. North American pines are an interesting group to test this multiple approach. Our aim is to combine cytoplasmic genetic markers with environmental information to clarify species boundaries and relationships of the species complex of Pinus flexilis, Pinus ayacahuite, and Pinus strobiformis. Methods Mitochondrial and chloroplast sequences were combined with previously obtained microsatellite data and contrasted with environmental information to reconstruct phylogenetic relationships of the species complex. Ecological niche models were compared to test if ecological divergence is significant among species. Key Results and Conclusion Separately, both genetic and ecological evidence support a clear differentiation of all three species but with different topology, but also reveal an ancestral contact zone between P. strobiformis and P. ayacahuite. The marked ecological differentiation of P. flexilis suggests that ecological speciation has occurred in this lineage, but this is not reflected in neutral markers. The inclusion of environmental traits in phylogenetic reconstruction improved the resolution of internal branches. We suggest that combining environmental and genetic information would be useful for species delimitation and phylogenetic studies in other recently diverged species complexes. PMID:24205167

Moreno-Letelier, Alejandra; Ortíz-Medrano, Alejandra; Pińero, Daniel

2013-01-01

229

Representation of genetic association via attributable familial relative risks in order to identify polymorphisms functionally relevant to rheumatoid arthritis.  

PubMed

The results from association studies are usually summarized by a measure of evidence of association (frequentist or Bayesian probability values) that does not directly reflect the impact of the detected signals on familial aggregation. This article investigates the possible advantage of a two-dimensional representation of genetic association in order to identify polymorphisms relevant to disease: a measure of evidence of association (the Bayes factor, BF) combined with the estimated contribution to familiality (the attributable sibling relative risk, lambdas). Simulation and data from the North American Rheumatoid Consortium (NARAC) were used to assess the possible benefit under several scenarios. Simulation indicated that the allele frequencies to reach the maximum BF and the maximum attributable lambdas diverged as the size of the genetic effect increased. The representation of BF versus attributable lambdas for selected regions of NARAC data revealed that SNPs involved in replicated associations clearly departed from the bulk of SNPs in these regions. In the 12 investigated regions, and particularly in the low-recombination major histocompatibility region, the ranking of SNPs according to BF differed from the ranking of SNPs according to attributable lambdas. The present results should be generalized using more extensive simulations and additional real data, but they suggest that a characterization of genetic association by both BF and attributable lambdas may result in an improved ranking of variants for further biological analyses. PMID:20017963

Bermejo, Justo Lorenzo; Fischer, Christine; Schulz, Anke; Cremer, Nadine; Hein, Rebecca; Beckmann, Lars; Chang-Claude, Jenny; Hemminki, Kari

2009-01-01

230

Natural diversity in the model legume Medicago truncatula allows identifying distinct genetic mechanisms conferring partial resistance to Verticillium wilt  

PubMed Central

Verticillium wilt is a major threat to alfalfa (Medicago sativa) and many other crops. The model legume Medicago truncatula was used as a host for studying resistance and susceptibility to Verticillium albo-atrum. In addition to presenting well-established genetic resources, this wild plant species enables to investigate biodiversity of the response to the pathogen and putative crosstalk between disease and symbiosis. Symptom scoring after root inoculation and modelling of disease curves allowed assessing susceptibility levels in recombinant lines of three crosses between susceptible and resistant lines, in a core collection of 32 lines, and in mutants affected in symbiosis with rhizobia. A GFP-expressing V. albo-atrum strain was used to study colonization of susceptible plants. Symptoms and colonization pattern in infected M. truncatula plants were typical of Verticillium wilt. Three distinct major quantitative trait loci were identified using a multicross, multisite design, suggesting that simple genetic mechanisms appear to control Verticillium wilt resistance in M. truncatula lines A17 and DZA45.5. The disease functional parameters varied largely in lines of the core collection. This biodiversity with regard to disease response encourages the development of association genetics and ecological approaches. Several mutants of the resistant line, impaired in different steps of rhizobial symbiosis, were affected in their response to V. albo-atrum, which suggests that mechanisms involved in the establishment of symbiosis or disease might have some common regulatory control points. PMID:23213135

Gentzbittel, Laurent

2013-01-01

231

Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits.  

PubMed

The proinflammatory cytokine interleukin (IL)-1? is implicated in the development of insulin resistance and ?-cell dysfunction, whereas higher circulating levels of IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor of IL-1?, has been suggested to improve glycemia and ?-cell function in patients with type 2 diabetes. To elucidate the protective role of IL-1RA, this study aimed to identify genetic determinants of circulating IL-1RA concentration and to investigate their associations with immunological and metabolic variables related to cardiometabolic risk. In the analysis of seven discovery and four replication cohort studies, two single nucleotide polymorphisms (SNPs) were independently associated with circulating IL-1RA concentration (rs4251961 at the IL1RN locus [n = 13,955, P = 2.76 × 10(-21)] and rs6759676, closest gene locus IL1F10 [n = 13,994, P = 1.73 × 10(-17)]). The proportion of the variance in IL-1RA explained by both SNPs combined was 2.0%. IL-1RA-raising alleles of both SNPs were associated with lower circulating C-reactive protein concentration. The IL-1RA-raising allele of rs6759676 was also associated with lower fasting insulin levels and lower HOMA insulin resistance. In conclusion, we show that circulating IL-1RA levels are predicted by two independent SNPs at the IL1RN and IL1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance. PMID:24969107

Herder, Christian; Nuotio, Marja-Liisa; Shah, Sonia; Blankenberg, Stefan; Brunner, Eric J; Carstensen, Maren; Gieger, Christian; Grallert, Harald; Jula, Antti; Kähönen, Mika; Kettunen, Johannes; Kivimäki, Mika; Koenig, Wolfgang; Kristiansson, Kati; Langenberg, Claudia; Lehtimäki, Terho; Luotola, Kari; Marzi, Carola; Müller, Christian; Peters, Annette; Prokisch, Holger; Raitakari, Olli; Rathmann, Wolfgang; Roden, Michael; Salmi, Marko; Schramm, Katharina; Swerdlow, Daniel; Tabak, Adam G; Thorand, Barbara; Wareham, Nick; Wild, Philipp S; Zeller, Tanja; Hingorani, Aroon D; Witte, Daniel R; Kumari, Meena; Perola, Markus; Salomaa, Veikko

2014-12-01

232

Common Genetic Determinants of Lung Function, Subclinical Atherosclerosis and Risk of Coronary Artery Disease  

PubMed Central

Chronic obstructive pulmonary disease (COPD) independently associates with an increased risk of coronary artery disease (CAD), but it has not been fully investigated whether this co-morbidity involves shared pathophysiological mechanisms. To identify potential common pathways across the two diseases, we tested all recently published single nucleotide polymorphisms (SNPs) associated with human lung function (spirometry) for association with carotid intima-media thickness (cIMT) in 3,378 subjects with multiple CAD risk factors, and for association with CAD in a case-control study of 5,775 CAD cases and 7,265 controls. SNPs rs2865531, located in the CFDP1 gene, and rs9978142, located in the KCNE2 gene, were significantly associated with CAD. In addition, SNP rs9978142 and SNP rs3995090 located in the HTR4 gene, were associated with average and maximal cIMT measures. Genetic risk scores combining the most robustly spirometry–associated SNPs from the literature were modestly associated with CAD, (odds ratio (OR) (95% confidence interval (CI95)?=?1.06 (1.03, 1.09); P-value?=?1.5×10?4, per allele). In conclusion, our study suggests that some genetic loci implicated in determining human lung function also influence cIMT and susceptibility to CAD. The present results should help elucidate the molecular underpinnings of the co-morbidity observed across COPD and CAD. PMID:25093840

Sabater-Lleal, Maria; Mälarstig, Anders; Folkersen, Lasse; Soler Artigas, María; Baldassarre, Damiano; Kavousi, Maryam; Almgren, Peter; Veglia, Fabrizio; Brusselle, Guy; Hofman, Albert; Engström, Gunnar; Franco, Oscar H.; Melander, Olle; Paulsson-Berne, Gabrielle; Watkins, Hugh; Eriksson, Per; Humphries, Steve E.; Tremoli, Elena; de Faire, Ulf; Tobin, Martin D.; Hamsten, Anders

2014-01-01

233

An Efficient Genetic Screen in Drosophila to Identify Nuclear-Encoded Genes With Mitochondrial Function  

PubMed Central

We conducted a screen for glossy-eye flies that fail to incorporate BrdU in the third larval instar eye disc but exhibit normal neuronal differentiation and isolated 23 complementation groups of mutants. These same phenotypes were previously seen in mutants for cytochrome c oxidase subunit Va. We have molecularly characterized six complementation groups and, surprisingly, each encodes a mitochondrial protein. Therefore, we believe our screen to be an efficient method for identifying genes with mitochondrial function. PMID:16849596

Liao, T. S. Vivian; Call, Gerald B.; Guptan, Preeta; Cespedes, Albert; Marshall, Jamie; Yackle, Kevin; Owusu-Ansah, Edward; Mandal, Sudip; Fang, Q. Angela; Goodstein, Gelsey L.; Kim, William; Banerjee, Utpal

2006-01-01

234

A High-Resolution Genetic Map of Yellow Monkeyflower Identifies Chemical Defense QTLs and Recombination Rate Variation  

PubMed Central

Genotyping-by-sequencing methods have vastly improved the resolution and accuracy of genetic linkage maps by increasing both the number of marker loci as well as the number of individuals genotyped at these loci. Using restriction-associated DNA sequencing, we construct a dense linkage map for a panel of recombinant inbred lines derived from a cross between divergent ecotypes of Mimulus guttatus. We used this map to estimate recombination rate across the genome and to identify quantitative trait loci for the production of several secondary compounds (PPGs) of the phenylpropanoid pathway implicated in defense against herbivores. Levels of different PPGs are correlated across recombinant inbred lines suggesting joint regulation of the phenylpropanoid pathway. However, the three quantitative trait loci identified in this study each act on a distinct PPG. Finally, we map three putative genomic inversions differentiating the two parental populations, including a previously characterized inversion that contributes to life-history differences between the annual/perennial ecotypes. PMID:24626287

Holeski, Liza M.; Monnahan, Patrick; Koseva, Boryana; McCool, Nick; Lindroth, Richard L.; Kelly, John K.

2014-01-01

235

Pharmacological Profiles of Alpha 2 Adrenergic Receptor Agonists Identified Using Genetically Altered Mice and Isobolographic Analysis  

PubMed Central

Endogenous, descending noradrenergic fibers convey powerful analgesic control over spinal afferent circuitry mediating the rostrad transmission of pain signals. These fibers target alpha 2 adrenergic receptors (?2ARs) on both primary afferent terminals and secondary neurons, and their activation mediates substantial inhibitory control over this transmission, rivaling that of opioid receptors which share similar a similar pattern of distribution. The terminals of primary afferent nociceptive neurons and secondary spinal dorsal horn neurons express ?2AAR and ?2CAR subtypes, respectively. Spinal delivery of these agents serves to reduce their side effects, which are mediated largely at supraspinal sites, by concentrating the drugs at the spinal level. Targeting these spinal ?2ARs with one of five selective therapeutic agonists, clonidine, dexmedetomidine, brimonidine, ST91 and moxonidine, produces significant antinociception that can work in concert with opioid agonists to yield synergistic antinociception. Application of several genetically altered mouse lines had facilitated identification of the primary receptor subtypes that likely mediate the antinociceptive effects of these agents. This review provides first an anatomical description of the localization of the three subtypes in the central nervous system, second a detailed account of the pharmacological history of each of these six primary agonists, and finally a comprehensive report of the specific interactions of other GPCR agonists with each of the six principal ?2AR agonists featured. PMID:19393691

Fairbanks, Carolyn A.; Stone, Laura S.; Wilcox, George L.

2009-01-01

236

Rank-based tests for identifying multiple genetic variants associated with quantitative traits.  

PubMed

We consider the analysis of multiple genetic variants within a gene or a region that are expected to confer risks to human complex diseases with quantitative traits, where the trait values do not follow the normal distribution even after some transformations. We rank the phenotypic values, calculate a score to measure the trend effect of a particular allele for each marker, and then construct three statistics based on the quadratic frameworks of methods Hotelling T(2) , the summation of squared univariate statistic and the inverse of the square root weighted statistics to combine the scores for different marker loci. Simulation results show that the above three test statistics can control the type I error rate well and are more robust than standard tests constructed based on linear regression. Application to GAW16 data for rheumatoid arthritis successfully detects the association between the HLA-DRB1 gene and anticyclic citrullinated protein measure, while the standard methods based on normal assumption cannot detect this association. PMID:24942081

Li, Zhengbang; Yuan, Ao; Han, Gang; Gao, Guimin; Li, Qizhai

2014-07-01

237

Genetics of canine diabetes mellitus: are the diabetes susceptibility genes identified in humans involved in breed susceptibility to diabetes mellitus in dogs?  

PubMed

Diabetes mellitus is a common endocrinopathy in companion animals, characterised by hyperglycaemia, glycosuria and weight loss, resulting from an absolute or relative deficiency in the pancreatic hormone insulin. There are breed differences in susceptibility to diabetes mellitus in dogs, with the Samoyed breed being overrepresented, while Boxers are relatively absent in the UK population of diabetic dogs, suggesting that genetic factors play an important role in determining susceptibility to the disease. A number of genes, linked with susceptibility to diabetes mellitus in humans, are associated with an increased risk of diabetes mellitus in dogs, some of which appear to be relatively breed-specific. Diabetes mellitus in dogs has been associated with major histocompatibility complex (MHC) class II genes (dog leucocyte antigen; DLA), with similar haplotypes and genotypes being identified in the most susceptible breeds. A region containing a variable number of tandem repeats (VNTR) and several polymorphisms have been identified in the canine insulin gene, with some alleles associated with susceptibility or resistance to diabetes mellitus in a breed-specific manner. Polymorphisms in the canine CTLA4 promoter and in other immune response genes are associated with susceptibility to diabetes mellitus in a number of pedigree breeds. Genome wide association studies are currently underway that should shed further light on the genetic factors responsible for the breed profile seen in the diabetic dog population. PMID:23265864

Catchpole, Brian; Adams, Jamie P; Holder, Angela L; Short, Andrea D; Ollier, William E R; Kennedy, Lorna J

2013-02-01

238

Genetic implanted fuzzy model for water saturation determination  

NASA Astrophysics Data System (ADS)

The portion of rock pore volume occupied with non-hydrocarbon fluids is called water saturation, which plays a significant role in reservoir description and management. Accurate water saturation, directly measured from special core analysis is highly expensive and time consuming. Furthermore, indirect measurements of water saturation from well log interpretation such as empirical correlations or statistical methods do not provide satisfying results. Recent works showed that fuzzy logic is a robust tool for handling geosciences problems which provide more reliable results compared with empirical correlations or statistical methods. This study goes further to improve fuzzy logic for enhancing accuracy of final prediction. It employs hybrid genetic algorithm-pattern search technique instead of widely held subtractive clustering approach for setting up fuzzy rules and for extracting optimal parameters involved in computational structure of fuzzy model. The proposed strategy, called genetic implanted fuzzy model, was used to formulate conventional well log data, including sonic transit time, neutron porosity, formation bulk density, true resistivity, and gamma ray into water saturation, obtained from subtractive clustering approach. Results indicated genetic implanted fuzzy model performed more satisfyingly compared with traditional fuzzy logic model. The propounded model was successfully applied to one of Iranian carbonate reservoir rocks.

Bagheripour, Parisa; Asoodeh, Mojtaba

2014-04-01

239

Human usage in the native range may determine future genetic structure of an invasion: insights from Acacia pycnantha  

PubMed Central

Background The influence of introduction history and post-introduction dynamics on genetic diversity and structure has been a major research focus in invasion biology. However, genetic diversity and structure in the invasive range can also be affected by human-mediated processes in the native range prior to species introductions, an aspect often neglected in invasion biology. Here we aim to trace the native provenance of the invasive tree Acacia pycnantha by comparing the genetic diversity and structure between populations in the native Australian range and the invasive range in South Africa. This approach also allowed us to explore how human actions altered genetic structure before and after the introduction of A. pycnantha into South Africa. We hypothesized that extensive movement and replanting in A. pycnantha’s Australian range prior to its introduction to South Africa might result in highly admixed genotypes in the introduced range, comparable genetic diversity in both ranges, and therefore preclude an accurate determination of native provenance(s) of invasive populations. Results In the native range Bayesian assignment tests identified three genetic clusters with substantial admixture and could not clearly differentiate previously identified genetic entities, corroborating admixture as a result of replantings within Australia. Assignment tests that included invasive populations from South Africa indicated similar levels of admixture compared to Australian populations and a lack of genetic structure. Invasive populations of A. pycnantha in South Africa are as genetically diverse as native populations, and could not be assigned to particular native range regions. Conclusions Our results indicate that the genetic structure of A. pycnantha in Australia has been greatly altered through various planting initiatives. Specifically, there is little geographic structure and high levels of admixture. While numerous introduction history scenarios may explain the levels of admixture observed in South Africa, planting records of A. pycnantha in Australia suggest that populations were probably already admixed before propagules were introduced to South Africa. These findings have important implications for the management of invasive A. pycnantha populations in South Africa, especially for classical biological control, and more broadly, for studies that aim to understand the evolutionary dynamics of the invasion process. PMID:24083397

2013-01-01

240

Coupling Genetics and Proteomics To Identify Aphid Proteins Associated with Vector-Specific Transmission of Polerovirus (Luteoviridae)?  

PubMed Central

Cereal yellow dwarf virus-RPV (CYDV-RPV) is transmitted specifically by the aphids Rhopalosiphum padi and Schizaphis graminum in a circulative nonpropagative manner. The high level of vector specificity results from the vector aphids having the functional components of the receptor-mediated endocytotic pathways to allow virus to transverse the gut and salivary tissues. Studies of F2 progeny from crosses of vector and nonvector genotypes of S. graminum showed that virus transmission efficiency is a heritable trait regulated by multiple genes acting in an additive fashion and that gut- and salivary gland-associated factors are not genetically linked. Utilizing two-dimensional difference gel electrophoresis to compare the proteomes of vector and nonvector parental and F2 genotypes, four aphid proteins (S4, S8, S29, and S405) were specifically associated with the ability of S. graminum to transmit CYDV-RPV. The four proteins were coimmunoprecipitated with purified RPV, indicating that the aphid proteins are capable of binding to virus. Analysis by mass spectrometry identified S4 as a luciferase and S29 as a cyclophilin, both of which have been implicated in macromolecular transport. Proteins S8 and S405 were not identified from available databases. Study of this unique genetic system coupled with proteomic analysis indicated that these four virus-binding aphid proteins were specifically inherited and conserved in different generations of vector genotypes and suggests that they play a major role in regulating polerovirus transmission. PMID:17959668

Yang, Xiaolong; Thannhauser, T. W.; Burrows, Mary; Cox-Foster, Diana; Gildow, Fred E.; Gray, Stewart M.

2008-01-01

241

Genetic determinants of immune-response to a polysaccharide vaccine for typhoid  

Microsoft Academic Search

Differences in immunological response among vaccine recipients are determined both by their genetic differences and environmental\\u000a factors. Knowledge of genetic determinants of immunological response to a vaccine can be used to design a vaccine that circumvents\\u000a immunogenetic restrictions. The currently available vaccine for typhoid is a pure polysaccharide vaccine, immune response\\u000a to which is T-cell independent. Little is known about

Partha P. Majumder; Herman F. Staats; Neeta Sarkar-Roy; Binuja Varma; Trina Ghosh; Sujit Maiti; K. Narayanasamy; Carol C. Whisnant; James L. Stephenson; Diane K. Wagener

2009-01-01

242

Application of genetic and spatial analyses to identify collection priorities for wild Malus species  

Technology Transfer Automated Retrieval System (TEKTRAN)

The USDA-ARS National Plant Germplasm System has 33 species of wild Malus, many of which were acquired from plant explorations performed over the past 30 years. The phylogenetic relationships among these species were determined by chloroplast sequencing (1681 bp from four regions). Five primary clad...

243

First Streptococcus pyogenes Signature-Tagged Mutagenesis Screen Identifies Novel Virulence Determinants?  

PubMed Central

The virulence of bacterial pathogens is a complex process that requires the dynamic expression of many genes for the pathogens to invade and circumvent host defenses, as well as to proliferate in vivo. In this study, we employed a large-scale screen, signature-tagged mutagenesis (STM), to identify Streptococcus pyogenes virulence genes important for pathogenesis within the host. Approximately 1,200 STM mutants were created and screened using the zebrafish infectious disease model. The transposon insertion site was identified for 29 of the 150 mutants that were considered attenuated for virulence. Previously reported streptococcal virulence genes, such as mga, hasA, amrA, smeZ, and two genes in the sil locus, were identified, confirming the utility of the model for revealing genes important for virulence. Multiple genes not previously implicated in virulence were also identified, including genes encoding putative transporters, hypothetical cytosolic proteins, and macrolide efflux pumps. The STM mutant strains display various levels of attenuation, and multiple separate insertions were identified in either the same gene or the same locus, suggesting that these factors are important for this type of acute, invasive infection. We further examined two such genes, silB and silC of a putative quorum-sensing regulon, and determined that they are significant virulence factors in our model of necrotizing fasciitis. sil locus promoter expression was examined under various in vitro conditions, as well as in zebrafish tissues, and was found to be differentially induced. This study was a unique investigation of S. pyogenes factors required for successful invasive infection. PMID:19223485

Kizy, Anne E.; Neely, Melody N.

2009-01-01

244

Systematic Confirmation Study of GWAS-Identified Genetic Variants for Kawasaki Disease in A Chinese Population.  

PubMed

Genome-wide association studies (GWASs) have identified multiple single nucleotide polymorphisms (SNPs) associated with Kawasaki disease (KD). In this study, we replicated the associations of 10 GWAS-identified SNPs with KD in a Han Chinese population. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression, and cumulative effect of non-risk genotypes were also performed. Although none of the SNPs reached the corrected significance level, 4 SNPs showed nominal associations with KD risk. Compared with their respective wild type counterparts, rs1801274 AG+GG genotypes and rs3818298 TC+CC genotypes were nominally associated with the reduced risk of KD (OR = 0.77, 95% CI = 0.59-0.99, P = 0.045; OR = 0.74, 95% CI = 0.56-0.98, P = 0.038). Meanwhile, rs1801274 GG genotype, rs2736340 CC genotype or rs4813003 TT genotype showed a reduced risk trend (OR = 0.57, 95% CI = 0.35-0.93, P = 0.024; OR = 0.46, 95% CI = 0.26-0.83, P = 0.010; OR = 0.64, 95% CI = 0.43-0.94, P = 0.022), compared with rs1801274 AG+AA genotypes, rs2736340 CT+TT genotypes or rs4813003 TC+CC genotypes, respectively. Furthermore, a cumulative effect was observed with the ORs being gradually decreased with the increasing accumulative number of non-risk genotypes (Ptrend<0.001). In conclusion, our study suggests that 4 GWAS-identified SNPs, rs2736340, rs4813003, rs3818298 and rs1801274, were nominally associated with KD risk in a Han Chinese population individually and jointly. PMID:25645453

Lou, Jiao; Zhong, Rong; Shen, Na; Lu, Xu-Zai; Ke, Jun-Tao; Duan, Jia-Yu; Qi, Yan-Qi; Wang, Yu-Jia; Zhang, Qing; Wang, Wei; Gong, Fang-Qi; Miao, Xiao-Ping

2015-01-01

245

Systematic Confirmation Study of GWAS-Identified Genetic Variants for Kawasaki Disease in A Chinese Population  

PubMed Central

Genome-wide association studies (GWASs) have identified multiple single nucleotide polymorphisms (SNPs) associated with Kawasaki disease (KD). In this study, we replicated the associations of 10 GWAS-identified SNPs with KD in a Han Chinese population. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression, and cumulative effect of non-risk genotypes were also performed. Although none of the SNPs reached the corrected significance level, 4 SNPs showed nominal associations with KD risk. Compared with their respective wild type counterparts, rs1801274 AG+GG genotypes and rs3818298 TC+CC genotypes were nominally associated with the reduced risk of KD (OR = 0.77, 95% CI = 0.59–0.99, P = 0.045; OR = 0.74, 95% CI = 0.56–0.98, P = 0.038). Meanwhile, rs1801274 GG genotype, rs2736340 CC genotype or rs4813003 TT genotype showed a reduced risk trend (OR = 0.57, 95% CI = 0.35–0.93, P = 0.024; OR = 0.46, 95% CI = 0.26–0.83, P = 0.010; OR = 0.64, 95% CI = 0.43–0.94, P = 0.022), compared with rs1801274 AG+AA genotypes, rs2736340 CT+TT genotypes or rs4813003 TC+CC genotypes, respectively. Furthermore, a cumulative effect was observed with the ORs being gradually decreased with the increasing accumulative number of non-risk genotypes (Ptrend<0.001). In conclusion, our study suggests that 4 GWAS-identified SNPs, rs2736340, rs4813003, rs3818298 and rs1801274, were nominally associated with KD risk in a Han Chinese population individually and jointly. PMID:25645453

Lou, Jiao; Zhong, Rong; Shen, Na; Lu, Xu-zai; Ke, Jun-tao; Duan, Jia-yu; Qi, Yan-qi; Wang, Yu-jia; Zhang, Qing; Wang, Wei; Gong, Fang-qi; Miao, Xiao-ping

2015-01-01

246

UTILIZATION OF AN EMR-BIOREPOSITORY TO IDENTIFY THE GENETIC PREDICTORS OF CALCINEURIN-INHIBITOR TOXICITY IN HEART TRANSPLANT RECIPIENTS  

PubMed Central

Calcineurin-inhibitors CI are immunosuppressive agents prescribed to patients after solid organ transplant to prevent rejection. Although these drugs have been transformative for allograft survival, long-term use is complicated by side effects including nephrotoxicity. Given the narrow therapeutic index of CI, therapeutic drug monitoring is used to prevent acute rejection from underdosing and acute toxicity from overdosing, but drug monitoring does not alleviate long-term side effects. Patients on calcineurin-inhibitors for long periods almost universally experience declines in renal function, and a subpopulation of transplant recipients ultimately develop chronic kidney disease that may progress to end stage renal disease attributable to calcineurin inhibitor toxicity (CNIT). Pharmacogenomics has the potential to identify patients who are at high risk for developing advanced chronic kidney disease caused by CNIT and providing them with existing alternate immunosuppressive therapy. In this study we utilized BioVU, Vanderbilt University Medical Center’s DNA biorepository linked to de-identified electronic medical records to identify a cohort of 115 heart transplant recipients prescribed calcineurin-inhibitors to identify genetic risk factors for CNIT We identified 37 cases of nephrotoxicity in our cohort, defining nephrotoxicity as a monthly median estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at least six months post-transplant for at least three consecutive months. All heart transplant patients were genotyped on the Illumina ADME Core Panel, a pharmacogenomic genotyping platform that assays 184 variants across 34 genes. In Cox regression analysis adjusting for age at transplant, pre-transplant chronic kidney disease, pre-transplant diabetes, and the three most significant principal components (PCAs), we did not identify any markers that met our multiple-testing threshold. As a secondary analysis we also modeled post-transplant eGFR directly with linear mixed models adjusted for age at transplant, cyclosporine use, median BMI, and the three most significant principal components. While no SNPs met our threshold for significance, a SNP previously identified in genetic studies of the dosing of tacrolimus CYP3A5 rs776746, replicated in an adjusted analysis at an uncorrected p-value of 0.02 (coeff(S.E.) = 14.60(6.41)). While larger independent studies will be required to further validate this finding, this study underscores the EMRs usefulness as a resource for longitudinal pharmacogenetic study designs. PMID:24297552

Oetjens, Matthew; Bush, William S.; Birdwell, Kelly A.; Dilks, Holli H.; Bowton, Erica A.; Denny, Joshua C.; Wilke, Russell A.; Roden, Dan M.; Crawford, Dana C.

