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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

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

Identifying the environmental factors that determine the genetic structure of populations.  

PubMed

The study of population genetic structure is a fundamental problem in population biology because it helps us obtain a deeper understanding of the evolutionary process. One of the issues most assiduously studied in this context is the assessment of the relative importance of environmental factors (geographic distance, language, temperature, altitude, etc.) on the genetic structure of populations. The most widely used method to address this question is the multivariate Mantel test, a nonparametric method that calculates a correlation coefficient between a dependent matrix of pairwise population genetic distances and one or more independent matrices of environmental differences. Here we present a hierarchical Bayesian method that estimates F(ST) values for each local population and relates them to environmental factors using a generalized linear model. The method is demonstrated by applying it to two data sets, a data set for a population of the argan tree and a human data set comprising 51 populations distributed worldwide. We also carry out a simulation study to investigate the performance of the method and find that it can correctly identify the factors that play a role in the structuring of genetic diversity under a wide range of scenarios. PMID:16951078

Foll, Matthieu; Gaggiotti, Oscar

2006-10-01

4

Sugarcane brown rust – determining genetic variation in the pathogen and identifying potential novel sources of resistance  

Technology Transfer Automated Retrieval System (TEKTRAN)

A major reason for the withdrawal of sugarcane cultivars from production in is the breakdown of resistance to brown rust caused by Puccinia melanaocephala. Genetic characterization of diversity among races of P. melanocephala would help in breeding for resistance to the pathogen. Breeding for durabl...

5

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

6

Genetic modification and genetic determinism  

Microsoft Academic Search

In this article we examine four objections to the genetic modification of human beings: the freedom argument, the giftedness argument, the authenticity argument, and the uniqueness argument. We then demonstrate that each of these arguments against genetic modification assumes a strong version of genetic determinism. Since these strong deterministic assumptions are false, the arguments against genetic modification, which assume and

David B. Resnik; Daniel B. Vorhaus

2006-01-01

7

Genetic modification and genetic determinism  

PubMed Central

In this article we examine four objections to the genetic modification of human beings: the freedom argument, the giftedness argument, the authenticity argument, and the uniqueness argument. We then demonstrate that each of these arguments against genetic modification assumes a strong version of genetic determinism. Since these strong deterministic assumptions are false, the arguments against genetic modification, which assume and depend upon these assumptions, are therefore unsound. Serious discussion of the morality of genetic modification, and the development of sound science policy, should be driven by arguments that address the actual consequences of genetic modification for individuals and society, not by ones propped up by false or misleading biological assumptions. PMID:16800884

Resnik, David B; Vorhaus, Daniel B

2006-01-01

8

A Genome-Wide Association Study Identifies rs2000999 as a Strong Genetic Determinant of Circulating Haptoglobin Levels  

PubMed Central

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far. We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (Poverall?=?8.1×10?59), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (??=?0.23±0.08, P?=?0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (Ptotal cholesterol?=?0.002 and PLDL?=?0.0008). Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact. PMID:22403646

Bonnefond, Amélie; Bouatia-Naji, Nabila; Dechaume, Aurélie; Siest, Gérard; Herbeth, Bernard; Falchi, Mario; Bottolo, Leonardo; Guéant-Rodriguez, Rosa-Maria; Lecoeur, Cécile; Langlois, Michel R.; Labrune, Yann; Ruokonen, Aimo; El Shamieh, Said; Stathopoulou, Maria G.; Morandi, Anita; Maffeis, Claudio; Meyre, David; Delanghe, Joris R.; Jacobson, Peter; Sjöström, Lars; Carlsson, Lena M. S.; Walley, Andrew; Elliott, Paul; Jarvelin, Marjo-Riita; Dedoussis, George V.; Visvikis-Siest, Sophie

2012-01-01

9

Forward Genetic Analysis to Identify Determinants of Dopamine Signaling in Caenorhabditis elegans Using Swimming-Induced Paralysis  

PubMed Central

Disrupted dopamine (DA) signaling is believed to contribute to the core features of multiple neuropsychiatric and neurodegenerative disorders. Essential features of DA neurotransmission are conserved in the nematode Caenorhabditis elegans, providing us with an opportunity to implement forward genetic approaches that may reveal novel, in vivo regulators of DA signaling. Previously, we identified a robust phenotype, termed Swimming-induced paralysis (Swip), that emerges in animals deficient in the plasma membrane DA transporter. Here, we report the use and quantitative analysis of Swip in the identification of mutant genes that control DA signaling. Two lines captured in our screen (vt21 and vt22) bear novel dat-1 alleles that disrupt expression and surface trafficking of transporter proteins in vitro and in vivo. Two additional lines, vt25 and vt29, lack transporter mutations but exhibit genetic, biochemical, and behavioral phenotypes consistent with distinct perturbations of DA signaling. Our studies validate the utility of the Swip screen, demonstrate the functional relevance of DA transporter structural elements, and reveal novel genomic loci that encode regulators of DA signaling. PMID:22908044

Hardaway, J. Andrew; Hardie, Shannon L.; Whitaker, Sarah M.; Baas, Sarah R.; Zhang, Bing; Bermingham, Daniel P.; Lichtenstein, Ariana J.; Blakely, Randy D.