2014-01-01

247

Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features  

PubMed Central

Background Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. Methods and Findings To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in ?-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas. Conclusions The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life. PMID:18769486

Kool, Marcel; Koster, Jan; Bunt, Jens; Hasselt, Nancy E.; Lakeman, Arjan; van Sluis, Peter; Troost, Dirk; Meeteren, Netteke Schouten-van; Caron, Huib N.; Cloos, Jacqueline; Mrši?, Alan; Ylstra, Bauke; Grajkowska, Wieslawa; Hartmann, Wolfgang; Pietsch, Torsten; Ellison, David; Clifford, Steven C.; Versteeg, Rogier

2008-01-01

248

A genetic pedigree analysis to identify gene mutations involved in femoral head necrosis.  

PubMed

The present study presents results from a linkage and mutation screening analysis aiming to identify the causative gene of femoral head necrosis, also known as osteonecrosis of femoral head (ONFH), in a Chinese pedigree. We collected clinical data on the osteonecrosis pedigree, and extracted blood and genomic DNA from the family members. Polymerase chain reaction (PCR) and direct sequencing allowed to identify a mutation in the COL2A1 gene of the proband; the clinical manifestations of the proband meet the criteria for osteonecrosis. The exons of COL2A1 were amplified by polymerase chain reaction and mutation screening was conducted by direct sequencing in all the family members. The locus was also sequenced in 50 unrelated healthy controls. The c.3665G>A heterozygous mutation was detected in patients of the pedigree, but not in healthy individuals. We conclude that a mutation in the COL2A1 gene is the causative agent of ONFH in this family. Therefore, this mutation may be associated with osteonecrosis in Chinese populations. PMID:25050885

Wang, Lin; Pan, Hehai; Zhu, Zhen-An

2014-10-01

249

A Model-Based Approach for Identifying Signatures of Ancient Balancing Selection in Genetic Data  

PubMed Central

While much effort has focused on detecting positive and negative directional selection in the human genome, relatively little work has been devoted to balancing selection. This lack of attention is likely due to the paucity of sophisticated methods for identifying sites under balancing selection. Here we develop two composite likelihood ratio tests for detecting balancing selection. Using simulations, we show that these methods outperform competing methods under a variety of assumptions and demographic models. We apply the new methods to whole-genome human data, and find a number of previously-identified loci with strong evidence of balancing selection, including several HLA genes. Additionally, we find evidence for many novel candidates, the strongest of which is FANK1, an imprinted gene that suppresses apoptosis, is expressed during meiosis in males, and displays marginal signs of segregation distortion. We hypothesize that balancing selection acts on this locus to stabilize the segregation distortion and negative fitness effects of the distorter allele. Thus, our methods are able to reproduce many previously-hypothesized signals of balancing selection, as well as discover novel interesting candidates. PMID:25144706

DeGiorgio, Michael; Lohmueller, Kirk E.; Nielsen, Rasmus

2014-01-01

250

Comparative analysis of Edwardsiella isolates from fish in the eastern United States identifies two distinct genetic taxa amongst organisms phenotypically classified as E. tarda.  

PubMed

Edwardsiella tarda, a Gram-negative member of the family Enterobacteriaceae, has been implicated in significant losses in aquaculture facilities worldwide. Here, we assessed the intra-specific variability of E. tarda isolates from 4 different fish species in the eastern United States. Repetitive sequence mediated PCR (rep-PCR) using 4 different primer sets (ERIC I & II, ERIC II, BOX, and GTG5) and multi-locus sequence analysis of 16S SSU rDNA, groEl, gyrA, gyrB, pho, pgi, pgm, and rpoA gene fragments identified two distinct genotypes of E. tarda (DNA group I; DNA group II). Isolates that fell into DNA group II demonstrated more similarity to E. ictaluri than DNA group I, which contained the reference E. tarda strain (ATCC #15947). Conventional PCR analysis using published E. tarda-specific primer sets yielded variable results, with several primer sets producing no observable amplification of target DNA from some isolates. Fluorometric determination of G+C content demonstrated 56.4% G+C content for DNA group I, 60.2% for DNA group II, and 58.4% for E. ictaluri. Surprisingly, these isolates were indistinguishable using conventional biochemical techniques, with all isolates demonstrating phenotypic characteristics consistent with E. tarda. Analysis using two commercial test kits identified multiple phenotypes, although no single metabolic characteristic could reliably discriminate between genetic groups. Additionally, anti-microbial susceptibility and fatty acid profiles did not demonstrate remarkable differences between groups. The significant genetic variation (<90% similarity at gyrA, gyrB, pho, phi and pgm; <40% similarity by rep-PCR) between these groups suggests organisms from DNA group II may represent an unrecognized, genetically distinct taxa of Edwardsiella that is phenotypically indistinguishable from E. tarda. PMID:23623688

Griffin, Matt J; Quiniou, Sylvie M; Cody, Theresa; Tabuchi, Maki; Ware, Cynthia; Cipriano, Rocco C; Mauel, Michael J; Soto, Esteban

2013-08-30

251

Recombinants of bean common mosaic virus (BCMV) and genetic determinants of BCMV involved in overcoming resistance in common bean.  

PubMed

Bean common mosaic virus (BCMV) exists as a complex of strains classified by reactions to resistance genes found in common bean (Phaseolus vulgaris); seven BCMV pathotypes have been distinguished thus far, numbered I to VII. Virus genetic determinants involved in pathogenicity interactions with resistance genes have not yet been identified. Here, we describe the characterization of two novel field isolates of BCMV that helped to narrow down these genetic determinants interacting with specific P. vulgaris resistance factors. Based on a biological characterization on common bean differentials, both isolates were classified as belonging to pathotype VII, similar to control isolate US10, and both isolates exhibited the B serotype. The whole genome was sequenced for both isolates and found to be 98 to 99% identical to the BCMV isolate RU1 (pathotype VI), and a single name was retained: BCMV RU1-OR. To identify a genetic determinant of BCMV linked to the BCMV pathotype VII, the whole genome was also sequenced for two control isolates, US10 and RU1-P. Inspection of the nucleotide sequences for BCMV RU1-OR and US10 (both pathotype VII) and three closely related sequences of BCMV (RU1-P, RU1-D, and RU1-W, all pathotype VI) revealed that RU1-OR originated through a series of recombination events between US10 and an as-yet-unidentified BCMV parental genome, resulting in changes in virus pathology. The data obtained suggest that a fragment of the RU1-OR genome between positions 723 and 1,961 nucleotides that is common to US10 and RU1-OR in the P1-HC-Pro region of the BCMV genome may be responsible for the ability to overcome resistance in bean conferred by the bc-2(2) gene. This is the first report of a virus genetic determinant responsible for overcoming a specific BCMV resistance gene in common bean. PMID:24915430

Feng, Xue; Poplawsky, Alan R; Nikolaeva, Olga V; Myers, James R; Karasev, Alexander V

2014-07-01

252

Determination of parameter identifiability in nonlinear biophysical models: A Bayesian approach  

PubMed Central

A major goal of biophysics is to understand the physical mechanisms of biological molecules and systems. Mechanistic models are evaluated based on their ability to explain carefully controlled experiments. By fitting models to data, biophysical parameters that cannot be measured directly can be estimated from experimentation. However, it might be the case that many different combinations of model parameters can explain the observations equally well. In these cases, the model parameters are not identifiable: the experimentation has not provided sufficient constraining power to enable unique estimation of their true values. We demonstrate that this pitfall is present even in simple biophysical models. We investigate the underlying causes of parameter non-identifiability and discuss straightforward methods for determining when parameters of simple models can be inferred accurately. However, for models of even modest complexity, more general tools are required to diagnose parameter non-identifiability. We present a method based in Bayesian inference that can be used to establish the reliability of parameter estimates, as well as yield accurate quantification of parameter confidence. PMID:24516188

Hines, Keegan E.; Middendorf, Thomas R.

2014-01-01

253

Integrated Model of De Novo and Inherited Genetic Variants Yields Greater Power to Identify Risk Genes  

PubMed Central

De novo mutations affect risk for many diseases and disorders, especially those with early-onset. An example is autism spectrum disorders (ASD). Four recent whole-exome sequencing (WES) studies of ASD families revealed a handful of novel risk genes, based on independent de novo loss-of-function (LoF) mutations falling in the same gene, and found that de novo LoF mutations occurred at a twofold higher rate than expected by chance. However successful these studies were, they used only a small fraction of the data, excluding other types of de novo mutations and inherited rare variants. Moreover, such analyses cannot readily incorporate data from case-control studies. An important research challenge in gene discovery, therefore, is to develop statistical methods that accommodate a broader class of rare variation. We develop methods that can incorporate WES data regarding de novo mutations, inherited variants present, and variants identified within cases and controls. TADA, for Transmission And De novo Association, integrates these data by a gene-based likelihood model involving parameters for allele frequencies and gene-specific penetrances. Inference is based on a Hierarchical Bayes strategy that borrows information across all genes to infer parameters that would be difficult to estimate for individual genes. In addition to theoretical development we validated TADA using realistic simulations mimicking rare, large-effect mutations affecting risk for ASD and show it has dramatically better power than other common methods of analysis. Thus TADA's integration of various kinds of WES data can be a highly effective means of identifying novel risk genes. Indeed, application of TADA to WES data from subjects with ASD and their families, as well as from a study of ASD subjects and controls, revealed several novel and promising ASD candidate genes with strong statistical support. PMID:23966865

He, Xin; Sanders, Stephan J.; Liu, Li; De Rubeis, Silvia; Lim, Elaine T.; Sutcliffe, James S.; Schellenberg, Gerard D.; Gibbs, Richard A.; Daly, Mark J.; Buxbaum, Joseph D.; State, Matthew W.; Devlin, Bernie; Roeder, Kathryn

2013-01-01

254

Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors.  

PubMed

Genome-wide association (GWA) studies of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci, some containing genes encoding proteins important in male germ cell development. Deletions of one of these genes, DMRT1, lead to male-to-female sex reversal and are associated with development of gonadoblastoma. To further explore genetic association with TGCT, we undertook a pathway-based analysis of SNP marker associations in the Penn GWAs (349 TGCT cases and 919 controls). We analyzed a custom-built sex determination gene set consisting of 32 genes using three different methods of pathway-based analysis. The sex determination gene set ranked highly compared with canonical gene sets, and it was associated with TGCT (FDRG = 2.28 × 10(-5), FDRM = 0.014 and FDRI = 0.008 for Gene Set Analysis-SNP (GSA-SNP), Meta-Analysis Gene Set Enrichment of Variant Associations (MAGENTA) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) analysis, respectively). The association remained after removal of DMRT1 from the gene set (FDRG = 0.0002, FDRM = 0.055 and FDRI = 0.009). Using data from the NCI GWA scan (582 TGCT cases and 1056 controls) and UK scan (986 TGCT cases and 4946 controls), we replicated these findings (NCI: FDRG = 0.006, FDRM = 0.014, FDRI = 0.033, and UK: FDRG = 1.04 × 10(-6), FDRM = 0.016, FDRI = 0.025). After removal of DMRT1 from the gene set, the sex determination gene set remains associated with TGCT in the NCI (FDRG = 0.039, FDRM = 0.050 and FDRI = 0.055) and UK scans (FDRG = 3.00 × 10(-5), FDRM = 0.056 and FDRI = 0.044). With the exception of DMRT1, genes in the sex determination gene set have not previously been identified as TGCT susceptibility loci in these GWA scans, demonstrating the complementary nature of a pathway-based approach for genome-wide analysis of TGCT. PMID:24943593

Koster, Roelof; Mitra, Nandita; D'Andrea, Kurt; Vardhanabhuti, Saran; Chung, Charles C; Wang, Zhaoming; Loren Erickson, R; Vaughn, David J; Litchfield, Kevin; Rahman, Nazneen; Greene, Mark H; McGlynn, Katherine A; Turnbull, Clare; Chanock, Stephen J; Nathanson, Katherine L; Kanetsky, Peter A

2014-11-15

255

A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis  

PubMed Central

ABSTRACT Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective death of motor neurons. In 5–10% of the familial cases, the disease is inherited because of mutations. One such mutation, P56S, was identified in human VAPB that behaves in a dominant negative manner, sequestering wild type protein into cytoplasmic inclusions. We have conducted a reverse genetic screen to identify interactors of Drosophila VAPB. We screened 2635 genes and identified 103 interactors, of which 45 were enhancers and 58 were suppressors of VAPB function. Interestingly, the screen identified known ALS loci – TBPH, alsin2 and SOD1. Also identified were genes involved in cellular energetics and homeostasis which were used to build a gene regulatory network of VAPB modifiers. One key modifier identified was Tor, whose knockdown reversed the large bouton phenotype associated with VAP(P58S) expression in neurons. A similar reversal was seen by over-expressing Tuberous Sclerosis Complex (Tsc1,2) that negatively regulates TOR signaling as also by reduction of S6K activity. In comparison, the small bouton phenotype associated with VAP(wt) expression was reversed with Tsc1 knock down as well as S6K-CA expression. Tor therefore interacts with both VAP(wt) and VAP(P58S), but in a contrasting manner. Reversal of VAP(P58S) bouton phenotypes in larvae fed with the TOR inhibitor Rapamycin suggests upregulation of TOR signaling in response to VAP(P58S) expression. The VAPB network and further mechanistic understanding of interactions with key pathways, such as the TOR cassette, will pave the way for a better understanding of the mechanisms of onset and progression of motor neuron disease. PMID:25361581

Deivasigamani, Senthilkumar; Verma, Hemant Kumar; Ueda, Ryu; Ratnaparkhi, Anuradha; Ratnaparkhi, Girish S.

2014-01-01

256

Genetic Analysis of Fin Development in Zebrafish Identifies Furin and Hemicentin1 as Potential Novel Fraser Syndrome Disease Genes  

PubMed Central

Using forward genetics, we have identified the genes mutated in two classes of zebrafish fin mutants. The mutants of the first class are characterized by defects in embryonic fin morphogenesis, which are due to mutations in a Laminin subunit or an Integrin alpha receptor, respectively. The mutants of the second class display characteristic blistering underneath the basement membrane of the fin epidermis. Three of them are due to mutations in zebrafish orthologues of FRAS1, FREM1, or FREM2, large basement membrane protein encoding genes that are mutated in mouse bleb mutants and in human patients suffering from Fraser Syndrome, a rare congenital condition characterized by syndactyly and cryptophthalmos. Fin blistering in a fourth group of zebrafish mutants is caused by mutations in Hemicentin1 (Hmcn1), another large extracellular matrix protein the function of which in vertebrates was hitherto unknown. Our mutant and dose-dependent interaction data suggest a potential involvement of Hmcn1 in Fraser complex-dependent basement membrane anchorage. Furthermore, we present biochemical and genetic data suggesting a role for the proprotein convertase FurinA in zebrafish fin development and cell surface shedding of Fras1 and Frem2, thereby allowing proper localization of the proteins within the basement membrane of forming fins. Finally, we identify the extracellular matrix protein Fibrillin2 as an indispensable interaction partner of Hmcn1. Thus we have defined a series of zebrafish mutants modelling Fraser Syndrome and have identified several implicated novel genes that might help to further elucidate the mechanisms of basement membrane anchorage and of the disease's aetiology. In addition, the novel genes might prove helpful to unravel the molecular nature of thus far unresolved cases of the human disease. PMID:20419147

Carney, Thomas J.; Feitosa, Natália Martins; Sonntag, Carmen; Slanchev, Krasimir; Kluger, Johannes; Kiyozumi, Daiji; Gebauer, Jan M.; Coffin Talbot, Jared; Kimmel, Charles B.; Sekiguchi, Kiyotoshi; Wagener, Raimund; Schwarz, Heinz; Ingham, Phillip W.; Hammerschmidt, Matthias

2010-01-01

257

Genetic approaches to chemotype determination in type B-trichothecene producing Fusaria.  

PubMed

This review summarises the genetic methods used for chemotype determination of the main Fusarium type B-trichothecene producing species. Literature on Fusarium chemotype epidemiology over the last 15 years is reviewed in order to describe temporal and spatial chemotype distribution of these fungi worldwide. Genetic approaches used for chemotype determination are also reviewed and discussed, highlighting successes and potential pitfalls of the technique. Results from both genetic and chemical approaches are summarised to compare reliability, advantages and limitations of the two methods. Potential applications of genetic chemotyping to toxigenic Fusarium species are evaluated in the light of improving food safety of agricultural products. The use of chemotype determination in population studies, toxin prediction as well as for breeding purpose is described. PMID:25150674

Pasquali, Matias; Migheli, Quirico

2014-10-17

258

Innate immunity and genetic determinants of urinary tract infection susceptibility  

PubMed Central

Purpose of review Urinary tract infections (UTIs) are common, dangerous and interesting. Susceptible individuals experience multiple, often clustered episodes, and in a subset of patients, infections progress to acute pyelonephritis (APN), sometimes accompanied by uro-sepsis. Others develop asymptomatic bacteriuria (ABU). Here, we review the molecular basis for these differences, with the intention to distinguish exaggerated host responses that drive disease from attenuated responses that favour protection and to highlight the genetic basis for these extremes, based on knock-out mice and clinical studies. Recent findings The susceptibility to UTI is controlled by specific innate immune signalling and by promoter polymorphisms and transcription factors that modulate the expression of genes controlling these pathways. Gene deletions that disturb innate immune activation either favour asymptomatic bacteriuria or create acute morbidity and disease. Promoter polymorphisms and transcription factor variants affecting those genes are associated with susceptibility in UTI-prone patients. Summary It is time to start using genetics in UTI-prone patients, to improve diagnosis and to assess the risk for chronic sequels such as renal malfunction, hypertension, spontaneous abortions, dialysis and transplantation. Furthermore, the majority of UTI patients do not need follow-up, but for lack of molecular markers, they are unnecessarily investigated. PMID:25539411

Godaly, Gabriela; Ambite, Ines; Svanborg, Catharina

2015-01-01

259

Maternal and genetic factors determine early life telomere length.  

PubMed

In a broad range of species--including humans--it has been demonstrated that telomere length declines throughout life and that it may be involved in cell and organismal senescence. This potential link to ageing and thus to fitness has triggered recent interest in understanding how variation in telomere length is inherited and maintained. However, previous studies suffer from two main drawbacks that limit the possibility of understanding the relative importance of genetic, parental and environmental influences on telomere length variation. These studies have been based on (i) telomere lengths measured at different time points in different individuals, despite the fact that telomere length changes over life, and (ii) parent-offspring regression techniques, which do not enable differentiation between genetic and parental components of inheritance. To overcome these drawbacks, in our study of a songbird, the great reed warbler, we have analysed telomere length measured early in life in both parents and offspring and applied statistical models (so-called 'animal models') that are based on long-term pedigree data. Our results showed a significant heritability of telomere length on the maternal but not on the paternal side, and that the mother's age was positively correlated with their offspring's telomere length. Furthermore, the pedigree-based analyses revealed a significant heritability and an equally large maternal effect. Our study demonstrates strong maternal influence on telomere length and future studies now need to elucidate possible underlying factors, including which types of maternal effects are involved. PMID:25621325

Asghar, Muhammad; Bensch, Staffan; Tarka, Maja; Hansson, Bengt; Hasselquist, Dennis

2015-01-22

260

Common genetic determinants of vitamin D insufficiency: a genome-wide association study  

PubMed Central

Background Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role. Methods We performed a genome-wide association study of 25-OH D among ?30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication cohorts (n=8,378). Association results were combined using z-score-weighted meta-analysis. Vitamin D insufficiency was defined as 25-OH D <75 nmol/L or <50 nmol/L. Findings Variants at three loci reached genome-wide significance in the discovery cohorts, and were confirmed in the replication cohorts: 4p12 (overall P=1.9 × 10-109 for rs2282679, in GC); 11q12 (P=2.1 × 10-27 for rs12785878, near DHCR7); 11p15 (P=3.3 × 10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (P=6.0 × 10-10 for rs6013897). A genotype score was constructed using the three confirmed variants. Those in the top quartile of genotype scores had 2- to 2.5-fold elevated odds of vitamin D insufficiency (P?1 × 10-26). Interpretation Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1, CYP24A1), and vitamin D transport (GC) influence vitamin D status. Genetic variation at these loci identifies individuals of European descent who have substantially elevated risk of vitamin D insufficiency. PMID:20541252

Wang, Thomas J.; Zhang, Feng; Richards, J. Brent; Kestenbaum, Bryan; van Meurs, Joyce B.; Berry, Diane; Kiel, Douglas; Streeten, Elizabeth A.; Ohlsson, Claes; Koller, Daniel L.; Palotie, Leena; Cooper, Jason D.; O'Reilly, Paul F.; Houston, Denise K.; Glazer, Nicole L.; Vandenput, Liesbeth; Peacock, Munro; Shi, Julia; Rivadeneira, Fernando; McCarthy, Mark I.; Anneli, Pouta; de Boer, Ian H.; Mangino, Massimo; Kato, Bernet; Smyth, Deborah J.; Booth, Sarah L.; Jacques, Paul F.; Burke, Greg L.; Goodarzi, Mark; Cheung, Ching-Lung; Wolf, Myles; Rice, Kenneth; Goltzman, David; Hidiroglou, Nick; Ladouceur, Martin; Hui, Siu L.; Wareham, Nicholas J.; Hocking, Lynne J.; Hart, Deborah; Arden, Nigel K.; Cooper, Cyrus; Malik, Suneil; Fraser, William D.; Hartikainen, Anna-Liisa; Zhai, Guangju; Macdonald, Helen; Forouhi, Nita G.; Loos, Ruth J.F.; Reid, David M.; Hakim, Alan; Dennison, Elaine; Liu, Yongmei; Power, Chris; Stevens, Helen E.; Jaana, Laitinen; Vasan, Ramachandran S.; Soranzo, Nicole; Bojunga, Jörg; Psaty, Bruce M.; Lorentzon, Mattias; Foroud, Tatiana; Harris, Tamara B.; Hofman, Albert; Jansson, John-Olov; Cauley, Jane A.; Uitterlinden, Andre G.; Gibson, Quince; Järvelin, Marjo-Riitta; Karasik, David; Siscovick, David S.; Econs, Michael J.; Kritchevsky, Stephen B.; Florez, Jose C.; Todd, John A.; Dupuis, Josee; Hypponen, Elina; Spector, Timothy D.

2010-01-01

261

A trans-ethnic genetic study of rheumatoid arthritis identified FCGR2A as a candidate common risk factor in Japanese and European populations  

Microsoft Academic Search

Rheumatoid arthritis (RA) is a common systemic autoimmune disease and its onset and prognosis are controlled by genetic, immunological,\\u000a and environmental factors. The HLA locus, particularly HLA-DRB1, is its strongest genetic risk determinant across ethnicities. Several other genes, including PTPN22 and PADI4, show modest association with RA. However, they cover only a part of its genetic components and their relative

Roubila Meziani; Ryo Yamada; Meiko Takahashi; Kenei Ohigashi; Akio Morinobu; Chikashi Terao; Hitomi Hiratani; Koichiro Ohmura; Masao Yamaguchi; Takashi Nomura; Alexandre Vasilescu; Miki Kokubo; Victor Renault; Katsura Hirosawa; Chanavee Ratanajaraya; Simon Heath; Tsuneyo Mimori; Shimon Sakaguchi; Mark Lathrop; Inga Melchers; Shunichi Kumagai; Fumihiko Matsuda

262

Coupled biophysical global ocean model and molecular genetic analyses identify multiple introductions of cryptogenic species.  