2012-01-01

10

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

11

Determining the identifiability of DNA database entries.  

PubMed Central

CleanGene is a software program that helps determine the identifiability of sequenced DNA, independent of any explicit demographics or identifiers maintained with the DNA. The program computes the likelihood that the release of DNA database entries could be related to specific individuals that are the subjects of the data. The engine within CleanGene relies on publicly available health care data and on knowledge of particular diseases to help relate identified individuals to DNA entries. Over 20 diseases, ranging over ataxias, blood diseases, and sex-linked mutations are accounted for, with 98-100% of individuals found identifiable. We assume the genetic material is released in a linear sequencing format from an individual's genome. CleanGene and its related experiments are useful tools for any institution seeking to provide anonymous genetic material for research purposes. PMID:11079941

Malin, B.; Sweeney, L.

2000-01-01

12

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

13

Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity.  

PubMed

Small-molecule inhibitors of PARP1/2, such as olaparib, have been proposed to serve as a synthetic lethal therapy for cancers that harbor BRCA1 or BRCA2 mutations. Indeed, in clinical trials, PARP1/2 inhibitors elicit sustained antitumor responses in patients with germline BRCA gene mutations. In hypothesizing that additional genetic determinants might direct use of these drugs, we conducted a genome-wide synthetic lethal screen for candidate olaparib sensitivity genes. In support of this hypothesis, the set of identified genes included known determinants of olaparib sensitivity, such as BRCA1, RAD51, and Fanconi's anemia susceptibility genes. In addition, the set included genes implicated in established networks of DNA repair, DNA cohesion, and chromatin remodeling, none of which were known previously to confer sensitivity to PARP1/2 inhibition. Notably, integration of the list of candidate sensitivity genes with data from tumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity. In models of high-grade serous ovarian cancer (HGS-OVCa), CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition, suppression of DNA repair via homologous recombination, and reduced expression of BRCA1. As one of only nine genes known to be significantly mutated in HGS-OVCa, CDK12 has properties that should confirm interest in its use as a biomarker, particularly in ongoing clinical trials of PARP1/2 inhibitors and other agents that trigger replication fork arrest. PMID:24240700

Bajrami, Ilirjana; Frankum, Jessica R; Konde, Asha; Miller, Rowan E; Rehman, Farah L; Brough, Rachel; Campbell, James; Sims, David; Rafiq, Rumana; Hooper, Sean; Chen, Lina; Kozarewa, Iwanka; Assiotis, Ioannis; Fenwick, Kerry; Natrajan, Rachael; Lord, Christopher J; Ashworth, Alan

2014-01-01

14

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

15

Hum Genet . Author manuscript Identifying modifier genes of monogenic disease: strategies and  

E-print Network

Hum Genet . Author manuscript Page /1 11 Identifying modifier genes of monogenic disease modifier gene, Mendelian disorders, disease expression, linkage, association Introduction Genetic factors determined diseases, and this variability may itself involve genetic factors, the so-called modifier genes

Boyer, Edmond

16

Genetic Determinants of Urolithiasis  

PubMed Central

Urolithiasis affects approximately 10% of individuals in Western societies by the seventh decade of life. The most common form, idiopathic calcium oxalate urolithiasis, results from the interaction of multiple genes and their interplay with dietary and environmental factors. To date, considerable progress has been made identifying the metabolic risk factors predisposing to this complex trait, among which hypercalciuria predominates. The specific genetic and epigenetic factors have remained less clear, in part due to the candidate gene and linkage methods available until now, which are inherently low in their power of resolution and in assessing modest effects in complex traits. Even so, this approach, together with investigations of rare, Mendelian forms of urolithiasis associated with various metabolic risk factors has afforded insights into biological pathways that appear to underlie the development of stones in the urinary tract. Monogenic diseases account for a greater proportion of stone formers in childhood and adolescence than in adults. Early diagnosis of monogenic forms of urolithiasis is of importance due to associated renal injury and other potentially treatable disease manifestations, but is often delayed due to lack of familiarity with these rare disorders. Genetic advances in polygenic and monogenic forms of urolithiasis are reviewed. PMID:22183508

Monico, Carla G.; Milliner, Dawn S.

2012-01-01

17

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.