PubMed

The anthropogenic introduction of exotic species is one of the greatest modern threats to marine biodiversity. Yet exotic species introductions remain difficult to predict and are easily misunderstood because knowledge of natural dispersal patterns, species diversity, and biogeography is often insufficient to distinguish between a broadly dispersed natural population and an exotic one. Here we compare a global molecular phylogeny of a representative marine meroplanktonic taxon, the moon-jellyfish Aurelia, with natural dispersion patterns predicted by a global biophysical ocean model. Despite assumed high dispersal ability, the phylogeny reveals many cryptic species and predominantly regional structure with one notable exception: the globally distributed Aurelia sp.1, which, molecular data suggest, may occasionally traverse the Pacific unaided. This possibility is refuted by the ocean model, which shows much more limited dispersion and patterns of distribution broadly consistent with modern biogeographic zones, thus identifying multiple introductions worldwide of this cryptogenic species. This approach also supports existing evidence that (i) the occurrence in Hawaii of Aurelia sp. 4 and other native Indo-West Pacific species with similar life histories is most likely due to anthropogenic translocation, and (ii) there may be a route for rare natural colonization of northeast North America by the European marine snail Littorina littorea, whose status as endemic or exotic is unclear. PMID:16103373

Dawson, Michael N; Sen Gupta, Alex; England, Matthew H

2005-08-23

263

Genome-Wide Reverse Genetics Framework to Identify Novel Functions of the Vertebrate Secretome  

PubMed Central

Background Understanding the functional role(s) of the more than 20,000 proteins of the vertebrate genome is a major next step in the post-genome era. The approximately 4,000 co-translationally translocated (CTT) proteins – representing the vertebrate secretome – are important for such vertebrate-critical processes as organogenesis. However, the role(s) for most of these genes is currently unknown. Results We identified 585 putative full-length zebrafish CTT proteins using cross-species genomic and EST-based comparative sequence analyses. We further investigated 150 of these genes (Figure 1) for unique function using morpholino-based analysis in zebrafish embryos. 12% of the CTT protein-deficient embryos resulted in specific developmental defects, a notably higher rate of gene function annotation than the 2%–3% estimate from random gene mutagenesis studies. Conclusion(s) This initial collection includes novel genes required for the development of vascular, hematopoietic, pigmentation, and craniofacial tissues, as well as lipid metabolism, and organogenesis. This study provides a framework utilizing zebrafish for the systematic assignment of biological function in a vertebrate genome. PMID:17218990

Pickart, Michael A.; Klee, Eric W.; Nielsen, Aubrey L.; Sivasubbu, Sridhar; Mendenhall, Eric M.; Bill, Brent R.; Chen, Eleanor; Eckfeldt, Craig E.; Knowlton, Michelle; Robu, Mara E.; Larson, Jon D.; Deng, Yun; Schimmenti, Lisa A.; Ellis, Lynda B.M.; Verfaillie, Catherine M.; Hammerschmidt, Matthias; Farber, Steven A.; Ekker, Stephen C.

2006-01-01

264

Coupled biophysical global ocean model and molecular genetic analyses identify multiple introductions of cryptogenic species  

PubMed Central

The anthropogenic introduction of exotic species is one of the greatest modern threats to marine biodiversity. Yet exotic species introductions remain difficult to predict and are easily misunderstood because knowledge of natural dispersal patterns, species diversity, and biogeography is often insufficient to distinguish between a broadly dispersed natural population and an exotic one. Here we compare a global molecular phylogeny of a representative marine meroplanktonic taxon, the moon-jellyfish Aurelia, with natural dispersion patterns predicted by a global biophysical ocean model. Despite assumed high dispersal ability, the phylogeny reveals many cryptic species and predominantly regional structure with one notable exception: the globally distributed Aurelia sp.1, which, molecular data suggest, may occasionally traverse the Pacific unaided. This possibility is refuted by the ocean model, which shows much more limited dispersion and patterns of distribution broadly consistent with modern biogeographic zones, thus identifying multiple introductions worldwide of this cryptogenic species. This approach also supports existing evidence that (i) the occurrence in Hawaii of Aurelia sp. 4 and other native Indo-West Pacific species with similar life histories is most likely due to anthropogenic translocation, and (ii) there may be a route for rare natural colonization of northeast North America by the European marine snail Littorina littorea, whose status as endemic or exotic is unclear. PMID:16103373

Dawson, Michael N; Gupta, Alex Sen; England, Matthew H.

2005-01-01

265

Chemical genetics of TOR identifies an SCF family E3 ubiquitin ligase inhibitor  

PubMed Central

The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control1. With prevalent hyper-activation of the mTOR pathway in human cancers2, novel strategies to enhance TOR pathway inhibition are highly desirable. We used a yeast-based platform to identify small-molecule enhancers of rapamycin (SMERs) and discovered an inhibitor of the SCFMet30 ubiquitin ligase (SMER3). The large SCF (Skp1-Cullin-F-box) family of ubiquitin ligases performs important functions in diverse cellular processes including transcription, cell-cycle control, and immune response3. Accordingly, there would be great value in developing SCF ligase inhibitors that act by a defined mechanism to specifically inactivate ligase activity. We show here that SMER3 selectively inhibits SCFMet30 in vivo and in vitro, but not the closely related SCFCdc4. Our results demonstrate that there is no fundamental barrier to obtaining specific inhibitors to modulate function of individual SCF complexes, and suggest new strategies for combination therapy with rapamycin. PMID:20581845

Aghajanyy, Mariam; Jonai, Nao; Flick, Karin; Fu, Fei; Luo, Manlin; Cai, Xiaolu; Ouni, Ikram; Pierce, Nathan; Tang, Xiaobo; Lomenick, Brett; Damoiseaux, Robert; Hao, Rui; del Moral, Pierre M.; Verma, Rati; Li, Ying; Li, Cheng; Houk, Kendall N.; Jung, Michael E.; Zheng, Ning; Huang, Lan; Deshaies, Raymond J.; Kaiser, Peter; Huang, Jing

2010-01-01

266

Application of a novel radioimmunoassay to identify baculovirus structural proteins that share interspecies antigenic determinants  

SciTech Connect

Immunological comparisons were made of baculovirus structural proteins by using a modification of the radioimmunological techniques described by Renart et al. and Towbin et al. Viral proteins were electrophoresed in polyacrylamide gels, transferred to nitrocellulose, and incubated with viral antisera, and the antibodies were detected with /sup 125/I-labeled Staphylococcus aureus protein A. Antisera were prepared to purified and intact virions from five baculoviruses: Autographa californica, Porthetria dispar, Trichoplusia ni, and Heliothis zea nuclear polyhedrosis viruses (NPVs) and T. ni granulosis virus (GV). These antisera were tested against the virion structural polypeptides of 17 different species of baculoviruses. Specific multiple-nucleocapsid NPV (MNPV), single-nucleocapsid NPV (SNPV), and GV virion polypeptides were shown to have similar antigenic determinants and thus be immunologically related. The molecular weights of the virion polypeptides with cross-reacting antigenic determinants were identified. Antisera prepared to purified A. californica and H. zea MNPV polyhedrin recognized antigenic determinants on all the polyhedrins and granulins that were tested. No immunological relationship was detected between A. californica MNPV polyhedrin and any of the A. californica MNPV virion structural polypeptides present on either the virus isolated from occlusion bodies or A. californica MNPV extracellular virus from infected-cell cultures.

Smith, G.E.; Summers, M.D.

1981-07-01

267

Application of a Novel Radioimmunoassay to Identify Baculovirus Structural Proteins That Share Interspecies Antigenic Determinants  

PubMed Central

Immunological comparisons were made of baculovirus structural proteins by using a modification of the radioimmunological techniques described by Renart et al. (Proc. Natl. Acad. Sci. U.S.A. 76: 3116-3120, 1979) and Towbin et al. (Proc. Natl. Acad. Sci. U.S.A. 76: 4350-4354, 1979). Viral proteins were electrophoresed in polyacrylamide gels, transferred to nitrocellulose, and incubated with viral antisera, and the antibodies were detected with 125I-labeled Staphylococcus aureus protein A. Antisera were prepared to purified and intact virions from five baculoviruses: Autographa californica, Porthetria dispar, Trichoplusia ni, and Heliothis zea nuclear polyhedrosis viruses (NPVs) and T. ni granulosis virus (GV). These antisera were tested against the virion structural polypeptides of 17 different species of baculoviruses. Specific multiple-nucleocapsid NPV (MNPV), single-nucleocapsid NPV (SNPV), and GV virion polypeptides were shown to have similar antigenic determinants and thus be immunologically related. The molecular weights of the virion polypeptides with cross-reacting antigenic determinants were identified. Antisera prepared to purified A. californica and H. zea MNPV polyhedrin (the occlusion body protein from NPVs) recognized antigenic determinants on all the polyhedrins and granulins (occlusion body protein from GVs) that were tested. No immunological relationship was detected between A. californica MNPV polyhedrin and any of the A. californica MNPV virion structural polypeptides present on either the virus isolated from occlusion bodies or A. californica MNPV extracellular virus from infected-cell cultures. Images PMID:16789210

Smith, Gale E.; Summers, Max D.

1981-01-01

268

Integrative Approach to Pain Genetics Identifies Pain Sensitivity Loci across Diseases  

PubMed Central

Identifying human genes relevant for the processing of pain requires difficult-to-conduct and expensive large-scale clinical trials. Here, we examine a novel integrative paradigm for data-driven discovery of pain gene candidates, taking advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories. First, thousands of diseases were ranked according to a disease-specific pain index (DSPI), derived from Medical Subject Heading (MESH) annotations in MEDLINE. Second, gene expression profiles of 121 of these human diseases were obtained from public sources. Third, genes with expression variation significantly correlated with DSPI across diseases were selected as candidate pain genes. Finally, selected candidate pain genes were genotyped in an independent human cohort and prospectively evaluated for significant association between variants and measures of pain sensitivity. The strongest signal was with rs4512126 (5q32, ABLIM3, P?=?1.3×10?10) for the sensitivity to cold pressor pain in males, but not in females. Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (P?=?1.7×10?4, 1.8×10?4, and 2.2×10?4 respectively). Our results demonstrate the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical data curated from MEDLINE to facilitate the discovery of pain-relevant genes. This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates. PMID:22685391

Ruau, David; Dudley, Joel T.; Chen, Rong; Phillips, Nicholas G.; Swan, Gary E.; Lazzeroni, Laura C.; Clark, J. David

2012-01-01

269

Genetic Analysis Identifies DDR2 as a Novel Gene Affecting Bone Mineral Density and Osteoporotic Fractures in Chinese Population  

PubMed Central

DDR2 gene, playing an essential role in regulating osteoblast differentiation and chondrocyte maturation, may influence bone mineral density (BMD) and osteoporosis, but the genetic variations actually leading to the association remain to be elucidated. Therefore, the aim of this study was to investigate whether the genetic variants in DDR2 are associated with BMD and fracture risk. This study was performed in three samples from two ethnicities, including 1,300 Chinese Han subjects, 700 Chinese Han subjects (350 with osteoporotic hip fractures and 350 healthy controls) and 2,286 US white subjects. Twenty-eight SNPs in DDR2 were genotyped and tested for associations with hip BMD and fractures. We identified 3 SNPs in DDR2 significantly associated with hip BMD in the Chinese population after multiple testing adjustments, which were rs7521233 (P = 1.06×10?4, ?: ?0.018 for allele C), rs7553831 (P = 1.30×10?4, ?: ?0.018 for allele T), and rs6697469 (P = 1.59×10?3, ?: ?0.015 for allele C), separately. These three SNPs were in high linkage disequilibrium. Haplotype analyses detected two significantly associated haplotypes, including one haplotype in block 2 (P = 9.54×10?4, ?: ?0.016) where these three SNPs located. SNP rs6697469 was also associated with hip fractures (P = 0.043, OR: 1.42) in the Chinese population. The effect on fracture risk was consistent with its association with lower BMD. However, in the white population, we didn’t observe significant associations with hip BMD. eQTL analyses revealed that SNPs associated with BMD also affected DDR2 mRNA expression levels in Chinese. Our findings, together with the prior biological evidence, suggest that DDR2 could be a new candidate for osteoporosis in Chinese population. Our results also reveal an ethnic difference, which highlights the need for further genetic studies in each ethnic group. PMID:25658585

Guo, Yan; Yang, Tie-Lin; Dong, Shan-Shan; Yan, Han; Hao, Ruo-Han; Chen, Xiao-Feng; Chen, Jia-Bin; Tian, Qing; Li, Jian; Shen, Hui; Deng, Hong-Wen

2015-01-01

270

Development of a chemical genetic approach for human aurora B kinase identifies novel substrates of the chromosomal passenger complex.  

PubMed

To understand how the chromosomal passenger complex ensures chromosomal stability, it is crucial to identify its substrates and to find ways to specifically inhibit the enzymatic core of the complex, Aurora B. We therefore developed a chemical genetic approach to selectively inhibit human Aurora B. By mutating the gatekeeper residue Leu-154 in the kinase active site, the ATP-binding pocket was enlarged, but kinase function was severely disrupted. A unique second site suppressor mutation was identified that rescued kinase activity in the Leu-154 mutant and allowed the accommodation of bulky N(6)-substituted adenine analogs. Using this analog-sensitive Aurora B kinase, we found that retention of the chromosomal passenger complex at the centromere depends on Aurora B kinase activity. Furthermore, analog-sensitive Aurora B was able to use bulky ATP?S analogs and could thiophosphorylate multiple proteins in cell extracts. Utilizing an unbiased approach for kinase substrate mapping, we identified several novel substrates of Aurora B, including the nucleosomal-binding protein HMGN2. We confirmed that HMGN2 is a bona fide Aurora B substrate in vivo and show that its dynamic association to chromatin is controlled by Aurora B. PMID:22267324

Hengeveld, Rutger C C; Hertz, Nicholas T; Vromans, Martijn J M; Zhang, Chao; Burlingame, Alma L; Shokat, Kevan M; Lens, Susanne M A

2012-05-01

271

Development of a Chemical Genetic Approach for Human Aurora B Kinase Identifies Novel Substrates of the Chromosomal Passenger Complex*  

PubMed Central

To understand how the chromosomal passenger complex ensures chromosomal stability, it is crucial to identify its substrates and to find ways to specifically inhibit the enzymatic core of the complex, Aurora B. We therefore developed a chemical genetic approach to selectively inhibit human Aurora B. By mutating the gatekeeper residue Leu-154 in the kinase active site, the ATP-binding pocket was enlarged, but kinase function was severely disrupted. A unique second site suppressor mutation was identified that rescued kinase activity in the Leu-154 mutant and allowed the accommodation of bulky N6-substituted adenine analogs. Using this analog-sensitive Aurora B kinase, we found that retention of the chromosomal passenger complex at the centromere depends on Aurora B kinase activity. Furthermore, analog-sensitive Aurora B was able to use bulky ATP?S analogs and could thiophosphorylate multiple proteins in cell extracts. Utilizing an unbiased approach for kinase substrate mapping, we identified several novel substrates of Aurora B, including the nucleosomal-binding protein HMGN2. We confirmed that HMGN2 is a bona fide Aurora B substrate in vivo and show that its dynamic association to chromatin is controlled by Aurora B. PMID:22267324

Hengeveld, Rutger C. C.; Hertz, Nicholas T.; Vromans, Martijn J. M.; Zhang, Chao; Burlingame, Alma L.; Shokat, Kevan M.; Lens, Susanne M. A.

2012-01-01

272

Genetic Complementation Screen Identifies a Mitogen-activated Protein Kinase Phosphatase, MKP3, as a Regulator of Dopamine Transporter Trafficking  

PubMed Central

The antidepressant and cocaine sensitive plasma membrane monoamine transporters are the primary mechanism for clearance of their respective neurotransmitters and serve a pivotal role in limiting monoamine neurotransmission. To identify molecules in pathways that regulate dopamine transporter (DAT) internalization, we used a genetic complementation screen in Xenopus oocytes to identify a mitogen-activated protein (MAP) kinase phosphatase, MKP3/Pyst1/DUSP6, as a molecule that inhibits protein kinase C–induced (PKC) internalization of transporters, resulting in enhanced DAT activity. The involvement of MKP3 in DAT internalization was verified using both overexpression and shRNA knockdown strategies in mammalian cell models including a dopaminergic cell line. Although the isolation of MKP3 implies a role for MAP kinases in DAT internalization, MAP kinase inhibitors have no effect on internalization. Moreover, PKC-dependent down-regulation of DAT does not correlate with the phosphorylation state of several well-studied MAP kinases (ERK1/2, p38, and SAPK/JNK). We also show that MKP3 does not regulate PKC-induced ubiquitylation of DAT but acts at a more downstream step to stabilize DAT at the cell surface by blocking dynamin-dependent internalization and delaying the targeting of DAT for degradation. These results indicate that MKP3 can act to enhance DAT function and identifies MKP3 as a phosphatase involved in regulating dynamin-dependent endocytosis. PMID:18434601

Larsen, Mads Breum; Prasad, Balakrishna M.; Amara, Susan G.

2008-01-01

273

Genetical and Comparative Genomics of Brassica under Altered Ca Supply Identifies Arabidopsis Ca-Transporter Orthologs[W][OPEN  

PubMed Central

Although Ca transport in plants is highly complex, the overexpression of vacuolar Ca2+ transporters in crops is a promising new technology to improve dietary Ca supplies through biofortification. Here, we sought to identify novel targets for increasing plant Ca accumulation using genetical and comparative genomics. Expression quantitative trait locus (eQTL) mapping to 1895 cis- and 8015 trans-loci were identified in shoots of an inbred mapping population of Brassica rapa (IMB211 × R500); 23 cis- and 948 trans-eQTLs responded specifically to altered Ca supply. eQTLs were screened for functional significance using a large database of shoot Ca concentration phenotypes of Arabidopsis thaliana. From 31 Arabidopsis gene identifiers tagged to robust shoot Ca concentration phenotypes, 21 mapped to 27 B. rapa eQTLs, including orthologs of the Ca2+ transporters At-CAX1 and At-ACA8. Two of three independent missense mutants of BraA.cax1a, isolated previously by targeting induced local lesions in genomes, have allele-specific shoot Ca concentration phenotypes compared with their segregating wild types. BraA.CAX1a is a promising target for altering the Ca composition of Brassica, consistent with prior knowledge from Arabidopsis. We conclude that multiple-environment eQTL analysis of complex crop genomes combined with comparative genomics is a powerful technique for novel gene identification/prioritization. PMID:25082855

Graham, Neil S.; Hammond, John P.; Lysenko, Artem; Mayes, Sean; Ó Lochlainn, Seosamh; Blasco, Bego; Bowen, Helen C.; Rawlings, Chris J.; Rios, Juan J.; Welham, Susan; Carion, Pierre W.C.; Dupuy, Lionel X.; King, Graham J.; White, Philip J.; Broadley, Martin R.

2014-01-01

274

Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk  

PubMed Central

Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted the largest genome-wide association study in East Asians with 14,963 CRC cases and 31,945 controls and identified six new loci associated with CRC risk (P = 3.42 × 10?8 to 9.22 × 10?21) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcription regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9) and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC loci. Our study provides insights into the genetic basis of CRC and suggests new biological pathways. PMID:24836286

Zhang, Ben; Jia, Wei-Hua; Matsuda, Koichi; Kweon, Sun-Seog; Matsuo, Keitaro; Xiang, Yong-Bing; Shin, Aesun; Jee, Sun Ha; Kim, Dong-Hyun; Cai, Qiuyin; Long, Jirong; Shi, Jiajun; Wen, Wanqing; Yang, Gong; Zhang, Yanfeng; Li, Chun; Li, Bingshan; Guo, Yan; Ren, Zefang; Ji, Bu-Tian; Pan, Zhi-Zhong; Takahashi, Atsushi; Shin, Min-Ho; Matsuda, Fumihiko; Gao, Yu-Tang; Oh, Jae Hwan; Kim, Soriul; Ahn, Yoon-Ok; Chan, Andrew T; Chang-Claude, Jenny; Slattery, Martha L.; Gruber, Stephen B.; Schumacher, Fredrick R.; Stenzel, Stephanie L.; Casey, Graham; Kim, Hyeong-Rok; Jeong, Jin-Young; Park, Ji Won; Li, Hong-Lan; Hosono, Satoyo; Cho, Sang-Hee; Kubo, Michiaki; Shu, Xiao-Ou; Zeng, Yi-Xin; Zheng, Wei

2014-01-01

275

Profiling a Caenorhabditis elegans behavioral parametric dataset with a supervised K-means clustering algorithm identifies genetic networks regulating locomotion  

PubMed Central

Defining genetic networks underlying animal behavior in a high throughput manner is an important but challenging task that has not yet been achieved for any organism. Using Caenorhabditis elegans, we collected quantitative parametric data related to various aspects of locomotion from wild type and thirty-one mutant worm strains with single mutations in genes functioning in sensory reception, neurotransmission, G-protein signaling, neuromuscular control or other facets of motor regulation. We applied unsupervised and constrained K-means clustering algorithms to the data and found that the genes that clustered together due to the behavioral similarity of their mutants encoded proteins in the same signaling networks. This approach provides a framework to identify genes and genetic networks underlying worm neuromotor function in a high-throughput manner. A publicly accessible database harboring the visual and quantitative behavioral data collected in this study adds valuable information to the rapidly growing C. elegans databanks that can be employed in a similar context. PMID:21376755

Zhang, Shijie; Jin, Wei; Huang, Ying; Su, Wei; Yang, Jiong; Feng, Zhaoyang

2011-01-01

276

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture  

PubMed Central

Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups. PMID:23563607

Berndt, Sonja I.; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F.; Justice, Anne E.; Monda, Keri L.; Croteau-Chonka, Damien C.; Day, Felix R.; Esko, Tőnu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U.; Luan, Jian’an; Randall, Joshua C.; Vedantam, Sailaja; Willer, Cristen J.; Winkler, Thomas W.; Wood, Andrew R.; Workalemahu, Tsegaselassie; Hu, Yi-Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan-Yu; Min, Josine L.; Neale, Benjamin M.; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L.; Cadby, Gemma; den Heijer, Martin; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Jarick, Ivonne; Johansson, Ĺsa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E.; König, Inke R.; Kristiansson, Kati; Kutalik, Zoltán; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L.; Medina-Gomez, Carolina; Müller-Nurasyid, Martina; Ngwa, Julius S.; Nolte, Ilja M.; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J.; Preuss, Michael; Rose, Lynda M.; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J.; Surakka, Ida; Teumer, Alexander; Trip, Mieke D.; Tyrer, Jonathan; Van Vliet-Ostaptchouk, Jana V.; Vandenput, Liesbeth; Waite, Lindsay L.; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W.; Atalay, Mustafa; Attwood, Antony P.; Balmforth, Anthony J.; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L.; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I.; Chines, Peter S.; Collins, Francis S.; Connell, John M.; Cookson, William; de Faire, Ulf; de Vegt, Femmie; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M.; Farrall, Martin; Ferrario, Marco M.; Ferričres, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V.; Grallert, Harald; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S.; Hall, Per; Hartikainen, Anna-Liisa; Hayward, Caroline; Heard-Costa, Nancy L.; Heath, Andrew C.; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B.; Hunt, Sarah E.; Hyppönen, Elina; Iribarren, Carlos; Jacobs, Kevin B.; Jansson, John-Olov; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay-Tee; Kivimaki, Mika; Koenig, Wolfgang; Kraja, Aldi T.; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H.; Lakka, Timo A.; Langenberg, Claudia; Launer, Lenore J.; Lind, Lars; Lindström, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja-Liisa; Lorentzon, Mattias; Madden, Pamela A.; Magnusson, Patrik K.; Manunta, Paolo; Marek, Diana; März, Winfried; Mateo Leach, Irene; McKnight, Barbara; Medland, Sarah E.; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W.; Mooser, Vincent; Mühleisen, Thomas W.; Munroe, Patricia B.; Musk, Arthur W.; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A.; Ong, Ken K.; Oostra, Ben A.; Palmer, Colin N.A.; Palotie, Aarno; Peden, John F.; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P.; Prokopenko, Inga; Pütter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E.; Sambrook, Jennifer G.; Sanders, Alan R.; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So-Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stan?áková, Alena; Stark, Klaus; Stephens, Jonathan C.; Stirrups, Kathleen; Stolk, Ronald P.; Stumvoll, Michael; Swift, Amy J.; Theodoraki, Eirini V.; Thorand, Barbara; Tregouet, David-Alexandre; Tremoli, Elena; Van der Klauw, Melanie M.; van Meurs, Joyce B.J.; Vermeulen, Sita H.; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Gérard; Wang, Zhaoming; Widén, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Winkelmann, Bernhard R.; Witteman, Jacqueline C.M.; Wolffenbuttel, Bruce H.R.; Wong, Andrew; Wright, Alan F.; Zillikens, M. Carola; Amouyel, Philippe; Boehm, Bernhard O.; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Cupples, L. Adrienne; Cusi, Daniele; Dedoussis, George V.; Erdmann, Jeanette; Eriksson, Johan G.; Franks, Paul W.; Froguel, Philippe; Gieger, Christian; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hengstenberg, Christian; Hicks, Andrew A.; Hingorani, Aroon; Hinney, Anke; Hofman, Albert; Hovingh, Kees G.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz

2014-01-01

277

A Specific Pathway Can Be Identified between Genetic Characteristics and Behaviour Profiles in Prader-Willi Syndrome via Cognitive, Environmental and Physiological Mechanisms  

ERIC Educational Resources Information Center

Background: Behavioural phenotypes associated with genetic syndromes have been extensively investigated in order to generate rich descriptions of phenomenology, determine the degree of specificity of behaviours for a particular syndrome, and examine potential interactions between genetic predispositions for behaviour and environmental influences.…

Woodcock, K. A.; Oliver, C.; Humphreys, G. W.

2009-01-01

278

Novel determinants of intestinal colonization of Salmonella enterica serotype typhimurium identified in bovine enteric infection.  

PubMed

Cattle are naturally infected with Salmonella enterica serotype Typhimurium and exhibit pathological features of enteric salmonellosis that closely resemble those in humans. Cattle are the most relevant model of gastrointestinal disease resulting from nontyphoidal Salmonella infection in an animal with an intact microbiota. We utilized this model to screen a library of targeted single-gene deletion mutants to identify novel genes of Salmonella Typhimurium required for survival during enteric infection. Fifty-four candidate mutants were strongly selected, including numerous mutations in genes known to be important for gastrointestinal survival of salmonellae. Three genes with previously unproven phenotypes in gastrointestinal infection were tested in bovine ligated ileal loops. Two of these mutants, STM3602 and STM3846, recapitulated the phenotype observed in the mutant pool. Complementation experiments successfully reversed the observed phenotypes, directly linking these genes to the colonization defects of the corresponding mutant strains. STM3602 encodes a putative transcriptional regulator that may be involved in phosphonate utilization, and STM3846 encodes a retron reverse transcriptase that produces a unique RNA-DNA hybrid molecule called multicopy single-stranded DNA. The genes identified in this study represent an exciting new class of virulence determinants for further mechanistic study to elucidate the strategies employed by Salmonella to survive within the small intestines of cattle. PMID:24019407

Elfenbein, Johanna R; Endicott-Yazdani, Tiana; Porwollik, Steffen; Bogomolnaya, Lydia M; Cheng, Pui; Guo, Jinbai; Zheng, Yi; Yang, Hee-Jeong; Talamantes, Marissa; Shields, Christine; Maple, Aimee; Ragoza, Yury; DeAtley, Kimberly; Tatsch, Tyler; Cui, Ping; Andrews, Katharine D; McClelland, Michael; Lawhon, Sara D; Andrews-Polymenis, Helene

2013-11-01

279

Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step  

PubMed Central

Aerobic glycolysis or the Warburg Effect (WE) is characterized by the increased metabolism of glucose to lactate. It remains unknown what quantitative changes to the activity of metabolism are necessary and sufficient for this phenotype. We developed a computational model of glycolysis and an integrated analysis using metabolic control analysis (MCA), metabolomics data, and statistical simulations. We identified and confirmed a novel mode of regulation specific to aerobic glycolysis where flux through GAPDH, the enzyme separating lower and upper glycolysis, is the rate-limiting step in the pathway and the levels of fructose (1,6) bisphosphate (FBP), are predictive of the rate and control points in glycolysis. Strikingly, negative flux control was found and confirmed for several steps thought to be rate-limiting in glycolysis. Together, these findings enumerate the biochemical determinants of the WE and suggest strategies for identifying the contexts in which agents that target glycolysis might be most effective. DOI: http://dx.doi.org/10.7554/eLife.03342.001 PMID:25009227

Shestov, Alexander A; Liu, Xiaojing; Ser, Zheng; Cluntun, Ahmad A; Hung, Yin P; Huang, Lei; Kim, Dongsung; Le, Anne; Yellen, Gary; Albeck, John G; Locasale, Jason W

2014-01-01

280

Genetic determinants of immune-response to a polysaccharide vaccine for typhoid  

PubMed Central

Differences in immunological response among vaccine recipients are determined both by their genetic differences and environmental factors. Knowledge of genetic determinants of immunological response to a vaccine can be used to design a vaccine that circumvents immunogenetic restrictions. The currently available vaccine for typhoid is a pure polysaccharide vaccine, immune response to which is T-cell independent. Little is known about whether genetic variation among vaccinees associates with variation in their antibody response to a polysaccharide vaccine. We conducted a study on 1,000 individuals resident in an area at high-risk for typhoid; vaccinated them with the typhoid vaccine, measured their antibody response to the vaccine, assayed >2,000 curated SNPs chosen from 283 genes that are known to participate in immune-response; and analyzed these data using a strategy to (a) minimize the statistical problems associated with testing of multiple hypotheses, and (b) internally cross-validate inferences, using a half-sample design, with little loss of statistical power. The first stage analysis, using the first half-sample, identified 54 SNPs in 43 genes to be significantly associated with immune response. In the second-stage, these inferences were cross-validated using the second half-sample. First-stage results of only 8 SNPs (out of 54) in 7 genes (out of 43) were cross-validated. We tested additional SNPs in these 7 genes, and found 8 more SNPs to be significantly associated. Haplotypes constructed with these SNPs in these 7 genes also showed significant association. These 7 genes are DEFB1, TLR1, IL1RL1, CTLA4, MAPK8, CD86 and IL17D. The overall picture that has emerged from this study is that (a) immune response to polysaccharide antigens is qualitatively different from that to protein antigens, and (b) polymorphisms in genes involved in polysaccharide recognition, signal transduction, inhibition of T-cell proliferation, pro-inflammatory signaling and eventual production of antimicrobial peptides are associated with antibody response to the polysaccharide vaccine for typhoid. Electronic supplementary material The online version of this article (doi:10.1007/s11568-010-9134-1) contains supplementary material, which is available to authorized users. PMID:21119757

Staats, Herman F.; Sarkar-Roy, Neeta; Varma, Binuja; Ghosh, Trina; Maiti, Sujit; Narayanasamy, K.; Whisnant, Carol C.; Stephenson, James L.; Wagener, Diane K.

2010-01-01

281

Genetic basis and biotechnological manipulation of sexual dimorphism and sex determination in fish.  

PubMed

Aquaculture has made an enormous contribution to the world food production, especially to the sustainable supply of animal proteins. The utility of diverse reproduction strategies in fish, such as the exploiting use of unisexual gynogenesis, has created a typical case of fish genetic breeding. A number of fish species show substantial sexual dimorphism that is closely linked to multiple economic traits including growth rate and body size, and the efficient development of sex-linked genetic markers and sex control biotechnologies has provided significant approaches to increase the production and value for commercial purposes. Along with the rapid development of genomics and molecular genetic techniques, the genetic basis of sexual dimorphism has been gradually deciphered, and great progress has been made in the mechanisms of fish sex determination and identification of sex-determining genes. This review summarizes the progress to provide some directive and objective thinking for further research in this field. PMID:25563981

Mei, Jie; Gui, Jian-Fang

2015-02-01

282

Comparison of French and Estonian Students' Conceptions in Genetic Determinism of Human Behaviours  

ERIC Educational Resources Information Center

Innatism is the belief that most of the human personality can be determined by genes. This ideology is dangerous, especially when it claims to be scientific. The present study investigates conceptions of 1060 students from Estonia and France related to genetic determinism of some human behaviours. Factors taken into account included students'…

Castera, Jeremy; Sarapuu, Tago; Clement, Pierre

2013-01-01

283

Genetic and Social Determinants of Initiation and Age at Onset of Smoking in Australian Twins  

Microsoft Academic Search

Retrospective data on age at onset of smoking, reported by 3810 adult Australian twin pairs, were analyzed to determine the role of genetic and environmental factors in the onset of smok- ing. Results of nonmetric multidimensional scaling supported a two-process model in which dif- ferent etiologic factors determined which individuals were at risk of becoming smokers and the age at

A. C. Heath; K. M. Kirk; J. M. Meyer; N. G. Martin

1999-01-01

284

Ecological and Genetic Determinants of Pepino Mosaic Virus Emergence  

PubMed Central

ABSTRACT Virus emergence is a complex phenomenon, which generally involves spread to a new host from a wild host, followed by adaptation to the new host. Although viruses account for the largest fraction of emerging crop pathogens, knowledge about their emergence is incomplete. We address here the question of whether Pepino Mosaic Virus (PepMV) emergence as a major tomato pathogen worldwide could have involved spread from wild to cultivated plant species and host adaptation. For this, we surveyed natural populations of wild tomatoes in southern Peru for PepMV infection. PepMV incidence, genetic variation, population structure, and accumulation in various hosts were analyzed. PepMV incidence in wild tomatoes was high, and a strain not yet reported in domestic tomato was characterized. This strain had a wide host range within the Solanaceae, multiplying efficiently in most assayed Solanum species and being adapted to wild tomato hosts. Conversely, PepMV isolates from tomato crops showed evidence of adaptation to domestic tomato, possibly traded against adaptation to wild tomatoes. Phylogenetic reconstructions indicated that the most probable ancestral sequence came from a wild Solanum species. A high incidence of PepMV in wild tomato relatives would favor virus spread to crops and its efficient multiplication in different Solanum species, including tomato, allowing its establishment as an epidemic pathogen. Later, adaptation to tomato, traded off against adaptation to other Solanum species, would isolate tomato populations from those in other hosts. IMPORTANCE Virus emergence is a complex phenomenon involving multiple ecological and genetic factors and is considered to involve three phases: virus encounter with the new host, virus adaptation to the new host, and changes in the epidemiological dynamics. We analyze here if this was the case in the recent emergence of Pepino Mosaic Virus (PepMV) in tomato crops worldwide. We characterized a new strain of PepMV infecting wild tomato populations in Peru. Comparison of this strain with PepMV isolates from tomato crops, plus phylogenetic reconstructions, supports a scenario in which PepMV would have spread to crops from wild tomato relatives, followed by adaptation to the new host and eventually leading to population isolation. Our data, which derive from the analysis of field isolates rather than from experimental evolution approaches, significantly contribute to understanding of plant virus emergence, which is necessary for its anticipation and prevention. PMID:24390328

Moreno-Pérez, Manuel G.; Pagán, Israel; Aragón-Caballero, Liliana; Cáceres, Fátima; Fraile, Aurora

2014-01-01

285

Environmental and Genetic Determinants of Colony Morphology in Yeast  

PubMed Central

Nutrient stresses trigger a variety of developmental switches in the budding yeast Saccharomyces cerevisiae. One of the least understood of such responses is the development of complex colony morphology, characterized by intricate, organized, and strain-specific patterns of colony growth and architecture. The genetic bases of this phenotype and the key environmental signals involved in its induction have heretofore remained poorly understood. By surveying multiple strain backgrounds and a large number of growth conditions, we show that limitation for fermentable carbon sources coupled with a rich nitrogen source is the primary trigger for the colony morphology response in budding yeast. Using knockout mutants and transposon-mediated mutagenesis, we demonstrate that two key signaling networks regulating this response are the filamentous growth MAP kinase cascade and the Ras-cAMP-PKA pathway. We further show synergistic epistasis between Rim15, a kinase involved in integration of nutrient signals, and other genes in these pathways. Ploidy, mating-type, and genotype-by-environment interactions also appear to play a role in the controlling colony morphology. Our study highlights the high degree of network reuse in this model eukaryote; yeast use the same core signaling pathways in multiple contexts to integrate information about environmental and physiological states and generate diverse developmental outputs. PMID:20107600

Granek, Joshua A.; Magwene, Paul M.

2010-01-01

286

Common genetic determinants of vitamin D insufficiency: the sunlight consortium  

Technology Transfer Automated Retrieval System (TEKTRAN)

Background: Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure an...

287

Reverse Genetic Screening Identifies Five E-class PPR Proteins Involved in RNA Editing in Mitochondria of Arabidopsis thaliana*  

PubMed Central

RNA editing in flowering plant mitochondria post-transcriptionally alters several hundred nucleotides from C to U, mostly in mRNAs. Several factors required for specific RNA-editing events in plant mitochondria and plastids have been identified, all of them PPR proteins of the PLS subclass with a C-terminal E-domain and about half also with an additional DYW domain. Based on this information, we here probe the connection between E-PPR proteins and RNA editing in plant mitochondria. We initiated a reverse genetics screen of T-DNA insertion lines in Arabidopsis thaliana and investigated 58 of the 150 E-PPR-coding genes for a function in RNA editing. Six genes were identified to be involved in mitochondrial RNA editing at specific sites. Homozygous mutants of the five genes MEF18-MEF22 display no gross disturbance in their growth or development patterns, suggesting that the editing sites affected are not crucial at least in the greenhouse. These results show that a considerable percentage of the E-PPR proteins are involved in the functional processing of site-specific RNA editing in plant mitochondria. PMID:20566637

Takenaka, Mizuki; Verbitskiy, Daniil; Zehrmann, Anja; Brennicke, Axel

2010-01-01

288

A Genetic Screen in Drosophila for Genes Interacting With senseless During Neuronal Development Identifies the Importin moleskin  

PubMed Central

Senseless (Sens) is a conserved transcription factor required for normal development of the Drosophila peripheral nervous system. In the Drosophila retina, sens is necessary and sufficient for differentiation of R8 photoreceptors and interommatidial bristles (IOBs). When Sens is expressed in undifferentiated cells posterior to the morphogenetic furrow, ectopic IOBs are formed. This phenotype was used to identify new members of the sens pathway in a dominant modifier screen. Seven suppressor and three enhancer complementation groups were isolated. Three groups from the screen are the known genes Delta, lilliputian, and moleskin/DIM-7 (msk), while the remaining seven groups represent novel genes with previously undefined functions in neural development. The nuclear import gene msk was identified as a potent suppressor of the ectopic interommatidial bristle phenotype. In addition, msk mutant adult eyes are extremely disrupted with defects in multiple cell types. Reminiscent of the sens mutant phenotype, msk eyes demonstrate reductions in the number of R8 photoreceptors due to an R8 to R2,5 fate switch, providing genetic evidence that Msk is a component of the sens pathway. Interestingly, in msk tissue, the loss of R8 fate occurs earlier than with sens and suggests a previously unidentified stage of R8 development between atonal and sens. PMID:17110483

Pepple, Kathryn L.; Anderson, Aimée E.; Frankfort, Benjamin J.; Mardon, Graeme

2007-01-01

289

Global genetic determinants of mitochondrial DNA copy number.  

PubMed

Many human diseases including development of cancer is associated with depletion of mitochondrial DNA (mtDNA) content. These diseases are collectively described as mitochondrial DNA depletion syndrome (MDS). High similarity between yeast and human mitochondria allows genomic study of the budding yeast to be used to identify human disease genes. In this study, we systematically screened the pre-existing respiratory-deficient Saccharomyces cerevisiae yeast strains using fluorescent microscopy and identified 102 nuclear genes whose deletions result in a complete mtDNA loss, of which 52 are not reported previously. Strikingly, these genes mainly encode protein products involved in mitochondrial protein biosynthesis process (54.9%). The rest of these genes either encode protein products associated with nucleic acid metabolism (14.7%), oxidative phosphorylation (3.9%), or other protein products (13.7%) responsible for bud-site selection, mitochondrial intermembrane space protein import, assembly of cytochrome-c oxidase, vacuolar protein sorting, protein-nucleus import, calcium-mediated signaling, heme biosynthesis and iron homeostasis. Thirteen (12.7%) of the genes encode proteins of unknown function. We identified human orthologs of these genes, conducted the interaction between the gene products and linked them to human mitochondrial disorders and other pathologies. In addition, we screened for genes whose defects affect the nuclear genome integrity. Our data provide a systematic view of the nuclear genes involved in maintenance of mitochondrial DNA. Together, our studies i) provide a global view of the genes regulating mtDNA content; ii) provide compelling new evidence toward understanding novel mechanism involved in mitochondrial genome maintenance and iii) provide useful clues in understanding human diseases in which mitochondrial defect and in particular depletion of mitochondrial genome plays a critical role. PMID:25170845

Zhang, Hengshan; Singh, Keshav K

2014-01-01

290

Genetic Determinants of Mycophenolate Related Anemia and Leukopenia Following Transplantation  

PubMed Central

Mycophenolate related anemia and leukopenia are well-known toxicities after transplantation. Toxicity leads to dose reduction, addition of colony-stimulating factors or erythropoietin, or discontinuation of immunosuppressive therapy. The causes of and risk factors associated with toxicity are unclear. Methods We studied the association between mycophenolate related anemia and leukopenia and 2,724 single nucleotide plymorphisms (SNP) in 978 patients undergoing living or deceased donor kidney transplant. Patients were followed to time of first anemia (hemoglobin <10gm/dL or hematocrit <30%) or first leukopenia (white blood cell [WBC] count <3000 cells/mm3) which required clinical intervention in the first 6 months posttransplant. Results Anemia occurred in 87 (9.5%) subjects and leukopenia in 224 (22.9%). In single SNP analyses, none of the SNPs were associated with time to leukopenia at a false discovery rate (FDR) of 20%. However, SNPs from the IL12A, HUS, CYP2C8 genes were associated with time to anemia allowing for an FDR of 20%. To assess the independence of these SNPs as predictors of anemia, we conducted a multi-SNP analysis including one SNP from each of the three genes. All three SNPs were associated with time to anemia, after adjusting for recipient age, weight, posttransplant dialysis and antiviral drug use and stratifying by clinical center. Conclusion While these SNPs require validation in an independent population, our results suggest genetics may play a role in risk of mycophenolate related hematologic toxicity. This may ultimately provide for better management of maintenance immunosuppression and gives insights into potential mechanism(s) by which toxicity occurs. PMID:21107304

Jacobson, PA; Schladt, D; Oetting, WS; Leduc, R; Guan, W; Matas, AJ; Lamba, V; Mannon, RB; Julian, BA; Israni, A

2013-01-01

291

Genetic determination of fatty acid composition in Spanish Churra sheep milk.  

PubMed

The objective of this study was to estimate the genetic variation of ovine milk fatty acid (FA) composition. We collected 4,100 milk samples in 14 herds from 976 Churra ewes sired mostly by 15 AI rams and analyzed them by gas-liquid chromatography for milk fatty acid composition. The studied traits were 12 individual FA contents (proportion in relation to the total amount of FA), 3 groups of fatty acids [saturated fatty acids (SFA), monounsaturated FA (MUFA), and polyunsaturated FA (PUFA)], and 2 FA ratios (n-6:n-3 and C18:2 cis-9,trans-11:C18:1 trans-11). In addition, percentages of fat and protein and daily milk yield were studied. For the analysis, repeatability animal models were implemented using Bayesian methods. In an initial step, univariate methods were conducted to test the hypothesis of the traits showing additive genetic determination. Deviance information criterion and Bayes factor were employed as model choice criteria. All the studied SFA showed additive genetic variance, but the estimated heritabilities were low. Among unsaturated FA (UFA), only C18:1 trans-11 and C18:2 cis-9,cis-12 showed additive genetic variation, their estimated heritabilities being [marginal posterior mean (marginal posterior SD)] 0.02(0.01) and 0.11(0.04), respectively. For the FA groups, only PUFA showed significant additive genetic variation. None of the studied ratios of FA showed additive genetic variation. In second multitrait analyses, genetic correlations between individual FA and production traits, and between groups of FA and ratios of FA and production traits, were investigated. Positive genetic correlations were estimated among medium-chain SFA, ranging from 0 to 0.85, but this parameter was close to zero between long-chain SFA (C16:0 and C18:0). Between long- and medium-chain SFA, estimated genetic correlations were negative, around -0.6. Among those UFA showing significant additive genetic variance, genetic correlations were close to zero. The estimated genetic correlations among all the investigated FA, milk yield, and fat and protein percentages were not different from zero. Our results suggest that low additive genetic variation is involved in the determination of the FA composition of milk fat in Churra sheep under current production conditions, which results in low values of heritabilities. PMID:20059931

Sánchez, J P; San Primitivo, F; Barbosa, E; Varona, L; de la Fuente, L F

2010-01-01

292

Whole exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma  

PubMed Central

The molecular foundations of lower-grade gliomas (LGGs)—astrocytoma, oligodendroglioma, and oligoastrocytoma—remain less well characterized than those of their fully malignant counterpart, glioblastoma. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) likely represent initiating pathogenic events. However, while IDH mutations appear to dramatically alter cellular epigenomic landscapes, definitive downstream transformative mechanisms have not been characterized. It remains likely, therefore, that additional genomic abnormalities collaborate with IDH mutation to drive oncogenesis in LGG. We performed whole exome sequencing in 4 LGGs, followed by focused resequencing in an additional 28, and found a high incidence of mutations in the ATRX gene (? thalassemia/mental retardation syndrome X-linked). ATRX forms a core component of a chromatin remodeling complex active in telomere biology. Mutations in ATRX have been identified in multiple tumor types and appear to cause alternative lengthening of telomeres (ALT), a presumed precursor to genomic instability. In our samples, ATRX mutation was entirely restricted to IDH-mutant tumors, closely correlated with TP53 mutation and astrocytic differentiation, and mutually exclusive with 1p/19q codeletion, the molecular hallmark of oligodendroglioma. Moreover, ATRX mutation was highly enriched in tumors of so-called early progenitor-like transcriptional subclass (~85%), which our prior work has linked to specific cells of origin in the forebrain subventricular zone. Finally, ATRX mutation correlated with ALT, providing a mechanistic link to genomic instability. In summary, our findings both identify ATRX mutation as a defining molecular determinant for a large subset of IDH-mutant gliomas and have direct implications on pathogenic mechanisms across the wide spectrum of LGGs. PMID:23104868

Kannan, Kasthuri; Inagaki, Akiko; Silber, Joachim; Gorovets, Daniel; Zhang, Jianan; Kastenhuber, Edward R.; Heguy, Adriana; Petrini, John H.; Chan, Timothy A.; Huse, Jason T.

2012-01-01

293

Genetically Determined Susceptibility to Tuberculosis in Mice Causally Involves Accelerated and Enhanced Recruitment of Granulocytes  

Microsoft Academic Search

Classical twin studies and recent linkage analyses of African populations have revealed a potential involve- ment of host genetic factors in susceptibility or resistance to Mycobacterium tuberculosis infection. In order to identify the candidate genes involved and test their causal implication, we capitalized on the mouse model of tuberculosis, since inbred mouse strains also differ substantially in their susceptibility to

Christine Keller; Reinhard Hoffmann; Roland Lang; Sven Brandau; Corinna Hermann; Stefan Ehlers

2006-01-01

294

Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus  

PubMed Central

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p?=?9.40×10?4, permutation p?=?1.0×10?3). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p?=?1.13×10?7). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases. PMID:21124985

Wilson, Gareth A.; Rakyan, Vardhman K.; Teschendorff, Andrew E.; Akan, Pelin; Stupka, Elia; Down, Thomas A.; Prokopenko, Inga; Morison, Ian M.; Mill, Jonathan; Pidsley, Ruth; Deloukas, Panos; Frayling, Timothy M.; Hattersley, Andrew T.; McCarthy, Mark I.; Beck, Stephan; Hitman, Graham A.

2010-01-01

295

Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus.  

PubMed

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p?=?9.40×10(-4), permutation p?=?1.0×10(-3)). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p?=?1.13×10(-7)). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases. PMID:21124985

Bell, Christopher G; Finer, Sarah; Lindgren, Cecilia M; Wilson, Gareth A; Rakyan, Vardhman K; Teschendorff, Andrew E; Akan, Pelin; Stupka, Elia; Down, Thomas A; Prokopenko, Inga; Morison, Ian M; Mill, Jonathan; Pidsley, Ruth; Deloukas, Panos; Frayling, Timothy M; Hattersley, Andrew T; McCarthy, Mark I; Beck, Stephan; Hitman, Graham A

2010-01-01

296

Application of Genomic and Quantitative Genetic Tools to Identify Candidate Resistance Genes for Brown Rot Resistance in Peach  

PubMed Central

The availability of a complete peach genome assembly and three different peach genome sequences created by our group provide new opportunities for application of genomic data and can improve the power of the classical Quantitative Trait Loci (QTL) approaches to identify candidate genes for peach disease resistance. Brown rot caused by Monilinia spp., is the most important fungal disease of stone fruits worldwide. Improved levels of peach fruit rot resistance have been identified in some cultivars and advanced selections developed in the UC Davis and USDA breeding programs. Whole genome sequencing of the Pop-DF parents lead to discovery of high-quality SNP markers for QTL genome scanning in this experimental population. Pop-DF created by crossing a brown rot moderately resistant cultivar ‘Dr. Davis’ and a brown rot resistant introgression line, ‘F8,1–42’, derived from an initial almond × peach interspecific hybrid, was evaluated for brown rot resistance in fruit of harvest maturity over three seasons. Using the SNP linkage map of Pop-DF and phenotypic data collected with inoculated fruit, a genome scan for QTL identified several SNP markers associated with brown rot resistance. Two of these QTLs were placed on linkage group 1, covering a large (physical) region on chromosome 1. The genome scan for QTL and SNP effects predicted several candidate genes associated with disease resistance responses in other host-pathogen systems. Two potential candidate genes, ppa011763m and ppa026453m, may be the genes primarily responsible for M. fructicola recognition in peach, activating both PAMP-triggered immunity (PTI) and effector-triggered immunity (ETI) responses. Our results provide a foundation for further genetic dissection, marker assisted breeding for brown rot resistance, and development of peach cultivars resistant to brown rot. PMID:24244329

Martínez-García, Pedro J.; Parfitt, Dan E.; Bostock, Richard M.; Fresnedo-Ramírez, Jonathan; Vazquez-Lobo, Alejandra; Ogundiwin, Ebenezer A.; Gradziel, Thomas M.; Crisosto, Carlos H.

2013-01-01

297

Two Different High Throughput Sequencing Approaches Identify Thousands of De Novo Genomic Markers for the Genetically Depleted Bornean Elephant  

PubMed Central

High throughput sequencing technologies are being applied to an increasing number of model species with a high-quality reference genome. The application and analyses of whole-genome sequence data in non-model species with no prior genomic information are currently under way. Recent sequencing technologies provide new opportunities for gathering genomic data in natural populations, laying the empirical foundation for future research in the field of conservation and population genomics. Here we present the case study of the Bornean elephant, which is the most endangered subspecies of Asian elephant and exhibits very low genetic diversity. We used two different sequencing platforms, the Roche 454 FLX (shotgun) and Illumina, GAIIx (Restriction site associated DNA, RAD) to evaluate the feasibility of the two methodologies for the discovery of de novo markers (single nucleotide polymorphism, SNPs and microsatellites) using low coverage data. Approximately, 6,683 (shotgun) and 14,724 (RAD) SNPs were detected within our elephant sequence dataset. Genotyping of a representative sample of 194 SNPs resulted in a SNP validation rate of ? 83 to 94% and 17% of the loci were polymorphic with a low diversity (Ho?=?0.057). Different numbers of microsatellites were identified through shotgun (27,226) and RAD (868) techniques. Out of all di-, tri-, and tetra-microsatellite loci, 1,706 loci had sufficient flanking regions (shotgun) while only 7 were found with RAD. All microsatellites were monomorphic in the Bornean but polymorphic in another elephant subspecies. Despite using different sample sizes, and the well known differences in the two platforms used regarding sequence length and throughput, the two approaches showed high validation rate. The approaches used here for marker development in a threatened species demonstrate the utility of high throughput sequencing technologies as a starting point for the development of genomic tools in a non-model species and in particular for a species with low genetic diversity. PMID:23185354

Sharma, Reeta; Goossens, Benoit; Kun-Rodrigues, Célia; Teixeira, Tatiana; Othman, Nurzhafarina; Boone, Jason Q.; Jue, Nathaniel K.; Obergfell, Craig; O'Neill, Rachel J.; Chikhi, Lounčs

2012-01-01

298

Identification of a genetic determinant responsible for host specificity in Streptococcus thermophilus bacteriophages.  

PubMed

Phage-host interactions remain poorly understood in lactic acid bacteria and essentially in all Gram-positive bacteria. The aim of this study was to identify the phage genetic determinant (anti-receptor) involved in the recognition of Streptococcus thermophilus hosts. The complete genomic sequence of the lytic S. thermophilus phage DT1 was determined previously, and bioinformatic analysis indicated that orf18 might be the anti-receptor gene. The orf18 of six additional S. thermophilus phages was determined (DT2, DT4, MD1, MD2, MD4 and Q5) and compared with the orf18 of DT1. The deduced ORF18 was divided into three domains. The first domain, which contains the N-terminal part of the protein, was conserved in all seven phages. The second domain was detected in only two phages and flanked by a motif called collagen-like repeats. The second domain also contained a variable region (VR1). All seven phages had a third domain that consisted of the C-terminal section of the protein as well as another variable region (VR2). Chimeric DT1 phages were constructed by recombination; a portion of its orf18 was replaced by the corresponding section in orf18 of the phage MD4. All DT1 chimeric phages acquired the host range of phage MD4. Analysis of the orf18 in the chimeric phages revealed that host specificity in phages DT1 and MD4 resulted from VR2. This is the first report on the identification and characterization of a phage gene involved in the host recognition process of Gram-positive bacteria. PMID:11489121

Duplessis, M; Moineau, S

2001-07-01

299

The triple helix of Plantago lanceolata: genetics and the environment interact to determine population dynamics.  

PubMed

The theory of evolution via natural selection predicts that the genetic composition of wild populations changes over time in response to the environment. Different genotypes should exhibit different demographic patterns, but genetic variation in demography is often impossible to separate from environmental variation. Here, we asked if genetic variation is important in determining demographic patterns. We answer this question using a long-term field experiment combined with general linear modeling of deterministic population growth rates (lambda), deterministic life table response experiment (LTRE) analysis, and stochastic simulation of demography by paternal lineage in a short-lived perennial plant, Plantago lanceolata, in which we replicated genotypes across four cohorts using a standard breeding design. General linear modeling showed that growth rate varied significantly with year, spatial block, and sire. In LTRE analysis of all cohorts, the strongest influences on growth rate were from year x spatial block, and cohort x year x spatial block interactions. In analysis of genetics vs. temporal environmental variation, the strongest impacts on growth rate were from year and year x sire. Finally, stochastic simulation suggested different genetic composition among cohorts after 100 years, and different population growth rates when genetic differences were accounted for than when they were not. We argue that genetic variation, genotype x environment interactions, natural selection, and cohort effects should be better integrated into population ecological studies, as these processes should result in deviations from projected deterministic and stochastic population parameters. PMID:22690630

Shefferson, Richard P; Roach, Deborah A

2012-04-01

300

Nickel-Resistance Determinants in Acidiphilium sp. PM Identified by Genome-Wide Functional Screening  

PubMed Central

Acidiphilium spp. are conspicuous dwellers of acidic, metal-rich environments. Indeed, they are among the most metal-resistant organisms; yet little is known about the mechanisms behind the metal tolerance in this genus. Acidiphilium sp. PM is an environmental isolate from Rio Tinto, an acidic, metal-laden river located in southwestern Spain. The characterization of its metal resistance revealed a remarkable ability to tolerate high Ni concentrations. Here we report the screening of a genomic library of Acidiphilium sp. PM to identify genes involved in Ni resistance. This approach revealed seven different genes conferring Ni resistance to E. coli, two of which form an operon encoding the ATP-dependent protease HslVU (ClpQY). This protease was found to enhance resistance to both Ni and Co in E. coli, a function not previously reported. Other Ni-resistance determinants include genes involved in lipopolysaccharide biosynthesis and the synthesis of branched amino acids. The diversity of molecular functions of the genes recovered in the screening suggests that Ni resistance in Acidiphilium sp. PM probably relies on different molecular mechanisms. PMID:24740277

San Martin-Uriz, Patxi; Mirete, Salvador; Alcolea, Pedro J.; Gomez, Manuel J.; Amils, Ricardo; Gonzalez-Pastor, Jose E.

2014-01-01

301

Genetic determination of male sterility in gynodioecious Silene nutans  

PubMed Central

Gynodioecy, the coexistence of female and hermaphrodite plants within a species, is often under nuclear–cytoplasmic sex determination, involving cytoplasmic male sterility (CMS) genes and nuclear restorers. A good knowledge of CMS and restorer polymorphism is essential for understanding the evolution and maintenance of gynodioecy, but reciprocal crossing studies remain scarce. Although mitochondrial diversity has been studied in a few gynodioecious species, the relationship between mitotype diversity and CMS status is poorly known. From a French sample of Silene nutans, a gynodioecious species whose sex determination remains unknown, we chose the four most divergent mitotypes that we had sampled at the cytochrome b gene and tested by reciprocal crosses whether they carry distinct CMS genes. We show that gynodioecy in S. nutans is under nuclear–cytoplasmic control, with at least two different CMSs and up to four restorers with epistatic interactions. Female occurrence and frequency were highly dependent on the mitotype, suggesting that the level of restoration varies greatly among CMSs. Two of the mitotypes, which have broad geographic distributions, represent different CMSs and are very unequally restored. We discuss the dynamics of gynodioecy at the large-scale meta-population level. PMID:20808324

Garraud, C; Brachi, B; Dufay, M; Touzet, P; Shykoff, J A

2011-01-01

302

Genetic determination of male sterility in gynodioecious Silene nutans.  

PubMed

Gynodioecy, the coexistence of female and hermaphrodite plants within a species, is often under nuclear-cytoplasmic sex determination, involving cytoplasmic male sterility (CMS) genes and nuclear restorers. A good knowledge of CMS and restorer polymorphism is essential for understanding the evolution and maintenance of gynodioecy, but reciprocal crossing studies remain scarce. Although mitochondrial diversity has been studied in a few gynodioecious species, the relationship between mitotype diversity and CMS status is poorly known. From a French sample of Silene nutans, a gynodioecious species whose sex determination remains unknown, we chose the four most divergent mitotypes that we had sampled at the cytochrome b gene and tested by reciprocal crosses whether they carry distinct CMS genes. We show that gynodioecy in S. nutans is under nuclear-cytoplasmic control, with at least two different CMSs and up to four restorers with epistatic interactions. Female occurrence and frequency were highly dependent on the mitotype, suggesting that the level of restoration varies greatly among CMSs. Two of the mitotypes, which have broad geographic distributions, represent different CMSs and are very unequally restored. We discuss the dynamics of gynodioecy at the large-scale meta-population level. PMID:20808324

Garraud, C; Brachi, B; Dufay, M; Touzet, P; Shykoff, J A

2011-05-01

303

Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma  

PubMed Central

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p?=?1.4×10?8), and with rs7555523, located in TMCO1 at 1q24.1 (p?=?1.6×10?8). In a meta-analysis of 4 case-control studies (total N?=?1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p?=?2.4×10?2 for rs11656696 and p?=?9.1×10?4 for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation. PMID:22570627

Ikram, M. Kamran; Jansonius, Nomdo M.; Pasutto, Francesca; Hysi, Pirro G.; Macgregor, Stuart; Janssen, Sarah F.; Hewitt, Alex W.; Viswanathan, Ananth C.; ten Brink, Jacoline B.; Hosseini, S. Mohsen; Amin, Najaf; Despriet, Dominiek D. G.; Willemse-Assink, Jacqueline J. M.; Kramer, Rogier; Rivadeneira, Fernando; Struchalin, Maksim; Aulchenko, Yurii S.; Weisschuh, Nicole; Zenkel, Matthias; Mardin, Christian Y.; Gramer, Eugen; Welge-Lüssen, Ulrich; Montgomery, Grant W.; Carbonaro, Francis; Young, Terri L.; Bellenguez, Céline; McGuffin, Peter; Foster, Paul J.; Topouzis, Fotis; Mitchell, Paul; Wang, Jie Jin; Wong, Tien Y.; Czudowska, Monika A.; Hofman, Albert; Uitterlinden, Andre G.; Wolfs, Roger C. W.; de Jong, Paulus T. V. M.; Oostra, Ben A.; Paterson, Andrew D.; Mackey, David A.; Bergen, Arthur A. B.; Reis, André; Hammond, Christopher J.; Vingerling, Johannes R.; Lemij, Hans G.; Klaver, Caroline C. W.; van Duijn, Cornelia M.

2012-01-01

304

High-Resolution Genetic Mapping in the Diversity Outbred Mouse Population Identifies Apobec1 as a Candidate Gene for Atherosclerosis  

PubMed Central

Inbred mice exhibit strain-specific variation in susceptibility to atherosclerosis and dyslipidemia that renders them useful in dissecting the genetic architecture of these complex diseases. Traditional quantitative trait locus (QTL) mapping studies using inbred strains often identify large genomic regions, containing many genes, due to limited recombination and/or sample size. This hampers candidate gene identification and translation of these results into possible risk factors and therapeutic targets. An alternative approach is the use of multiparental outbred lines for genetic mapping, such as the Diversity Outbred (DO) mouse panel, which can be more informative than traditional two-parent crosses and can aid in the identification of causal genes and variants associated with QTL. We fed 292 female DO mice either a high-fat, cholesterol-containing (HFCA) diet, to induce atherosclerosis, or a low-fat, high-protein diet for 18 wk and measured plasma lipid levels before and after diet treatment. We measured markers of atherosclerosis in the mice fed the HFCA diet. The mice were genotyped on a medium-density single-nucleotide polymorphism array and founder haplotypes were reconstructed using a hidden Markov model. The reconstructed haplotypes were then used to perform linkage mapping of atherosclerotic lesion size as well as plasma total cholesterol, triglycerides, insulin, and glucose. Among our highly significant QTL we detected a ~100 kb QTL interval for atherosclerosis on Chromosome 6, as well as a 1.4 Mb QTL interval on Chromosome 9 for triglyceride levels at baseline and a coincident 22.2 Mb QTL interval on Chromosome 9 for total cholesterol after dietary treatment. One candidate gene within the Chromosome 6 peak region associated with atherosclerosis is Apobec1, the apolipoprotein B (ApoB) mRNA-editing enzyme, which plays a role in the regulation of ApoB, a critical component of low-density lipoprotein, by editing ApoB mRNA. This study demonstrates the value of the DO population to improve mapping resolution and to aid in the identification of potential therapeutic targets for cardiovascular disease. Using a DO mouse population fed an HFCA diet, we were able to identify an A/J-specific isoform of Apobec1 that contributes to atherosclerosis. PMID:25344410

Smallwood, Tangi L.; Gatti, Daniel M.; Quizon, Pamela; Weinstock, George M.; Jung, Kuo-Chen; Zhao, Liyang; Hua, Kunjie; Pomp, Daniel; Bennett, Brian J.

2014-01-01

305

Characterization of the genetic environment of blaESBL genes, integrons and toxin-antitoxin systems identified on large transferrable plasmids in multi-drug resistant Escherichia coli  

PubMed Central

Objectives: Previously 14 conjugative plasmids from multi-drug resistant (MDR) Escherichia coli from healthy humans and food-producing animals in Switzerland were sequenced. The aim of this study was to extend the genetic characterization of these plasmids with a focus on blaESBL genes including blaCTX-M-1 and blaTEM, class 1 integrons and toxin-antitoxin (TA) systems contained therein. Methods: The nucleotide sequences and subsequent annotation therein of 14 conjugative plasmids were previously determined from their corresponding transconjugants. The TA loci were confirmed by RASTA-Bacteria. Results: Eight of the conjugative plasmids identified were found to encode genes expressing ESBLs. Structural heterogeneity was noted in the regions flanking both the blaCTX-M-1 and blaTEM genes. The blaCTX-M-1 genes were associated with the common insertion sequences ISEcp1 and IS26, and uniquely with an IS5 element in one case; while blaTEM genes were found to be associated with IS26 and Tn2. A new blaTEM-210 gene was identified. Seven class 1 integrons were also identified and assigned into 3 groups, denoted as In54, In369 and In501. Sixteen TA loci belonging to 4 of the TA gene families (relBE, vapBC, ccd and mazEF) were identified on 11 of these plasmids. Conclusions: Comparative sequence analysis of these plasmids provided data on the structures likely to contribute to sequence diversity associated with these accessory genes, including IS26, ISEcp1 and Tn2. All of them contribute to the dissemination of the corresponding resistance genes located on the different plasmids. There appears to be no association between ?-lactam encoding genes and TA systems. PMID:25610429

Wang, Juan; Stephan, Roger; Zurfluh, Katrin; Hächler, Herbert; Fanning, Séamus

2015-01-01

306

Determinants of Genetic Structure in a Nonequilibrium Metapopulation of the Plant Silene latifolia  

PubMed Central

Population genetic differentiation will be influenced by the demographic history of populations, opportunities for migration among neighboring demes and founder effects associated with repeated extinction and recolonization. In natural populations, these factors are expected to interact with each other and their magnitudes will vary depending on the spatial distribution and age structure of local demes. Although each of these effects has been individually identified as important in structuring genetic variance, their relative magnitude is seldom estimated in nature. We conducted a population genetic analysis in a metapopulation of the angiosperm, Silene latifolia, from which we had more than 20 years of data on the spatial distribution, demographic history, and extinction and colonization of demes. We used hierarchical Bayesian methods to disentangle which features of the populations contributed to among population variation in allele frequencies, including the magnitude and direction of their effects. We show that population age, long-term size and degree of connectivity all combine to affect the distribution of genetic variance; small, recently-founded, isolated populations contributed most to increase FST in the metapopulation. However, the effects of population size and population age are best understood as being modulated through the effects of connectivity to other extant populations, i.e. FST diminishes as populations age, but at a rate that depends how isolated the population is. These spatial and temporal correlates of population structure give insight into how migration, founder effect and within-deme genetic drift have combined to enhance and restrict genetic divergence in a natural metapopulation. PMID:25198341

Fields, Peter D.; Taylor, Douglas R.

2014-01-01

307

41 CFR 102-5.85 - What information should our determination for field work include if positions are identified...  

Code of Federal Regulations, 2013 CFR

...information should our determination for field work include if positions are identified rather than...MANAGEMENT REGULATION GENERAL 5-HOME-TO-WORK TRANSPORTATION Authorizing Home-to-Work Transportation § 102-5.85 What...

2013-07-01

308

41 CFR 102-5.85 - What information should our determination for field work include if positions are identified...  

Code of Federal Regulations, 2012 CFR

...information should our determination for field work include if positions are identified rather than...MANAGEMENT REGULATION GENERAL 5-HOME-TO-WORK TRANSPORTATION Authorizing Home-to-Work Transportation § 102-5.85 What...

2012-01-01

309

41 CFR 102-5.85 - What information should our determination for field work include if positions are identified...  

Code of Federal Regulations, 2010 CFR

...information should our determination for field work include if positions are identified rather than...MANAGEMENT REGULATION GENERAL 5-HOME-TO-WORK TRANSPORTATION Authorizing Home-to-Work Transportation § 102-5.85 What...

2010-07-01

310

41 CFR 102-5.85 - What information should our determination for field work include if positions are identified...  

Code of Federal Regulations, 2011 CFR

...information should our determination for field work include if positions are identified rather than...MANAGEMENT REGULATION GENERAL 5-HOME-TO-WORK TRANSPORTATION Authorizing Home-to-Work Transportation § 102-5.85 What...

2011-01-01

311

41 CFR 102-5.85 - What information should our determination for field work include if positions are identified...  

Code of Federal Regulations, 2014 CFR

...information should our determination for field work include if positions are identified rather than...MANAGEMENT REGULATION GENERAL 5-HOME-TO-WORK TRANSPORTATION Authorizing Home-to-Work Transportation § 102-5.85 What...

2014-01-01

312

Genetic determinants of haemolysis in sickle cell anaemia.  

PubMed

Haemolytic anaemia is variable among patients with sickle cell anaemia and can be estimated by reticulocyte count, lactate dehydrogenase, aspartate aminotransferase and bilirubin levels. Using principal component analysis of these measurements we computed a haemolytic score that we used as a subphenotype in a genome-wide association study. We identified in one cohort and replicated in two additional cohorts the association of a single nucleotide polymorphism in NPRL3 (rs7203560; chr16p13·3) (P = 6·04 × 10(-07) ). This association was validated by targeted genotyping in a fourth independent cohort. The HBA1/HBA2 regulatory elements, hypersensitive sites (HS)-33, HS-40 and HS-48 are located in introns of NPRL3. Rs7203560 was in perfect linkage disequilibrium (LD) with rs9926112 (r(2)  = 1) and in strong LD with rs7197554 (r(2)  = 0·75) and rs13336641 (r(2)  = 0·77); the latter is located between HS-33 and HS-40 sites and next to a CTCF binding site. The minor allele for rs7203560 was associated with the -?(3·7) thalassaemia gene deletion. When adjusting for HbF and ? thalassaemia, the association of NPRL3 with the haemolytic score was significant (P = 0·00375) and remained significant when examining only cases without gene deletion? thalassaemia (P = 0·02463). Perhaps by independently down-regulating expression of the HBA1/HBA2 genes, variants of the HBA1/HBA2 gene regulatory loci, tagged by rs7203560, reduce haemolysis in sickle cell anaemia. PMID:23406172

Milton, Jacqueline N; Rooks, Helen; Drasar, Emma; McCabe, Elizabeth L; Baldwin, Clinton T; Melista, Efi; Gordeuk, Victor R; Nouraie, Mehdi; Kato, Gregory R; Kato, Gregory J; Minniti, Caterina; Taylor, James; Campbell, Andrew; Luchtman-Jones, Lori; Rana, Sohail; Castro, Oswaldo; Zhang, Yingze; Thein, Swee Lay; Sebastiani, Paola; Gladwin, Mark T; Steinberg, Martin H

2013-04-01

313

Fine-Mapping and Phenotypic Analysis of the Ity3 Salmonella Susceptibility Locus Identify a Complex Genetic Structure  

PubMed Central

Experimental animal models of Salmonella infections have been widely used to identify genes important in the host immune response to infection. Using an F2 cross between the classical inbred strain C57BL/6J and the wild derived strain MOLF/Ei, we have previously identified Ity3 (Immunity to Typhimurium locus 3) as a locus contributing to the early susceptibility of MOLF/Ei mice to infection with Salmonella Typhimurium. We have also established a congenic strain (B6.MOLF-Ity/Ity3) with the MOLF/Ei Ity3 donor segment on a C57BL/6J background. The current study was designed to fine map and characterize functionally the Ity3 locus. We generated 12 recombinant sub-congenic strains that were characterized for susceptibility to infection, bacterial load in target organs, cytokine profile and anti-microbial mechanisms. These analyses showed that the impact of the Ity3 locus on survival and bacterial burden was stronger in male mice compared to female mice. Fine mapping of Ity3 indicated that two subloci contribute collectively to the susceptibility of B6.MOLF-Ity/Ity3 congenic mice to Salmonella infection. The Ity3.1 sublocus controls NADPH oxidase activity and is characterized by decreased ROS production, reduced inflammatory cytokine response and increased bacterial burden, thereby supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying this sublocus. The Ity3.2 sub-locus is characterized by a hyperresponsive inflammatory cytokine phenotype after exposure to Salmonella. Overall, this research provides support to the combined action of hormonal influences and complex genetic factors within the Ity3 locus in the innate immune response to Salmonella infection in wild-derived MOLF/Ei mice. PMID:24505352

Khan, Rabia T.; Yuki, Kyoko E.; Malo, Danielle

2014-01-01

314

Genetic suppression of a phosphomimic myosin II identifies system-level factors that promote myosin II cleavage furrow accumulation.  

PubMed

How myosin II localizes to the cleavage furrow in Dictyostelium and metazoan cells remains largely unknown despite significant advances in understanding its regulation. We designed a genetic selection using cDNA library suppression of 3xAsp myosin II to identify factors involved in myosin cleavage furrow accumulation. The 3xAsp mutant is deficient in bipolar thick filament assembly, fails to accumulate at the cleavage furrow, cannot rescue myoII-null cytokinesis, and has impaired mechanosensitive accumulation. Eleven genes suppressed this dominant cytokinesis deficiency when 3xAsp was expressed in wild-type cells. 3xAsp myosin II's localization to the cleavage furrow was rescued by constructs encoding rcdBB, mmsdh, RMD1, actin, one novel protein, and a 14-3-3 hairpin. Further characterization showed that RMD1 is required for myosin II cleavage furrow accumulation, acting in parallel with mechanical stress. Analysis of several mutant strains revealed that different thresholds of myosin II activity are required for daughter cell symmetry than for furrow ingression dynamics. Finally, an engineered myosin II with a longer lever arm (2xELC), producing a highly mechanosensitive motor, could also partially suppress the intragenic 3xAsp. Overall, myosin II accumulation is the result of multiple parallel and partially redundant pathways that comprise a cellular contractility control system. PMID:25318674

Ren, Yixin; West-Foyle, Hoku; Surcel, Alexandra; Miller, Christopher; Robinson, Douglas N

2014-12-15

315

A PCR-based forward genetics screening, using expression domain-specific markers, identifies mutants in endosperm transfer cell development  

PubMed Central

Mutant collections are an invaluable source of material on which forward genetic approaches allow the identification of genes affecting a wide variety of biological processes. However, some particular developmental stages and morphological structures may resist analysis due to their physical inaccessibility or to deleterious effects associated to their modification. Furthermore, lethal mutations acting early in development may escape detection. We have approached the characterization of 101 maize seed mutants, selected from a collection of 27,500 visually screened Mu-insertion lines, using a molecular marker approach based on a set of genes previously ascribed to different tissue compartments within the early developing kernel. A streamlined combination of qRT-PCR assays has allowed us to preliminary pinpoint the affected compartment, establish developmental comparisons to WT siblings and select mutant lines with alterations in the different compartments. Furthermore, clusters of markers co-affected by the underlying mutation were identified. We have analyzed more extensively a set of lines presenting significant variation in transfer cell-associated expression markers, and have performed morphological observations, and immunolocalization experiments to confirm the results, validating this approach as an efficient mutant description tool. PMID:24808899

Muńiz, Luis M.; Gómez, Elisa; Guyon, Virginie; López, Maribel; Khbaya, Bouchaib; Sellam, Olivier; Peréz, Pascual; Hueros, Gregorio

2014-01-01

316

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism  

PubMed Central

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes, and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study (up to 69,308 individuals of European descent from 43 studies), we have now extended the number of genome-wide significant loci to seven, accounting for a similar proportion of variance to maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes; ADRB1 with adult blood pressure; and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism. PMID:23202124

Horikoshi, Momoko; Yaghootkar, Hanieh; Mook-Kanamori, Dennis O.; Sovio, Ulla; Taal, H. Rob; Hennig, Branwen J.; Bradfield, Jonathan P.; St. Pourcain, Beate; Evans, David M.; Charoen, Pimphen; Kaakinen, Marika; Cousminer, Diana L.; Lehtimäki, Terho; Kreiner-Mřller, Eskil; Warrington, Nicole M.; Bustamante, Mariona; Feenstra, Bjarke; Berry, Diane J.; Thiering, Elisabeth; Pfab, Thiemo; Barton, Sheila J.; Shields, Beverley M.; Kerkhof, Marjan; van Leeuwen, Elisabeth M.; Fulford, Anthony J.; Kutalik, Zoltán; Zhao, Jing Hua; den Hoed, Marcel; Mahajan, Anubha; Lindi, Virpi; Goh, Liang-Kee; Hottenga, Jouke-Jan; Wu, Ying; Raitakari, Olli T.; Harder, Marie N.; Meirhaeghe, Aline; Ntalla, Ioanna; Salem, Rany M.; Jameson, Karen A.; Zhou, Kaixin; Monies, Dorota M.; Lagou, Vasiliki; Kirin, Mirna; Heikkinen, Jani; Adair, Linda S.; Alkuraya, Fowzan S.; Al-Odaib, Ali; Amouyel, Philippe; Andersson, Ehm Astrid; Bennett, Amanda J.; Blakemore, Alexandra I.F.; Buxton, Jessica L.; Dallongeville, Jean; Das, Shikta; de Geus, Eco J. C.; Estivill, Xavier; Flexeder, Claudia; Froguel, Philippe; Geller, Frank; Godfrey, Keith M.; Gottrand, Frédéric; Groves, Christopher J.; Hansen, Torben; Hirschhorn, Joel N.; Hofman, Albert; Hollegaard, Mads V.; Hougaard, David M.; Hyppönen, Elina; Inskip, Hazel M.; Isaacs, Aaron; Jřrgensen, Torben; Kanaka-Gantenbein, Christina; Kemp, John P.; Kiess, Wieland; Kilpeläinen, Tuomas O.; Klopp, Norman; Knight, Bridget A.; Kuzawa, Christopher W.; McMahon, George; Newnham, John P.; Niinikoski, Harri; Oostra, Ben A.; Pedersen, Louise; Postma, Dirkje S.; Ring, Susan M.; Rivadeneira, Fernando; Robertson, Neil R.; Sebert, Sylvain; Simell, Olli; Slowinski, Torsten; Tiesler, Carla M.T.; Tönjes, Anke; Vaag, Allan; Viikari, Jorma S.; Vink, Jacqueline M.; Vissing, Nadja Hawwa; Wareham, Nicholas J.; Willemsen, Gonneke; Witte, Daniel R.; Zhang, Haitao; Zhao, Jianhua; Wilson, James F.; Stumvoll, Michael; Prentice, Andrew M.; Meyer, Brian F.; Pearson, Ewan R.; Boreham, Colin A.G.; Cooper, Cyrus; Gillman, Matthew W.; Dedoussis, George V.; Moreno, Luis A; Pedersen, Oluf; Saarinen, Maiju; Mohlke, Karen L.; Boomsma, Dorret I.; Saw, Seang-Mei; Lakka, Timo A.; Körner, Antje; Loos, Ruth J.F.; Ong, Ken K.; Vollenweider, Peter; van Duijn, Cornelia M.; Koppelman, Gerard H.; Hattersley, Andrew T.; Holloway, John W.; Hocher, Berthold; Heinrich, Joachim; Power, Chris; Melbye, Mads; Guxens, Mňnica; Pennell, Craig E.; Břnnelykke, Klaus; Bisgaard, Hans; Eriksson, Johan G.; Widén, Elisabeth; Hakonarson, Hakon; Uitterlinden, André G.; Pouta, Anneli; Lawlor, Debbie A.; Smith, George Davey; Frayling, Timothy M.; McCarthy, Mark I.; Grant, Struan F.A.; Jaddoe, Vincent W.V.; Jarvelin, Marjo-Riitta; Timpson, Nicholas J.; Prokopenko, Inga; Freathy, Rachel M.

2012-01-01

317

Deep sequencing identifies two genotypes and high viral genetic diversity of human pegivirus (GB virus C) in rural Ugandan patients  

PubMed Central

Human pegivirus (HPgV), formerly ‘GB virus C’ or ‘hepatitis G virus’, is a member of the genus Flavivirus (Flaviviridae) that has garnered significant attention due to its inhibition of HIV, including slowing disease progression and prolonging survival in HIV-infected patients. Currently, there are six proposed HPgV genotypes that have roughly distinct geographical distributions. Genotypes 2 and 3 are the most comprehensively characterized, whereas those genotypes occurring on the African continent, where HPgV prevalence is highest, are less well studied. Using deep sequencing methods, we identified complete coding HPgV sequences in four of 28 patients (14.3?%) in rural Uganda, east Africa. One of these sequences corresponds to genotype 1 and is the first complete genome of this genotype from east Africa. The remaining three sequences correspond to genotype 5, a genotype that was previously considered exclusively South African. All four positive samples were collected within a geographical area of less than 25 km2, showing that multiple HPgV genotypes co-circulate in this area. Analysis of intra-host viral genetic diversity revealed that total single-nucleotide polymorphism frequency was approximately tenfold lower in HPgV than in hepatitis C virus. Finally, one patient was co-infected with HPgV and HIV, which, in combination with the high prevalence of HIV, suggests that this region would be a useful locale to study the interactions and co-evolution of these viruses. PMID:24077364

Ghai, Ria R.; Sibley, Samuel D.; Lauck, Michael; Dinis, Jorge M.; Bailey, Adam L.; Chapman, Colin A.; Omeja, Patrick; Friedrich, Thomas C.; O’Connor, David H.

2013-01-01

318

Determination of quantitative structure–octane rating relationships of hydrocarbons by genetic algorithms  

Microsoft Academic Search

The influence of the molecular structure of organic compounds on their knocking behavior was determined using a non-binary genetic algorithm (GA). The molecular structures of 240 potential gasoline components were described by use of 16 different structural groups. Partial octane numbers were calculated for these structural groups dependent on the substance classes paraffins, naphthenes, olefins, aromatics and oxygenates. The sum

Reinhard Meusinger; Ralf Moros

1999-01-01

319

Interpretation of electrophoretograms of seven microsatellite loci to determine the genetic diversity of the Arabian Oryx  

Microsoft Academic Search

Microsatellite markers are commonly used for examining population structure, especially inbreeding, outbreeding and gene flow. An array of microsatellite loci, preferably with multiallelic presentation, is preferable for ensuring accurate results. However, artifact peaks or stutters in the electrophoretograms significantly hamper the reliable interpretation of genotypes. We interpreted electrophoretograms of seven microsatellite loci to determine the genetic diversity of the Arabian

I. A. Arif; H. A. Khan; M. Shobrak; A. A. Al Homaidan; M. Al Sadoon; A. H. Al Farhan; A. H. Bahkali

2010-01-01

320

Determination of a Unique Solution to Parallel Proton Transfer Reactions Using the Genetic Algorithm  

E-print Network

Determination of a Unique Solution to Parallel Proton Transfer Reactions Using the Genetic proton transfer reactions to rigorous kinetic analysis, which consists of solving a set of coupled of Mathematics, The Faculty of Exact Sciences, and y Laser Laboratory for Fast Reactions in Biology, Department

Fibich, Gadi

321

Clinical applications of fetal sex determination in maternal blood in a preimplantation genetic diagnosis centre  

Microsoft Academic Search

BACKGROUND: Couples with a risk of transmitting X-linked diseases who are included in a preimplantation genetic diagnosis (PGD) programme need early and rapid fetal sex determination in two situations. The first situation is for the control of embryo sexing after PGD and the second situation is for those couples having a spontaneous pregnancy before the start of their PGD cycle.

Gerard Tachdjian; Nelly Frydman; Francois Audibert; Pierre Ray; Violaine Kerbrat

322

Teachers' Conceptions about the Genetic Determinism of Human Behaviour: A Survey in 23 Countries  

ERIC Educational Resources Information Center

This work analyses the answers to a questionnaire from 8,285 in-service and pre-service teachers from 23 countries, elaborated by the Biohead-Citizen research project, to investigate teachers' conceptions related to the genetic determinism of human behaviour. A principal components analysis is used to assess the main trends in all the…

Castéra, Jérémy; Clément, Pierre

2014-01-01

323

Determining Confidence Intervals When Measuring Genetic Diversity and the Discriminatory Abilities of Typing Methods for Microorganisms  

PubMed Central

We describe here a method for determining confidence intervals for a commonly used index of diversity. This approach facilitates the comparison of the genetic population structure of microorganisms isolated from different environments and improves the objective assessment of the discriminatory power of typing techniques. PMID:11682558

Grundmann, Hajo; Hori, Satoshi; Tanner, Gregor

2001-01-01

324

Comparative population genomics in animals uncovers the determinants of genetic diversity.  

PubMed

Genetic diversity is the amount of variation observed between DNA sequences from distinct individuals of a given species. This pivotal concept of population genetics has implications for species health, domestication, management and conservation. Levels of genetic diversity seem to vary greatly in natural populations and species, but the determinants of this variation, and particularly the relative influences of species biology and ecology versus population history, are still largely mysterious. Here we show that the diversity of a species is predictable, and is determined in the first place by its ecological strategy. We investigated the genome-wide diversity of 76 non-model animal species by sequencing the transcriptome of two to ten individuals in each species. The distribution of genetic diversity between species revealed no detectable influence of geographic range or invasive status but was accurately predicted by key species traits related to parental investment: long-lived or low-fecundity species with brooding ability were genetically less diverse than short-lived or highly fecund ones. Our analysis demonstrates the influence of long-term life-history strategies on species response to short-term environmental perturbations, a result with immediate implications for conservation policies. PMID:25141177

Romiguier, J; Gayral, P; Ballenghien, M; Bernard, A; Cahais, V; Chenuil, A; Chiari, Y; Dernat, R; Duret, L; Faivre, N; Loire, E; Lourenco, J M; Nabholz, B; Roux, C; Tsagkogeorga, G; Weber, A A-T; Weinert, L A; Belkhir, K; Bierne, N; Glémin, S; Galtier, N

2014-11-13

325

Environmental versus genetic sex determination: a possible factor in dinosaur extinction?  

Microsoft Academic Search

This study examined the possibility that genetically based sex-determination mechanisms have evolved to ensure a balanced male\\/female ratio and that this temperature-independent checkpoint might have been unavailable to long-extinct reptiles, notably the dinosaurs. A review of the literature on molecular and phylogenetic relationships between modes of reproduction and sex determination in extant animals was conducted. Mammals, birds, all snakes and

David Miller; Jonathan Summers; Sherman Silber

2004-01-01

326

Identifying some determinants of "jet lag" and its symptoms: a study of athletes and other travellers  

PubMed Central

Background: Travelling across multiple time zones disrupts normal circadian rhythms and induces "jet lag". Possible effects of this on training and performance in athletes were concerns before the Sydney Olympic Games. Objective: To identify some determinants of jet lag and its symptoms. Methods: A mixture of athletes, their coaches, and academics attending a conference (n = 85) was studied during their flights from the United Kingdom to Australia (two flights with a one hour stopover in Singapore), and for the first six days in Australia. Subjects differed in age, sex, chronotype, flexibility of sleeping habits, feelings of languor, fitness, time of arrival in Australia, and whether or not they had previous experience of travel to Australia. These variables and whether the body clock adjusted to new local time by phase advance or delay were tested as predictors for jet lag and some of its symptoms by stepwise multiple regression analyses. Results: The amount of sleep in the first flight was significantly greater in those who had left the United Kingdom in the evening than the morning (medians of 5.5 hours and 1.5 hours respectively; p = 0.0002, Mann-Whitney), whereas there was no significant difference on the second flight (2.5 hours v 2.8 hours; p = 0.72). Only the severity of jet lag and assessments of sleep and fatigue were commonly predicted significantly (p<0.05) by regression analysis, and then by only some of the variables. Thus increasing age and a later time of arrival in Australia were associated with less jet lag and fatigue, and previous experience of travel to Australia was associated with an earlier time of getting to sleep. Subjects who had adjusted by phase advance suffered worse jet lag during the 5th and 6th days in Australia. Conclusions: These results indicate the importance of an appropriate choice of itinerary and lifestyle for reducing the negative effects of jet lag in athletes and others who wish to perform optimally in the new time zone. PMID:11867494

Waterhouse, J; Edwards, B; Nevill, A; Carvalho, S; Atkinson, G; Buckley, P; Reilly, T; Godfrey, R; Ramsay, R

2002-01-01

327

Evolutionary Determinants of Genetic Variation in Susceptibility to Infectious Diseases in Humans  

PubMed Central

Although genetic variation among humans in their susceptibility to infectious diseases has long been appreciated, little focus has been devoted to identifying patterns in levels of variation in susceptibility to different diseases. Levels of genetic variation in susceptibility associated with 40 human infectious diseases were assessed by a survey of studies on both pedigree-based quantitative variation, as well as studies on different classes of marker alleles. These estimates were correlated with pathogen traits, epidemiological characteristics, and effectiveness of the human immune response. The strongest predictors of levels of genetic variation in susceptibility were disease characteristics negatively associated with immune effectiveness. High levels of genetic variation were associated with diseases with long infectious periods and for which vaccine development attempts have been unsuccessful. These findings are consistent with predictions based on theoretical models incorporating fitness costs associated with the different types of resistance mechanisms. An appreciation of these observed patterns will be a valuable tool in directing future research given that genetic variation in disease susceptibility has large implications for vaccine development and epidemiology. PMID:22242158

Baker, Christi; Antonovics, Janis

2012-01-01

328

DETERMINATION OF NEWLY IDENTIFIED DISINFECTION BY-PRODUCTS IN DRINKING WATER  

EPA Science Inventory

The Metropolitan Water District of Southern California (MWDSC) is investigating the occurrence of 39 newly identified disinfection by-products (DBPs)-which were not included in the Information Collection Rule (ICR)-in drinking waters. Halomethanes (HMs), haloacetonitriles (HANs),...

329

Using the Social Communication Questionnaire to Identify "Autistic Spectrum" Disorders Associated with Other Genetic Conditions: Findings from a Study of Individuals with Cohen Syndrome  

ERIC Educational Resources Information Center

Increasingly, recent research has identified relatively high rates of autistic types of symptoms in a variety of genetic conditions, such as fragile X (Turk and Graham, 1997), tuberous sclerosis (Bolton and Griffiths, 1997), Angelman syndrome (Trillingsgaard and Ostergaard, this issue) and others (see Gillberg and Coleman, 2000). Detailed…

Howlin, Patricia; Karpf, Janne

2004-01-01

330

A Matter of Timing: Identifying Significant Multi-Dose Radiotherapy Improvements by Numerical Simulation and Genetic Algorithm Search  

PubMed Central

Multi-dose radiotherapy protocols (fraction dose and timing) currently used in the clinic are the product of human selection based on habit, received wisdom, physician experience and intra-day patient timetabling. However, due to combinatorial considerations, the potential treatment protocol space for a given total dose or treatment length is enormous, even for relatively coarse search; well beyond the capacity of traditional in-vitro methods. In constrast, high fidelity numerical simulation of tumor development is well suited to the challenge. Building on our previous single-dose numerical simulation model of EMT6/Ro spheroids, a multi-dose irradiation response module is added and calibrated to the effective dose arising from 18 independent multi-dose treatment programs available in the experimental literature. With the developed model a constrained, non-linear, search for better performing cadidate protocols is conducted within the vicinity of two benchmarks by genetic algorithm (GA) techniques. After evaluating less than 0.01% of the potential benchmark protocol space, candidate protocols were identified by the GA which conferred an average of 9.4% (max benefit 16.5%) and 7.1% (13.3%) improvement (reduction) on tumour cell count compared to the two benchmarks, respectively. Noticing that a convergent phenomenon of the top performing protocols was their temporal synchronicity, a further series of numerical experiments was conducted with periodic time-gap protocols (10 h to 23 h), leading to the discovery that the performance of the GA search candidates could be replicated by 17–18 h periodic candidates. Further dynamic irradiation-response cell-phase analysis revealed that such periodicity cohered with latent EMT6/Ro cell-phase temporal patterning. Taken together, this study provides powerful evidence towards the hypothesis that even simple inter-fraction timing variations for a given fractional dose program may present a facile, and highly cost-effecitive means of significantly improving clinical efficacy. PMID:25460164

Angus, Simon D.; Piotrowska, Monika Joanna

2014-01-01

331

Characteristic patterns of dendritic remodeling in early-stage glaucoma: evidence from genetically identified retinal ganglion cell types.  

PubMed

Retinal ganglion cell (RGC) loss is a hallmark of glaucoma and the second leading cause of blindness worldwide. The type and timing of cellular changes leading to RGC loss in glaucoma remain incompletely understood, including whether specific RGC subtypes are preferentially impacted at early stages of this disease. Here we applied the microbead occlusion model of glaucoma to different transgenic mouse lines, each expressing green fluorescent protein in 1-2 specific RGC subtypes. Targeted filling, reconstruction, and subsequent comparison of the genetically identified RGCs in control and bead-injected eyes revealed that some subtypes undergo significant dendritic rearrangements as early as 7 d following induction of elevated intraocular pressure (IOP). By comparing specific On-type, On-Off-type and Off-type RGCs, we found that RGCs that target the majority of their dendritic arbors to the scleral half or "Off" sublamina of the inner plexiform layer (IPL) undergo the greatest changes, whereas RGCs with the majority of their dendrites in the On sublamina did not alter their structure at this time point. Moreover, M1 intrinsically photosensitive RGCs, which functionally are On RGCs but structurally stratify their dendrites in the Off sublamina of the IPL, also underwent significant changes in dendritic structure 1 week after elevated IOP. Thus, our findings reveal that certain RGC subtypes manifest significant changes in dendritic structure after very brief exposure to elevated IOP. The observation that RGCs stratifying most of their dendrites in the Off sublamina are first to alter their structure may inform the development of new strategies to detect, monitor, and treat glaucoma in humans. PMID:25673829

El-Danaf, Rana N; Huberman, Andrew D

2015-02-11

332

A Systems Genetics Approach Identifies CXCL14, ITGAX, and LPCAT2 as Novel Aggressive Prostate Cancer Susceptibility Genes  

PubMed Central

Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n?=?228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will facilitate the identification of novel germline factors driving aggressive disease susceptibility and allow for new insights into these deadly forms of prostate cancer. PMID:25411967

Andreas, Jonathan; Patel, Shashank J.; Zhang, Suiyuan; Chines, Peter; Elkahloun, Abdel; Chandrasekharappa, Settara; Gutkind, J. Silvio; Molinolo, Alfredo A.; Crawford, Nigel P. S.

2014-01-01

333

Extensive Genetic Diversity Identified among Sporadic Methicillin-Resistant Staphylococcus aureus Isolates Recovered in Irish Hospitals between 2000 and 2012  

PubMed Central

Clonal replacement of predominant nosocomial methicillin-resistant Staphylococcus aureus (MRSA) strains has occurred several times in Ireland during the last 4 decades. However, little is known about sporadically occurring MRSA in Irish hospitals or in other countries. Eighty-eight representative pvl-negative sporadic MRSA isolates recovered in Irish hospitals between 2000 and 2012 were investigated. These yielded unusual pulsed-field gel electrophoresis and antibiogram-resistogram typing patterns distinct from those of the predominant nosocomial MRSA clone, ST22-MRSA-IV, during the study period. Isolates were characterized by spa typing and DNA microarray profiling for multilocus sequence type (MLST) clonal complex (CC) and/or sequence type (ST) and SCCmec type assignment, as well as for detection of virulence and antimicrobial resistance genes. Conventional PCR-based SCCmec subtyping was undertaken when necessary. Extensive diversity was detected, including 38 spa types, 13 MLST-CCs (including 18 STs among 62 isolates assigned to STs), and 25 SCCmec types (including 2 possible novel SCCmec elements and 7 possible novel SCCmec subtypes). Fifty-four MLST-spa-SCCmec type combinations were identified. Overall, 68.5% of isolates were assigned to nosocomial lineages, with ST8-t190-MRSA-IID/IIE ± SCCM1 predominating (17.4%), followed by CC779/ST779-t878-MRSA-?SCCmec-SCC-SCCCRISPR (7.6%) and CC22/ST22-t032-MRSA-IVh (5.4%). Community-associated clones, including CC1-t127/t386/t2279-MRSA-IV, CC59-t216-MRSA-V, CC8-t008-MRSA-IVa, and CC5-t002/t242-MRSA-IV/V, and putative animal-associated clones, including CC130-t12399-MRSA-XI, ST8-t064-MRSA-IVa, ST398-t011-MRSA-IVa, and CC6-t701-MRSA-V, were also identified. In total, 53.3% and 47.8% of isolates harbored genes for resistance to two or more classes of antimicrobial agents and two or more mobile genetic element-encoded virulence-associated factors, respectively. Effective ongoing surveillance of sporadic nosocomial MRSA is warranted for early detection of emerging clones and reservoirs of virulence, resistance, and SCCmec genes. PMID:24395241

Kinnevey, Peter M.; Shore, Anna C.; Brennan, Grainne I.; Sullivan, Derek J.; Ehricht, Ralf; Monecke, Stefan

2014-01-01

334

Genetic linkage analysis of the lesser grain borer Rhyzopertha dominica identifies two loci that confer high-level resistance to the fumigant phosphine.  

PubMed Central

High levels of inheritable resistance to phosphine in Rhyzopertha dominica have recently been detected in Australia and in an effort to isolate the genes responsible for resistance we have used random amplified DNA fingerprinting (RAF) to produce a genetic linkage map of R. dominica. The map consists of 94 dominant DNA markers with an average distance between markers of 4.6 cM and defines nine linkage groups with a total recombination distance of 390.1 cM. We have identified two loci that are responsible for high-level resistance. One provides approximately 50x resistance to phosphine while the other provides 12.5x resistance and in combination, the two genes act synergistically to provide a resistance level 250x greater than that of fully susceptible beetles. The haploid genome size has been determined to be 4.76 x 10(8) bp, resulting in an average physical distance of 1.2 Mbp per map unit. No recombination has been observed between either of the two resistance loci and their adjacent DNA markers in a population of 44 fully resistant F5 individuals, which indicates that the genes are likely to reside within 0.91 cM (1.1 Mbp) of the DNA markers. PMID:12072472

Schlipalius, David I; Cheng, Qiang; Reilly, Paul E B; Collins, Patrick J; Ebert, Paul R

2002-01-01

335

Genetic mapping identifies a major locus spanning P450 clusters associated with pyrethroid resistance in kdr-free Anopheles arabiensis from Chad  

PubMed Central

Prevention of malaria transmission throughout much of Africa is dependent on bednets that are impregnated with pyrethroid insecticides. Anopheles arabiensis is the major malaria vector in Chad and efforts to control this vector are threatened by the emergence of pyrethroid resistance. WHO bioassays revealed that An. arabiensis from Ndjamena is resistant to pyrethroids and dichlorodiphenyltrichloroethane (DDT) but fully susceptible to carbamates and organophosphates. No 1014F or 1014S kdr alleles were detected in this population. To determine the mechanisms that are responsible for resistance, genetic crosses were established between the Ndja strain and an insecticide susceptible population from Mozambique. Resistance was inherited as an autosomal trait and quantitative trait locus (QTL) mapping identified a single major locus on chromosome 2R, which explained 24.4% of the variance in resistance. This QTL is enriched in P450 genes including 25 cytochrome P450s in total. One of these, Cyp6p4 is 22-fold upregulated in the Ndja strain compared with the susceptible. Piperonyl butoxide (PBO) synergist and biochemical assays further support a role for P450s in conferring pyrethroid resistance in this population. PMID:23299100

Witzig, C; Parry, M; Morgan, J C; Irving, H; Steven, A; Cuamba, N; Kerah-Hinzoumbé, C; Ranson, H; Wondji, C S

2013-01-01

336

Host genetic determinants of microbiota-dependent nutrition revealed by genome-wide analysis of Drosophila melanogaster.  

PubMed

Animals bear communities of gut microorganisms with substantial effects on animal nutrition, but the host genetic basis of these effects is unknown. Here we use Drosophila to demonstrate substantial among-genotype variation in the effects of eliminating the gut microbiota on five host nutritional indices (weight, protein, lipid, glucose and glycogen contents); this includes variation in both the magnitude and direction of microbiota-dependent effects. Genome-wide association studies to identify the genetic basis of the microbiota-dependent variation reveal polymorphisms in largely non-overlapping sets of genes associated with variation in the nutritional traits, including strong representation of conserved genes functioning in signalling. Key genes identified by the GWA study are validated by loss-of-function mutations that altered microbiota-dependent nutritional effects. We conclude that the microbiota interacts with the animal at multiple points in the signalling and regulatory networks that determine animal nutrition. These interactions with the microbiota are probably conserved across animals, including humans. PMID:25692519

Dobson, Adam J; Chaston, John M; Newell, Peter D; Donahue, Leanne; Hermann, Sara L; Sannino, David R; Westmiller, Stephanie; Wong, Adam C-N; Clark, Andrew G; Lazzaro, Brian P; Douglas, Angela E

2015-01-01

337

The Birds and the Bees and the Flowers and the Trees: Lessons from Genetic Mapping of Sex Determination in Plants and Animals  

PubMed Central

The ability to identify genetic markers in nonmodel systems has allowed geneticists to construct linkage maps for a diversity of species, and the sex-determining locus is often among the first to be mapped. Sex determination is an important area of study in developmental and evolutionary biology, as well as ecology. Its importance for organisms might suggest that sex determination is highly conserved. However, genetic studies have shown that sex determination mechanisms, and the genes involved, are surprisingly labile. We review studies using genetic mapping and phylogenetic inferences, which can help reveal evolutionary pattern within this lability and potentially identify the changes that have occurred among different sex determination systems. We define some of the terminology, particularly where confusion arises in writing about such a diverse range of organisms, and highlight some major differences between plants and animals, and some important similarities. We stress the importance of studying taxa suitable for testing hypotheses, and the need for phylogenetic studies directed to taxa where the patterns of changes can be most reliably inferred, if the ultimate goal of testing hypotheses regarding the selective forces that have led to changes in such an essential trait is to become feasible. PMID:20855574

Charlesworth, Deborah; Mank, Judith E.

2010-01-01

338

Genetically determined inflammatory-response related cytokine and chemokine transcript profiles between mammary carcinoma resistant and susceptible rat strains.  

PubMed

Multiple human breast and rat mammary carcinoma susceptibility (Mcs) alleles have been identified. Wistar Kyoto (WKY) rats are resistant to developing mammary carcinomas, while Wistar Furth (WF) females are susceptible. Gene transcripts at Mcs5a1, Mcs5a2, and Mcs5c are differentially expressed between resistant WKY and susceptible WF alleles in immune-system tissues. We hypothesized that immune-related gene transcript profiles are genetically determined in mammary carcinoma resistant and susceptible mammary glands. Low-density QPCR arrays were used to compare inflammation related genes between mammary carcinoma resistant WKY and susceptible WF females. Mammary gland gene transcript levels predicted to be different based on arrays were tested in independent samples. In total, 20 females per strain were exposed to 7,12-dimethylbenz(a)anthracene (DMBA) to induce mammary carcinogenesis. Twelve age-matched controls per strain without DMBA were included to determine main effects of DMBA-exposure. Significant (ANOVA P ? 0.01) effects of strain on mammary gland transcript level were observed for Cx3cl1, Il11ra, Il4, C3, Ccl20, Ccl11, Itgb2, Cxcl12, and Cxcr7. Significant effects of DMBA-exposure were observed for Cx3cl1, Il11ra, Cxcr4, Il4ra, and Il4. Strain and DMBA-exposure interaction effects were significant for Cx3cl1. Transcript levels of Cxcr7 relative to Cxcr4 were modified differently by DMBA in mammary carcinoma resistant and susceptible strains. In conclusion, several genetically-determined differences in cytokine, chemokine, and receptor gene transcript levels were identified between mammary carcinoma susceptible and resistant mammary glands, which may be indicative of cell populations and activities that suppress mammary carcinogenesis in resistant genotypes. PMID:22609213

Devapatla, Bharat; Sanders, Jennifer; Samuelson, David J

2012-08-01

339

USGS Genetics and Genomics Showcase  

USGS Multimedia Gallery

The USGS Biology Resources Discipline showcased research in the fields of genetics and genomics on March 10, 2010 in the South Interior Building of the Department of the Interior. Topics included genetics to determine populations and recover endangered species, genetics that can identify wildlife in...

2010-03-25

340

Robust Flight Path Determination for Mars Precision Landing Using Genetic Algorithms  

NASA Technical Reports Server (NTRS)

This paper documents the application of genetic algorithms (GAs) to the problem of robust flight path determination for Mars precision landing. The robust flight path problem is defined here as the determination of the flight path which delivers a low-lift open-loop controlled vehicle to its desired final landing location while minimizing the effect of perturbations due to uncertainty in the atmospheric model and entry conditions. The genetic algorithm was capable of finding solutions which reduced the landing error from 111 km RMS radial (open-loop optimal) to 43 km RMS radial (optimized with respect to perturbations) using 200 hours of computation on an Ultra-SPARC workstation. Further reduction in the landing error is possible by going to closed-loop control which can utilize the GA optimized paths as nominal trajectories for linearization.

Bayard, David S.; Kohen, Hamid

1997-01-01

341

Human genome screen to identify the genetic basis of the anti-inflammatory effects of Boswellia in microvascular endothelial cells.  

PubMed

Inflammatory disorders represent a substantial health problem. Medicinal plants belonging to the Burseraceae family, including Boswellia, are especially known for their anti-inflammatory properties. The gum resin of Boswellia serrata contains boswellic acids, which inhibit leukotriene biosynthesis. A series of chronic inflammatory diseases are perpetuated by leukotrienes. Although Boswellia extract has proven to be anti-inflammatory in clinical trials, the underlying mechanisms remain to be characterized. TNF alpha represents one of the most widely recognized mediators of inflammation. One mechanism by which TNFalpha causes inflammation is by potently inducing the expression of adhesion molecules such as VCAM-1. We sought to test the genetic basis of the antiinflammatory effects of BE (standardized Boswellia extract, 5-Loxin) in a system of TNF alpha-induced gene expression in human microvascular endothelial cells. We conducted the first whole genome screen for TNF alpha- inducible genes in human microvascular cells (HMEC). Acutely, TNF alpha induced 522 genes and downregulated 141 genes in nine out of nine pairwise comparisons. Of the 522 genes induced by TNF alpha in HMEC, 113 genes were clearly sensitive to BE treatment. Such genes directly related to inflammation, cell adhesion, and proteolysis. The robust BE-sensitive candidate genes were then subjected to further processing for the identification of BE-sensitive signaling pathways. The use of resources such as GenMAPP, KEGG, and gene ontology led to the recognition of the primary BE-sensitive TNF alpha-inducible pathways. BE prevented the TNF alpha-induced expression of matrix metalloproteinases. BE also prevented the inducible expression of mediators of apoptosis. Most strikingly, however, TNF alpha-inducible expression of VCAM-1 and ICAM-1 were observed to be sensitive to BE. Realtime PCR studies showed that while TNF alpha potently induced VCAM-1 gene expression, BE completely prevented it. This result confirmed our microarray findings and built a compelling case for the anti-inflammatory property of BE. In an in vivo model of carrageenan-induced rat paw inflammation, we observed a significant antiinflammatory property of BE consistent with our in vitro findings. These findings warrant further research aimed at identifying the signaling mechanisms by which BE exerts its anti-inflammatory effects. PMID:15812241

Roy, Sashwati; Khanna, Savita; Shah, Hiral; Rink, Cameron; Phillips, Christina; Preuss, Harry; Subbaraju, Gottumukkala V; Trimurtulu, Golakoti; Krishnaraju, Alluri V; Bagchi, Manashi; Bagchi, Debasis; Sen, Chandan K

2005-04-01

342

Determining salinization extent, identifying salinity sources, and estimating chloride mass using surface, borehole, and airborne electromagnetic induction methods  

Microsoft Academic Search

(1) Using an example from an oil field in the semiarid Red River basin in Texas, we show that electromagnetic (EM) methods are useful in locating salinized soil and water, determining salinization extent, identifying likely salinity sources, and estimating the total mass of chloride within a saline-water plume. Each of these aspects assists in managing salinization and assessing its impact.

Jeffrey G. Paine

2003-01-01

343

The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation  

PubMed Central

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection. PMID:21051598

Pereyra, Florencia; Jia, Xiaoming; McLaren, Paul J.; Telenti, Amalio; de Bakker, Paul I.W.; Walker, Bruce D.; Jia, Xiaoming; McLaren, Paul J.; Ripke, Stephan; Brumme, Chanson J.; Pulit, Sara L.; Telenti, Amalio; Carrington, Mary; Kadie, Carl M.; Carlson, Jonathan M.; Heckerman, David; de Bakker, Paul I.W.; Pereyra, Florencia; de Bakker, Paul I.W.; Graham, Robert R.; Plenge, Robert M.; Deeks, Steven G.; Walker, Bruce D.; Gianniny, Lauren; Crawford, Gabriel; Sullivan, Jordan; Gonzalez, Elena; Davies, Leela; Camargo, Amy; Moore, Jamie M.; Beattie, Nicole; Gupta, Supriya; Crenshaw, Andrew; Burtt, Noël P.; Guiducci, Candace; Gupta, Namrata; Carrington, Mary; Gao, Xiaojiang; Qi, Ying; Yuki, Yuko; Pereyra, Florencia; Piechocka-Trocha, Alicja; Cutrell, Emily; Rosenberg, Rachel; Moss, Kristin L.; Lemay, Paul; O’Leary, Jessica; Schaefer, Todd; Verma, Pranshu; Toth, Ildiko; Block, Brian; Baker, Brett; Rothchild, Alissa; Lian, Jeffrey; Proudfoot, Jacqueline; Alvino, Donna Marie L.; Vine, Seanna; Addo, Marylyn M.; Allen, Todd M.; Altfeld, Marcus; Henn, Matthew R.; Le Gall, Sylvie; Streeck, Hendrik; Walker, Bruce D.; Haas, David W.; Kuritzkes, Daniel R.; Robbins, Gregory K.; Shafer, Robert W.; Gulick, Roy M.; Shikuma, Cecilia M.; Haubrich, Richard; Riddler, Sharon; Sax, Paul E.; Daar, Eric S.; Ribaudo, Heather J.; Agan, Brian; Agarwal, Shanu; Ahern, Richard L.; Allen, Brady L.; Altidor, Sherly; Altschuler, Eric L.; Ambardar, Sujata; Anastos, Kathryn; Anderson, Ben; Anderson, Val; Andrady, Ushan; Antoniskis, Diana; Bangsberg, David; Barbaro, Daniel; Barrie, William; Bartczak, J.; Barton, Simon; Basden, Patricia; Basgoz, Nesli; Bazner, Suzane; Bellos, Nicholaos C.; Benson, Anne M.; Berger, Judith; Bernard, Nicole F.; Bernard, Annette M.; Birch, Christopher; Bodner, Stanley J.; Bolan, Robert K.; Boudreaux, Emilie T.; Bradley, Meg; Braun, James F.; Brndjar, Jon E.; Brown, Stephen J.; Brown, Katherine; Brown, Sheldon T.; Burack, Jedidiah; Bush, Larry M.; Cafaro, Virginia; Campbell, Omobolaji; Campbell, John; Carlson, Robert H.; Carmichael, J. Kevin; Casey, Kathleen K.; Cavacuiti, Chris; Celestin, Gregory; Chambers, Steven T.; Chez, Nancy; Chirch, Lisa M.; Cimoch, Paul J.; Cohen, Daniel; Cohn, Lillian E.; Conway, Brian; Cooper, David A.; Cornelson, Brian; Cox, David T.; Cristofano, Michael V.; Cuchural, George; Czartoski, Julie L.; Dahman, Joseph M.; Daly, Jennifer S.; Davis, Benjamin T.; Davis, Kristine; Davod, Sheila M.; Deeks, Steven G.; DeJesus, Edwin; Dietz, Craig A.; Dunham, Eleanor; Dunn, Michael E.; Ellerin, Todd B.; Eron, Joseph J.; Fangman, John J.W.; Farel, Claire E.; Ferlazzo, Helen; Fidler, Sarah; Fleenor-Ford, Anita; Frankel, Renee; Freedberg, Kenneth A.; French, Neel K.; Fuchs, Jonathan D.; Fuller, Jon D.; Gaberman, Jonna; Gallant, Joel E.; Gandhi, Rajesh T.; Garcia, Efrain; Garmon, Donald; Gathe, Joseph C.; Gaultier, Cyril R.; Gebre, Wondwoosen; Gilman, Frank D.; Gilson, Ian; Goepfert, Paul A.; Gottlieb, Michael S.; Goulston, Claudia; Groger, Richard K.; Gurley, T. Douglas; Haber, Stuart; Hardwicke, Robin; Hardy, W. David; Harrigan, P. Richard; Hawkins, Trevor N.; Heath, Sonya; Hecht, Frederick M.; Henry, W. Keith; Hladek, Melissa; Hoffman, Robert P.; Horton, James M.; Hsu, Ricky K.; Huhn, Gregory D.; Hunt, Peter; Hupert, Mark J.; Illeman, Mark L.; Jaeger, Hans; Jellinger, Robert M.; John, Mina; Johnson, Jennifer A.; Johnson, Kristin L.; Johnson, Heather; Johnson, Kay; Joly, Jennifer; Jordan, Wilbert C.; Kauffman, Carol A.; Khanlou, Homayoon; Killian, Robert K.; Kim, Arthur Y.; Kim, David D.; Kinder, Clifford A.; Kirchner, Jeffrey T.; Kogelman, Laura; Kojic, Erna Milunka; Korthuis, P. Todd; Kurisu, Wayne; Kwon, Douglas S.; LaMar, Melissa; Lampiris, Harry; Lanzafame, Massimiliano; Lederman, Michael M.; Lee, David M.; Lee, Jean M.L.; Lee, Marah J.; Lee, Edward T.Y.; Lemoine, Janice; Levy, Jay A.; Llibre, Josep M.; Liguori, Michael A.; Little, Susan J.; Liu, Anne Y.; Lopez, Alvaro J.; Loutfy, Mono R.; Loy, Dawn; Mohammed, Debbie Y.; Man, Alan; Mansour, Michael K.; Marconi, Vincent C.; Markowitz, Martin; Marques, Rui; Martin, Jeffrey N.; Martin, Harold L.; Mayer, Kenneth Hugh; McElrath, M. Juliana; McGhee, Theresa A.; McGovern, Barbara H.; McGowan, Katherine; McIntyre, Dawn; Mcleod, Gavin X.; Menezes, Prema; Mesa, Greg; Metroka, Craig E.; Meyer-Olson, Dirk; Miller, Andy O.; Montgomery, Kate; Mounzer, Karam C.; Nagami, Ellen H.; Nagin, Iris; Nahass, Ronald G.; Nelson, Margret O.; Nielsen, Craig; Norene, David L.; O’Connor, David H.; Ojikutu, Bisola O.; Okulicz, Jason; Oladehin, Olakunle O.; Oldfield, Edward C.

2011-01-01

344

Fine mapping genetic determinants of the highly variably expressed MHC gene ZFP57.  

PubMed

ZFP57 is an important transcriptional regulator involved in DNA methylation and genomic imprinting during development. Here we demonstrate that gene expression also occurs at a low level in adult peripheral blood cells and other tissues including the kidney and thymus, but is critically dependent on underlying local genetic variation within the MHC. We resolve a highly significant expression quantitative trait locus for ZFP57 involving single-nucleotide polymorphisms (SNPs) in the first intron of the gene co-localizing with a DNase I hypersensitive site and evidence of CTCF recruitment. These data identify ZFP57 as a candidate gene underlying reported MHC disease associations, notably for putative regulatory variants associated with cancer and HIV-1. The work highlights the role that ZFP57 may play in DNA methylation and epigenetic regulation beyond early development into adult life dependent on genetic background, with important potential implications for disease. PMID:24193346

Plant, Katharine; Fairfax, Benjamin P; Makino, Seiko; Vandiedonck, Claire; Radhakrishnan, Jayachandran; Knight, Julian C

2014-04-01

345

Genetic Diversity and Geographic Population Structure of Bovine Neospora caninum Determined by Microsatellite Genotyping Analysis  

PubMed Central

The cyst-forming protozoan parasite Neosporacaninum is one of the main causes of bovine abortion worldwide and is of great economic importance in the cattle industry. Recent studies have revealed extensive genetic variation among N. caninum isolates based on microsatellite sequences (MSs). MSs may be suitable molecular markers for inferring the diversity of parasite populations, molecular epidemiology and the basis for phenotypic variations in N. caninum, which have been poorly defined. In this study, we evaluated nine MS markers using a panel of 11 N. caninum-derived reference isolates from around the world and 96 N. caninum bovine clinical samples and one ovine clinical sample collected from four countries on two continents, including Spain, Argentina, Germany and Scotland, over a 10-year period. These markers were used as molecular tools to investigate the genetic diversity, geographic distribution and population structure of N. caninum. Multilocus microsatellite genotyping based on 7 loci demonstrated high levels of genetic diversity in the samples from all of the different countries, with 96 microsatellite multilocus genotypes (MLGs) identified from 108 N. caninum samples. Geographic sub-structuring was present in the country populations according to pairwise FST. Principal component analysis (PCA) and Neighbor Joining tree topologies also suggested MLG segregation partially associated with geographical origin. An analysis of the MLG relationships, using eBURST, confirmed that the close genetic relationship observed between the Spanish and Argentinean populations may be the result of parasite migration (i.e., the introduction of novel MLGs from Spain to South America) due to cattle movement. The eBURST relationships also revealed genetically different clusters associated with the abortion. The presence of linkage disequilibrium, the co-existence of specific MLGs to individual farms and eBURST MLG relationships suggest a predominant clonal propagation for Spanish N. caninum MLGs in cattle. PMID:23940816

Regidor-Cerrillo, Javier; Díez-Fuertes, Francisco; García-Culebras, Alicia; Moore, Dadín P.; González-Warleta, Marta; Cuevas, Carmen; Schares, Gereon; Katzer, Frank; Pedraza-Díaz, Susana; Mezo, Mercedes; Ortega-Mora, Luis M.

2013-01-01

346

Direct calorimetry identifies deficiencies in respirometry for the determination of resting metabolic rate in C57Bl/6 and FVB mice  

PubMed Central

Substantial research efforts have been aimed at identifying novel targets to increase resting metabolic rate (RMR) as an adjunct approach to the treatment of obesity. Respirometry (one form of “indirect calorimetry”) is unquestionably the dominant technique used in the obesity research field to assess RMR in vivo, although this method relies upon a lengthy list of assumptions that are likely to be violated in pharmacologically or genetically manipulated animals. A “total” calorimeter, including a gradient layer direct calorimeter coupled to a conventional respirometer, was used to test the accuracy of respirometric-based estimations of RMR in laboratory mice (Mus musculus Linnaeus) of the C57Bl/6 and FVB background strains. Using this combined calorimeter, we determined that respirometry underestimates RMR of untreated 9- to 12-wk-old male mice by ?10–12%. Quantitative and qualitative differences resulted between methods for untreated C57Bl/6 and FVB mice, C57Bl/6 mice treated with ketamine-xylazine anesthesia, and FVB mice with genetic deletion of the angiotensin II type 2 receptor. We conclude that respirometric methods underestimate RMR in mice in a magnitude that is similar to or greater than the desired RMR effects of novel therapeutics. Sole reliance upon respirometry to assess RMR in mice may lead to false quantitative and qualitative conclusions regarding the effects of novel interventions. Increased use of direct calorimetry for the assessment of RMR and confirmation of respirometry results and the reexamination of previously discarded potential obesity therapeutics are warranted. PMID:23964071

Burnett, Colin M. L.

2013-01-01

347

New insights into the pathogenesis of pseudoxanthoma elasticum and related soft tissue calcification disorders by identifying genetic interactions and modifiers  

PubMed Central

Screening of the adenosine triphosphate binding cassette transporter protein subfamily C member 6 gene (ABCC6) in pseudoxanthoma elasticum (PXE) revealed a mutation detection rate of approximately 87%. Although 25% of the unidentified disease alleles underlie deletions/insertions, there remain several PXE patients with no clear genotype. The recent identification of PXE-related diseases and the high intra-familiar and inter-individual clinical variability of PXE led to the assumption that secondary genetic co-factors exist. Here, we summarize current knowledge of the genetics underlying PXE and PXE-related disorders based on human and animal studies. Furthermore, we discuss the role of genetic interactions and modifier genes in PXE and PXE-related diseases characterized by soft tissue calcification. PMID:23802012

Hendig, Doris; Knabbe, Cornelius; Götting, Christian

2013-01-01

348

New insights into the pathogenesis of pseudoxanthoma elasticum and related soft tissue calcification disorders by identifying genetic interactions and modifiers.  

PubMed

Screening of the adenosine triphosphate binding cassette transporter protein subfamily C member 6 gene (ABCC6) in pseudoxanthoma elasticum (PXE) revealed a mutation detection rate of approximately 87%. Although 25% of the unidentified disease alleles underlie deletions/insertions, there remain several PXE patients with no clear genotype. The recent identification of PXE-related diseases and the high intra-familiar and inter-individual clinical variability of PXE led to the assumption that secondary genetic co-factors exist. Here, we summarize current knowledge of the genetics underlying PXE and PXE-related disorders based on human and animal studies. Furthermore, we discuss the role of genetic interactions and modifier genes in PXE and PXE-related diseases characterized by soft tissue calcification. PMID:23802012

Hendig, Doris; Knabbe, Cornelius; Götting, Christian

2013-01-01

349

Genetic, nongenetic and epigenetic risk determinants in developmental programming of type 2 diabetes.  

PubMed

Low birthweight (LBW) individuals and offspring of women with gestational diabetes mellitus (GDM) exhibit increased risk of developing type 2 diabetes (T2D) and associated cardiometabolic traits in adulthood, which for both groups may be mediated by adverse events and developmental changes in fetal life. T2D is a multifactorial disease occurring as a result of complicated interplay between genetic and both prenatal and postnatal nongenetic factors, and it remains unknown to what extent the increased risk of T2D associated with LBW or GDM in the mother may be due to, or confounded by, genetic factors. Indeed, it has been shown that genetic changes influencing risk of diabetes may also be associated with reduced fetal growth as a result of reduced insulin secretion and/or action. Similarly, increased risk of T2D among offspring could be explained by T2D susceptibility genes shared between the mother and her offspring. Epigenetic mechanisms may explain the link between factors operating in fetal life and later risk of developing T2D, but so far convincing evidence is lacking for epigenetic changes as a prime and direct cause of T2D. This review addresses recent literature on the early origins of adult disease hypothesis, with a special emphasis on the role of genetic compared with nongenetic and epigenetic risk determinants and disease mechanisms. PMID:25179736

Vaag, Allan; Brřns, Charlotte; Gillberg, Linn; Hansen, Ninna S; Hjort, Line; Arora, Geeti P; Thomas, Nihal; Broholm, Christa; Ribel-Madsen, Rasmus; Grunnet, Louise G

2014-11-01

350

Methodology of determining the uncertainty in the accessible geothermal resource base of identified hydrothermal convection systems  

USGS Publications Warehouse

In order to quantify the uncertainty of estimates of the geothermal resource base in identified hydrothermal convection systems, a methodology is presented for combining estimates with uncertainties for temperature, area, and thickness of a geothermal reservoir into an estimate of the stored energy with uncertainty. Probability density functions for temperature, area, and thickness are assumed to be triangular in form. In order to calculate the probability distribution function for the stored energy in a single system or in many systems, a computer program for aggregating the input distribution functions using the Monte-Carlo method has been developed. To calculate the probability distribution of stored energy in a single system, an analytical expression is also obtained that is useful for calibrating the Monte Carlo approximation. For the probability distributions of stored energy in a single and in many systems, the central limit approximation is shown to give results ranging from good to poor.

Nathenson, Manuel

1978-01-01

351

Identifying and selecting for genetic diversity in Papua New Guinea sweetpotato Ipomoea batatas (L.) Lam. germplasm collected as botanical seed  

Technology Transfer Automated Retrieval System (TEKTRAN)

Genetic analysis was conducted on 141 "Ipomoea batatas" L. (Lam.) Genotypes derived from botanical seed originally collected from 26 sites in 4 provinces in Papua New Guinea. Relatedness among accessions was estimated by analysis of the AFLP data using the Dice coefficient of similarity and UPGMA. ...

352

A screen for genetic suppressor elements of hepatitis C virus identifies a supercharged protein inhibitor of viral replication  

E-print Network

by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 153: 1011–1022. 25. Primiano T, Baig M, Maliyekkel A, Chang BD, Fellars S, et al. (2003) Identification of potential anticancer drug targets through the selection of growth-inhibitory genetic...

Simeon, Rudo L.; Chen, Zhilei

2013-12-31

353

Copyright 1999 by the Genetics Society of America Suppressors of the Arabidopsis lsd5 Cell Death Mutation Identify Genes  

E-print Network

Copyright © 1999 by the Genetics Society of America Suppressors of the Arabidopsis lsd5 Cell Death hypersensitive reaction (HR). Arabidopsis lsd mutants that spontaneously exhibit cell death reminiscent of the HR disease resistance, one of these mutants, lsd5, was used to isolate new mutations that suppress its cell

Dangl, Jeff

354

A molecular genetic linkage map identifying the St and H sub-genomes of Elymus wheatgrass (Poaceae: Triticeae)  

Technology Transfer Automated Retrieval System (TEKTRAN)

Elymus L. is the largest and most complex genus in the Triticeae with approximately 150 polyploid perennial grass species occurring worldwide. We report here the first genetic linkage map for Elymus. Backcross mapping populations were created by crossing caespitose Elymus wawawaiensis (EW) (Snake ...

355

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution  

Microsoft Academic Search

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an

Iris M Heid; Anne U Jackson; Joshua C Randall; Thomas W Winkler; Lu Qi; Valgerdur Steinthorsdottir; Gudmar Thorleifsson; M Carola Zillikens; Elizabeth K Speliotes; Reedik Magi; Tsegaselassie Workalemahu; Charles C White; Nabila Bouatia-Naji; Tamara B Harris; Sonja I Berndt; Erik Ingelsson; Cristen J Willer; Michael N Weedon; Jian'an Luan; Sailaja Vedantam; Tonu Esko; Tuomas O Kilpelainen; Zoltan Kutalik; Shengxu Li; Keri L Monda; Anna L Dixon; Christopher C Holmes; Lee M Kaplan; Liming Liang; Josine L Min; Miriam F Moffatt; Cliona Molony; George Nicholson; Eric E Schadt; Krina T Zondervan; Mary F Feitosa; Teresa Ferreira; Hana Lango Allen; Robert J Weyant; Eleanor Wheeler; Andrew R Wood; Karol Estrada; Michael E Goddard; Guillaume Lettre; Massimo Mangino; Dale R Nyholt; Shaun Purcell; Albert Vernon Smith; Peter M Visscher; Jian Yang; Steven A McCarroll; James Nemesh; Benjamin F Voight; Devin Absher; Najaf Amin; Thor Aspelund; Lachlan Coin; Nicole L Glazer; Caroline Hayward; Nancy L Heard-Costa; Jouke-Jan Hottenga; Asa Johansson; Toby Johnson; Marika Kaakinen; Karen Kapur; Shamika Ketkar; Joshua W Knowles; Peter Kraft; Aldi T Kraja; Claudia Lamina; Michael F Leitzmann; Barbara McKnight; Andrew P Morris; Ken K Ong; John R B Perry; Marjolein J Peters; Ozren Polasek; Inga Prokopenko; Nigel W Rayner; Samuli Ripatti; Fernando Rivadeneira; Neil R Robertson; Serena Sanna; Ulla Sovio; Ida Surakka; Alexander Teumer; Sophie van Wingerden; Veronique Vitart; Jing Hua Zhao; Christine Cavalcanti-Proenca; Peter S Chines; Eva Fisher; Jennifer R Kulzer; Cecile Lecoeur; Narisu Narisu; Camilla Sandholt; Laura J Scott; Kaisa Silander; Klaus Stark; Mari-Liis Tammesoo; Tanya M Teslovich; Nicholas John Timpson; Richard M Watanabe; Ryan Welch; Daniel I Chasman; Matthew N Cooper; John-Olov Jansson; Johannes Kettunen; Robert W Lawrence; Niina Pellikka; Markus Perola; Liesbeth Vandenput; Helene Alavere; Peter Almgren; Larry D Atwood; Amanda J Bennett; Reiner Biffar; Lori L Bonnycastle; Stefan R Bornstein; Thomas A Buchanan; Harry Campbell; Ian N M Day; Mariano Dei; Marcus Dorr; Paul Elliott; Michael R Erdos; Johan G Eriksson; Nelson B Freimer; Mao Fu; Stefan Gaget; Eco J C Geus; Anette P Gjesing; Harald Grallert; Jurgen Graszler; Christopher J Groves; Candace Guiducci; Anna-Liisa Hartikainen; Neelam Hassanali; Aki S Havulinna; Karl-Heinz Herzig; Andrew A Hicks; Jennie Hui; Wilmar Igl; Pekka Jousilahti; Antti Jula; Eero Kajantie; Leena Kinnunen; Ivana Kolcic; Seppo Koskinen; Peter Kovacs; Heyo K Kroemer; Vjekoslav Krzelj; Johanna Kuusisto; Kirsti Kvaloy; Jaana Laitinen; Olivier Lantieri; G Mark Lathrop; Marja-Liisa Lokki; Robert N Luben; Barbara Ludwig; Wendy L McArdle; Anne McCarthy; Mario A Morken; Mari Nelis; Matt J Neville; Guillaume Pare; Alex N Parker; John F Peden; Irene Pichler; Kirsi H Pietilainen; Carl G P Platou; Anneli Pouta; Martin Ridderstrale; Nilesh J Samani; Jouko Saramies; Juha Sinisalo; Jan H Smit; Rona J Strawbridge; Heather M Stringham; Amy J Swift; Maris Teder-Laving; Brian Thomson; Gianluca Usala; Joyce B J van Meurs; Gert-Jan van Ommen; Vincent Vatin; Claudia B Volpato; Henri Wallaschofski; G Bragi Walters; Elisabeth Widen; Sarah H Wild; Gonneke Willemsen; Daniel R Witte; Lina Zgaga; Paavo Zitting; John P Beilby; Alan L James; Mika Kahonen; Terho Lehtimaki; Markku S Nieminen; Claes Ohlsson; Lyle J Palmer; Olli Raitakari; Paul M Ridker; Michael Stumvoll; Anke Tonjes; Jorma Viikari; Beverley Balkau; Yoav Ben-Shlomo; Richard N Bergman; Heiner Boeing; George Davey Smith; Shah Ebrahim; Philippe Froguel; Torben Hansen; Christian Hengstenberg; Kristian Hveem; Bo Isomaa; Torben Jorgensen; Fredrik Karpe; Kay-Tee Khaw; Markku Laakso; Debbie A Lawlor; Michel Marre; Thomas Meitinger; Andres Metspalu; Kristian Midthjell; Oluf Pedersen; Veikko Salomaa; Peter E H Schwarz; Tiinamaija Tuomi; Jaakko Tuomilehto; Timo T Valle; Nicholas J Wareham; Alice M Arnold; Jacques S Beckmann; Sven Bergmann; Eric Boerwinkle; Dorret I Boomsma; Mark J Caulfield; Francis S Collins; Gudny Eiriksdottir; Vilmundur Gudnason; Ulf Gyllensten; Anders Hamsten; Andrew T Hattersley; Albert Hofman; Frank B Hu; Thomas Illig; Carlos Iribarren; Marjo-Riitta Jarvelin; W H Linda Kao; Jaakko Kaprio; Lenore J Launer; Patricia B Munroe; Ben Oostra; Brenda W Penninx; Peter P Pramstaller; Bruce M Psaty; Thomas Quertermous; Aila Rissanen; Igor Rudan; Alan R Shuldiner; Nicole Soranzo; Timothy D Spector; Ann-Christine Syvanen; Manuela Uda; Andre Uitterlinden; Henry Volzke; Peter Vollenweider; James F Wilson; Jacqueline C Witteman; Alan F Wright; Goncalo R Abecasis; Michael Boehnke; Ingrid B Borecki; Panos Deloukas

2010-01-01

356

Genetic architecture of sex determination in fish: applications to sex ratio control in aquaculture.  

PubMed

Controlling the sex ratio is essential in finfish farming. A balanced sex ratio is usually good for broodstock management, since it enables to develop appropriate breeding schemes. However, in some species the production of monosex populations is desirable because the existence of sexual dimorphism, primarily in growth or first time of sexual maturation, but also in color or shape, can render one sex more valuable. The knowledge of the genetic architecture of sex determination (SD) is convenient for controlling sex ratio and for the implementation of breeding programs. Unlike mammals and birds, which show highly conserved master genes that control a conserved genetic network responsible for gonad differentiation (GD), a huge diversity of SD mechanisms has been reported in fish. Despite theory predictions, more than one gene is in many cases involved in fish SD and genetic differences have been observed in the GD network. Environmental factors also play a relevant role and epigenetic mechanisms are becoming increasingly recognized for the establishment and maintenance of the GD pathways. Although major genetic factors are frequently involved in fish SD, these observations strongly suggest that SD in this group resembles a complex trait. Accordingly, the application of quantitative genetics combined with genomic tools is desirable to address its study and in fact, when applied, it has frequently demonstrated a multigene trait interacting with environmental factors in model and cultured fish species. This scenario has notable implications for aquaculture and, depending upon the species, from chromosome manipulation or environmental control techniques up to classical selection or marker assisted selection programs, are being applied. In this review, we selected four relevant species or fish groups to illustrate this diversity and hence the technologies that can be used by the industry for the control of sex ratio: turbot and European sea bass, two reference species of the European aquaculture, and salmonids and tilapia, representing the fish for which there are well established breeding programs. PMID:25324858

Martínez, Paulino; Vińas, Ana M; Sánchez, Laura; Díaz, Noelia; Ribas, Laia; Piferrer, Francesc

2014-01-01

357

Genetic architecture of sex determination in fish: applications to sex ratio control in aquaculture  

PubMed Central

Controlling the sex ratio is essential in finfish farming. A balanced sex ratio is usually good for broodstock management, since it enables to develop appropriate breeding schemes. However, in some species the production of monosex populations is desirable because the existence of sexual dimorphism, primarily in growth or first time of sexual maturation, but also in color or shape, can render one sex more valuable. The knowledge of the genetic architecture of sex determination (SD) is convenient for controlling sex ratio and for the implementation of breeding programs. Unlike mammals and birds, which show highly conserved master genes that control a conserved genetic network responsible for gonad differentiation (GD), a huge diversity of SD mechanisms has been reported in fish. Despite theory predictions, more than one gene is in many cases involved in fish SD and genetic differences have been observed in the GD network. Environmental factors also play a relevant role and epigenetic mechanisms are becoming increasingly recognized for the establishment and maintenance of the GD pathways. Although major genetic factors are frequently involved in fish SD, these observations strongly suggest that SD in this group resembles a complex trait. Accordingly, the application of quantitative genetics combined with genomic tools is desirable to address its study and in fact, when applied, it has frequently demonstrated a multigene trait interacting with environmental factors in model and cultured fish species. This scenario has notable implications for aquaculture and, depending upon the species, from chromosome manipulation or environmental control techniques up to classical selection or marker assisted selection programs, are being applied. In this review, we selected four relevant species or fish groups to illustrate this diversity and hence the technologies that can be used by the industry for the control of sex ratio: turbot and European sea bass, two reference species of the European aquaculture, and salmonids and tilapia, representing the fish for which there are well established breeding programs. PMID:25324858

Martínez, Paulino; Vińas, Ana M.; Sánchez, Laura; Díaz, Noelia; Ribas, Laia; Piferrer, Francesc

2014-01-01

358

Vibrational stark effects to identify ion pairing and determine reduction potentials in electrolyte-free environments.  

PubMed

A recently developed instrument for time-resolved infrared detection following pulse radiolysis has been used to measure the ?(C?N) IR band of the radical anion of a CN-substituted fluorene in tetrahydrofuran. Specific vibrational frequencies can exhibit distinct frequency shifts due to ion pairing, which can be explained in the framework of the vibrational Stark effect. Measurements of the ratio of free ions and ion pairs in different electrolyte concentrations allowed us to obtain an association constant and free energy change for ion pairing. This new method has the potential to probe the geometry of ion pairing and allows the reduction potentials of molecules to be determined in the absence of electrolyte in an environment of low dielectric constant. PMID:25554821

Mani, Tomoyasu; Grills, David C; Miller, John R

2015-01-28

359

Haploid Genetic Screens Identify an Essential Role for PLP2 in the Downregulation of Novel Plasma Membrane Targets by Viral E3 Ubiquitin Ligases  

PubMed Central

The Kaposi's sarcoma-associated herpesvirus gene products K3 and K5 are viral ubiquitin E3 ligases which downregulate MHC-I and additional cell surface immunoreceptors. To identify novel cellular genes required for K5 function we performed a forward genetic screen in near-haploid human KBM7 cells. The screen identified proteolipid protein 2 (PLP2), a MARVEL domain protein of unknown function, as essential for K5 activity. Genetic loss of PLP2 traps the viral ligase in the endoplasmic reticulum, where it is unable to ubiquitinate and degrade its substrates. Subsequent analysis of the plasma membrane proteome of K5-expressing KBM7 cells in the presence and absence of PLP2 revealed a wide range of novel K5 targets, all of which required PLP2 for their K5-mediated downregulation. This work ascribes a critical function to PLP2 for viral ligase activity and underlines the power of non-lethal haploid genetic screens in human cells to identify the genes involved in pathogen manipulation of the host immune system. PMID:24278019

Timms, Richard T.; Duncan, Lidia M.; Tchasovnikarova, Iva A.; Antrobus, Robin; Smith, Duncan L.; Dougan, Gordon; Weekes, Michael P.; Lehner, Paul J.

2013-01-01

360

Genetic determinants in ischaemic stroke subtypes: Seven year findings and a review.  

PubMed

Stroke is a global health problem and a leading cause of disability worldwide. There have been numerable studies undertaking research on different aspects of ischaemic stroke employing various epidemiological, clinical and molecular parameters. Nevertheless ischaemic stroke being a complex disorder with different subtypes demands equal attention towards its subtypes too. Since there has been enough evidence that disposition to certain subtype is genetically determined and there is a distinct mechanism that influences its development, association studies should focus on subtypes simultaneously while studying specific genes. Data from such studies will thus provide better and intricate findings with regard to heterogenous ischaemic stroke. In the present review we discuss the genes studied by our group over a period of seven years in association with stroke subtypes in a South Indian population and correlate the findings with similar genetic studies from other populations so as to provide an overview of various genes involved in the pathogenesis of ischaemic stroke subtypes. PMID:25447900

Munshi, Anjana; Das, Satrupa; Kaul, Subhash

2015-01-25

361

Genetics  

NSDL National Science Digital Library

This activity helps students to understand basic principles of genetics, including relationships of genotype to phenotype, concepts of recessive and dominant alleles, and how understanding meiosis and fertilization provides the basis for understanding inheritance, as summarized in Punnett squares. The Student Handout includes an analysis of the inheritance of albinism that teaches all of these concepts, a Coin Toss Genetics activity that helps students understand the probabilistic nature of Punnett square predictions, and an analysis of the inheritance of sickle cell anemia that reinforces the basic concepts and introduces some of the complexities of genetics. The Genetics Supplement includes two additional activities, an analysis of student data on the sex makeup of sibships and pedigree analyses of recessive and dominant alleles with challenge questions that introduce the role of mutations and an evaluation of Punnett squares and pedigrees as models of inheritance.

Doherty, Jennifer; Waldron, Ingrid; Poethig, Scott

362

Genetics  

MedlinePLUS

... made up of strands of genetic information called DNA. Genes are sections of DNA. The location of the gene is called the ... differences occur in less than 1% of the DNA sequence and produce variants of a particular gene ...

363

A High-Throughput Forward Genetic Screen Identifies Genes Required for Virulence of Pseudomonas syringae pv. maculicola ES4326 on Arabidopsis  

PubMed Central

Successful pathogenesis requires a number of coordinated processes whose genetic bases remain to be fully characterized. We utilized a high-throughput, liquid media-based assay to screen transposon disruptants of the phytopathogen Pseudomonas syringae pv. maculicola ES4326 to identify genes required for virulence on Arabidopsis. Many genes identified through this screen were involved in processes such as type III secretion, periplasmic glucan biosynthesis, flagellar motility, and amino acid biosynthesis. A small set of genes did not fall into any of these functional groups, and their disruption resulted in context-specific effects on in planta bacterial growth. PMID:22870224

Schreiber, Karl J.; Ye, David; Fich, Eric; Jian, Allen; Lo, Timothy; Desveaux, Darrell

2012-01-01

364

A Participatory Method to Identify Root Determinants of Health: The Heart of the Matter  

PubMed Central

Background Co-learning is one of the core principles of community-based participatory research (CBPR). Often, it is difficult to engage community members beyond those involved in the formal partnership in co-learning processes. However, to understand and address locally relevant root factors of health, it is essential to engage the broader community in participatory dialogues around these factors. Objective This article provides a glimpse into how using a photo-elicitation process allowed a community–academic partnership to engage community members in a participatory dialogue about root factors influencing health. The article details the decision to use photo-elicitation and describes the photo-elicitation method. Method Similar to a focus group process, photo-elicitation uses photographs and questions to prompt reflection and dialogue. Used in conjunction with an economic development framework, this method allows participants to discuss underlying, or root, community processes and structures that influence health. Conclusion Photo-elicitation is one way to engage community members in a participatory dialogue that stimulates action around root factors of health. To use this method successfully within a CBPR approach, it is important to build on existing relationships of trust among community and academic partners and create opportunities for community partners to determine the issues for discussion. PMID:20364079

Barnidge, Ellen; Baker, Elizabeth A.; Motton, Freda; Rose, Frank; Fitzgerald, Teresa

2010-01-01

365

Genome-Wide Association Mapping Combined with Reverse Genetics Identifies New Effectors of Low Water Potential-Induced Proline Accumulation in Arabidopsis1[W][OPEN  

PubMed Central

Arabidopsis (Arabidopsis thaliana) exhibits natural genetic variation in drought response, including varying levels of proline (Pro) accumulation under low water potential. As Pro accumulation is potentially important for stress tolerance and cellular redox control, we conducted a genome-wide association (GWAS) study of low water potential-induced Pro accumulation using a panel of natural accessions and publicly available single-nucleotide polymorphism (SNP) data sets. Candidate genomic regions were prioritized for subsequent study using metrics considering both the strength and spatial clustering of the association signal. These analyses found many candidate regions likely containing gene(s) influencing Pro accumulation. Reverse genetic analysis of several candidates identified new Pro effector genes, including thioredoxins and several genes encoding Universal Stress Protein A domain proteins. These new Pro effector genes further link Pro accumulation to cellular redox and energy status. Additional new Pro effector genes found include the mitochondrial protease LON1, ribosomal protein RPL24A, protein phosphatase 2A subunit A3, a MADS box protein, and a nucleoside triphosphate hydrolase. Several of these new Pro effector genes were from regions with multiple SNPs, each having moderate association with Pro accumulation. This pattern supports the use of summary approaches that incorporate clusters of SNP associations in addition to consideration of individual SNP probability values. Further GWAS-guided reverse genetics promises to find additional effectors of Pro accumulation. The combination of GWAS and reverse genetics to efficiently identify new effector genes may be especially applicable for traits difficult to analyze by other genetic screening methods. PMID:24218491

Verslues, Paul E.; Lasky, Jesse R.; Juenger, Thomas E.; Liu, Tzu-Wen; Kumar, M. Nagaraj

2014-01-01

366

Finding Markers That Make a Difference: DNA Pooling and SNP-Arrays Identify Population Informative Markers for Genetic Stock Identification  

PubMed Central

Genetic stock identification (GSI) using molecular markers is an important tool for management of migratory species. Here, we tested a cost-effective alternative to individual genotyping, known as allelotyping, for identification of highly informative SNPs for accurate genetic stock identification. We estimated allele frequencies of 2880 SNPs from DNA pools of 23 Atlantic salmon populations using Illumina SNP-chip. We evaluated the performance of four common strategies (global FST, pairwise FST, Delta and outlier approach) for selection of the most informative set of SNPs and tested their effectiveness for GSI compared to random sets of SNP and microsatellite markers. For the majority of cases, SNPs selected using the outlier approach performed best followed by pairwise FST and Delta methods. Overall, the selection procedure reduced the number of SNPs required for accurate GSI by up to 53% compared with randomly chosen SNPs. However, GSI accuracy was more affected by populations in the ascertainment group rather than the ranking method itself. We demonstrated for the first time the compatibility of different large-scale SNP datasets by compiling the largest population genetic dataset for Atlantic salmon to date. Finally, we showed an excellent performance of our top SNPs on an independent set of populations covering the main European distribution range of Atlantic salmon. Taken together, we demonstrate how combination of DNA pooling and SNP arrays can be applied for conservation and management of salmonids as well as other species. PMID:24358184

Ozerov, Mikhail; Vasemägi, Anti; Wennevik, Vidar; Diaz-Fernandez, Rogelio; Kent, Matthew; Gilbey, John; Prusov, Sergey; Niemelä, Eero; Vähä, Juha-Pekka

2013-01-01

367

Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene  

PubMed Central

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P?=?0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF?=?0.042] and rs116541814 [MAF?=?0.021], combined P?=?3.2×10?6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P?=?0.049 for C-alpha test and P?=?0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. PMID:24520335

Okada, Yukinori; Diogo, Dorothee; Greenberg, Jeffrey D.; Mouassess, Faten; Achkar, Walid A. L.; Fulton, Robert S.; Denny, Joshua C.; Gupta, Namrata; Mirel, Daniel; Gabriel, Stacy; Li, Gang; Kremer, Joel M.; Pappas, Dimitrios A.; Carroll, Robert J.; Eyler, Anne E.; Trynka, Gosia; Stahl, Eli A.; Cui, Jing; Saxena, Richa; Coenen, Marieke J. H.; Guchelaar, Henk-Jan; Huizinga, Tom W. J.; Dieudé, Philippe; Mariette, Xavier; Barton, Anne; Canhăo, Helena; Fonseca, Joăo E.; de Vries, Niek; Tak, Paul P.; Moreland, Larry W.; Bridges, S. Louis; Miceli-Richard, Corinne; Choi, Hyon K.; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Raj, Towfique; De Jager, Philip L.; Raychaudhuri, Soumya; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Siminovitch, Katherine A.; Gregersen, Peter K.; Mardis, Elaine R.; Arayssi, Thurayya; Kazkaz, Layla A.; Plenge, Robert M.

2014-01-01

368

Genetic Variation Is the Major Determinant of Individual Differences in Leukocyte Endothelial Adhesion  

PubMed Central

Objective To determine the genetic contribution to leukocyte endothelial adhesion. Methods Leukocyte endothelial adhesion was assessed through a novel cell-based assay using human lymphoblastoid cell lines. A high-throughput screening method was developed to evaluate the inter-individual variability in leukocyte endothelial adhesion using lymphoblastoid cell lines derived from different donors. To assess heritability, ninety-two lymphoblastoid cell lines derived from twenty-three monozygotic twin pairs and twenty-three sibling pairs were compared. These lymphoblastoid cell lines were plated with the endothelial cell line EA.hy926 and labeled with Calcein AM dye. Fluorescence was assessed to determine endothelial cell adhesion to each lymphoblastoid cell line. Intra-pair similarity was determined for monozygotic twins and siblings using Pearson pairwise correlation coefficients. Results A leukocyte endothelial adhesion assay for lymphoblastoid cell lines was developed and optimized (CV?=?8.68, Z?-factor?=?0.67, SNR?=?18.41). A higher adhesion correlation was found between the twins than that between the siblings. Intra-pair similarity for leukocyte endothelial adhesion in monozygotic twins was 0.60 compared to 0.25 in the siblings. The extent to which these differences are attributable to underlying genetic factors was quantified and the heritability of leukocyte endothelial adhesion was calculated to be 69.66% (p-value<0.0001). Conclusions There is a heritable component to leukocyte endothelial adhesion. Underlying genetic predisposition plays a significant role in inter-individual variability of leukocyte endothelial adhesion. PMID:24520339

Grassi, Michael A.; Rao, Vidhya; Winkler, Kathryn P.; Zhang, Wei; Bogaard, Joseph D.; Chen, Siquan; LaCroix, Bonnie; Lenkala, Divya; Rehman, Jalees; Malik, Asrar B.; Cox, Nancy J.; Huang, R. Stephanie

2014-01-01

369

Determination of genetic transferrin variants in human serum by high-resolution capillary zone electrophoresis(†).  

PubMed

High-resolution capillary zone electrophoresis in the routine arena with stringent quality assurance is employed for the determination of carbohydrate-deficient transferrin in human serum. The assay comprises mixing of human serum with a Fe(III) -containing solution prior to analysis of the iron-saturated mixture in a dynamically double-coated capillary using a commercial buffer at alkaline pH. In contrast to other assays, it provides sufficient resolution for proper recognition of genetic transferrin variants. Analysis of 7290 patient sera revealed 166 isoform patterns that could be assigned to genetic variants, namely, 109 BC, 53 CD, one BD and three CC variants. Several subtypes of transferrin D can be distinguished as they have large enough differences in pI values. Subtypes of transferrin C and B cannot be resolved. However, analysis of the detection time ratios of tetrasialo isoforms of transferrin BC and transferrin CD variants revealed multimodal frequency histograms, indicating the presence of subtypes of transferrin C, B and D. The data gathered over 11 years demonstrate the robustness of the high-resolution capillary zone electrophoresis assay. This is the first account of a capillary zone electrophoresis based carbohydrate-deficient transferrin assay with a broad overview on transferrin isoform patterns associated with genetic transferrin variants. PMID:24737700

Caslavska, Jitka; Joneli, Jeannine; Wanzenried, Ursula; Schiess, Jeannette; Lanz, Christian; Thormann, Wolfgang

2014-07-01

370

Review Article Sensitization to Cockroach Allergen: Immune Regulation and Genetic Determinants  

E-print Network

permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Asthma is a major public health concern. Cockroach allergen exposure and cockroach allergic sensitization could contribute to the higher prevalence of asthma. However, the underlying immune mechanism and the genetic etiology remain unclear. Recent advances have demonstrated that several receptors (PAR-2, TLRs, CLRs) and their pathways mediate antigen uptake from the environment and induce allergies by signaling T cells to activate an inappropriate immune response. Cockroach-derived protease can disturb airway epithelial integrity via PAR-2 and leads to an increased penetration of cockroach allergen, resulting in activation of innate immune cells (e.g., DCs) via binding to either TLRs or CLRs. The activated DCs can direct cells of the adaptive immune system to facilitate promotion of Th2 cell response and subsequently increase risk of sensitization. Mannose receptor (MR), as a CLR, has been shown to mediate Bla g2 (purified cockroach allergen) uptake by DCs and to determine allergen-induced T cell polarization. Additionally, genetic factors may play an important role in conferring the susceptibility to cockroach sensitization. Several genes have been associated with cockroach sensitization and related phenotypes (HLA-D,TSLP,IL-12A,MBL2). In this review, we have focused on studies on the cockroach allergen induced immunologic responses and genetic basis for cockroach sensitization. 1.

Peisong Gao

2011-01-01

371

Genetic Determinants of Sindbis Virus Mosquito Infection Are Associated with a Highly Conserved Alphavirus and Flavivirus Envelope Sequence?  

PubMed Central

Wild-type Sindbis virus (SINV) strain MRE16 efficiently infects Aedes aegypti midgut epithelial cells (MEC), but laboratory-derived neurovirulent SINV strain TE/5?2J infects MEC poorly. SINV determinants for MEC infection have been localized to the E2 glycoprotein. The E2 amino acid sequences of MRE16 and TE/5?2J differ at 60 residue sites. To identify the genetic determinants of MEC infection of MRE16, the TE/5?2J virus genome was altered to contain either domain chimeras or more focused nucleotide substitutions of MRE16. The growth patterns of derived viruses in cell culture were determined, as were the midgut infection rates (MIR) in A. aegypti mosquitoes. The results showed that substitutions of MRE16 E2 aa 95 to 96 and 116 to 119 into the TE/5?2J virus increased MIR both independently and in combination with each other. In addition, a unique PPF/.GDS amino acid motif was located between these two sites that was found to be a highly conserved sequence among alphaviruses and flaviviruses but not other arboviruses. PMID:18160430

Pierro, Dennis J.; Powers, Erik L.; Olson, Ken E.

2008-01-01

372

Genome-wide association study in RPGRIP1?/? dogs identifies a modifier locus that determines the onset of retinal degeneration  

PubMed Central

Cone-rod dystrophy (CRD) is a form of inherited retinal degeneration (RD) causing blindness in man as well as in several breeds of dog. Previously, a 44 bp insertion in RPGRIP1 (retinitis pigmentosa GTPase regulator interacting protein-1) was associated with a recessive early-onset CRD (cone-rod dystrophy 1, cord1) in a Miniature longhaired dachshund (MLHD) research colony. Yet in the MLHD pet population, extensive range of the onset age has been observed among RD cases, with some RPGRIP1?/? dogs lacking obvious clinical signs. Phenotypic variation has been known in human homologous diseases, including retinitis pigmentosa and Leber congenital amaurosis, indicating possible involvement of modifiers. To explore additional genetic loci associated with the phenotypic variation observed in MLHDs, a genome-wide association study was carried out using Canine SNP20 arrays in 83 RPGRIP1?/? MLHDs with variable ages of onset or no clinical abnormality. Using these samples, comparison of 31 early-onset RD cases against 49 controls (15 late-onset RD and 34 normal dogs combined) identified a strong association (P = 5.05 × 10?13) at a single locus on canine chromosome 15. At this locus, the majority of early-onset RD cases but few of the controls were homozygous for a 1.49 Mb interval containing ?11 genes. We conclude that homozygosity at both RPGRIP1 and the newly mapped second locus is necessary to develop early-onset RD, whereas RPGRIP1?/? alone leads to late-onset RD or no apparent clinical phenotype. This study establishes a unique model of canine RD requiring homozygous mutations at two distinct genetic loci for the manifestation of early-onset RD. PMID:22193413

Kato, Kumiko; Boursnell, Mike; Mellersh, Cathryn S.; Sargan, David R.

2014-01-01

373

76 FR 8707 - Syngenta Seeds, Inc.; Determination of Nonregulated Status for Corn Genetically Engineered To...  

Federal Register 2010, 2011, 2012, 2013, 2014

...Corn Genetically Engineered To Produce an Enzyme That Facilitates Ethanol Production AGENCY...genetically engineered to produce a microbial enzyme that facilitates ethanol production...genetically engineered to produce a microbial enzyme that facil