18

Genetic Inactivation of Kcnj16 Identifies Kir5.1 as an Important Determinant of Neuronal PCO2/pH Sensitivity*  

PubMed Central

The molecular identity of ion channels which confer PCO2/pH sensitivity in the brain is unclear. Heteromeric Kir4.1/Kir5.1 channels are highly sensitive to inhibition by intracellular pH and are widely expressed in several brainstem nuclei involved in cardiorespiratory control, including the locus coeruleus. This has therefore led to a proposed role for these channels in neuronal CO2 chemosensitivity. To examine this, we generated mutant mice lacking the Kir5.1 (Kcnj16) gene. We show that although locus coeruleus neurons from Kcnj16(+/+) mice rapidly respond to cytoplasmic alkalinization and acidification, those from Kcnj16(?/?) mice display a dramatically reduced and delayed response. These results identify Kir5.1 as an important determinant of PCO2/pH sensitivity in locus coeruleus neurons and suggest that Kir5.1 may be involved in the response to hypercapnic acidosis. PMID:21047793

D'Adamo, M. Cristina; Shang, Lijun; Imbrici, Paola; Brown, Steve D. M.; Pessia, Mauro; Tucker, Stephen J.

2011-01-01

19

Genetic inactivation of Kcnj16 identifies Kir5.1 as an important determinant of neuronal PCO2/pH sensitivity.  

PubMed

The molecular identity of ion channels which confer PCO(2)/pH sensitivity in the brain is unclear. Heteromeric Kir4.1/Kir5.1 channels are highly sensitive to inhibition by intracellular pH and are widely expressed in several brainstem nuclei involved in cardiorespiratory control, including the locus coeruleus. This has therefore led to a proposed role for these channels in neuronal CO(2) chemosensitivity. To examine this, we generated mutant mice lacking the Kir5.1 (Kcnj16) gene. We show that although locus coeruleus neurons from Kcnj16((+/+)) mice rapidly respond to cytoplasmic alkalinization and acidification, those from Kcnj16((-/-)) mice display a dramatically reduced and delayed response. These results identify Kir5.1 as an important determinant of PCO(2)/pH sensitivity in locus coeruleus neurons and suggest that Kir5.1 may be involved in the response to hypercapnic acidosis. PMID:21047793

D'Adamo, M Cristina; Shang, Lijun; Imbrici, Paola; Brown, Steve D M; Pessia, Mauro; Tucker, Stephen J

2011-01-01

20

Genetic determinants of neuroglobin transcription  

PubMed Central

Neuroglobin (NGB) is a neuron specific vertebrate globin shown to protect against hypoxia, ischemia, oxidative stress and the toxic effects of Amyloid-beta. Following on our and others' results highlighting the importance of NGB expression in disease we searched for genetic determinants of its expression. We found that a microRNA expressed with the NGB transcript shows significant target enrichments in the angiogenesis pathway and the Alzheimer disease / presenilin pathway. Using reporter constructs we identified potential promoter/enhancer elements between the transcription start site and 1142 bp upstream. Using 184 post mortem temporal lobe samples we replicated the reported negative effect of age, and after genotyping tagging SNPs we found one (rs981471) showing a significant correlation with the gene’s expression and another (rs8014408) showing an interaction with age, the rare C allele being correlated with higher expression and faster decline. The two SNPs are towards the 3' end of NGB within the same LD block, 52 Kb apart and modestly correlated (r2 = 0.5). Next generation sequencing of the same 184 temporal lobe samples and 79 confirmed AD patients across the entire gene region (including >12 Kb on the 3’ and 5’ flank) revealed limited coding variation, suggesting purifying selection of NGB, but did not identify regulatory or disease associated rare variants. A dinucleotide repeat in intron 1 with extensive evidence of functionality showed interesting but inconclusive results, as it was not amenable to further molecular analysis. PMID:24362753

Wang, R; Halper-Stromberg, E; Szymanski-Pierce, M; Bassett, SS; Avramopoulos, D

2014-01-01

21

Genetic determinants of urolithiasis  

Microsoft Academic Search

Urolithiasis affects approximately 10% of individuals in Western societies by the seventh decade of life. The most common form, idiopathic calcium oxalate urolithiasis, results from the interaction of multiple genes and their interplay with dietary and environmental factors. To date, considerable progress has been made in identifying the metabolic risk factors that predispose to this complex trait, among which hypercalciuria

Carla G. Monico; Dawn S. Milliner

2011-01-01

22

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 Ã? Helene H. Wagner Ã? 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

23

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

24

Genetic markers cannot determine Jewish descent.  

PubMed

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

2014-01-01

25

Reconnoiter by Candle: Identifying Assumptions in Genetic Programming  

E-print Network

Reconnoiter by Candle: Identifying Assumptions in Genetic Programming Jason M. Daida The University tradition to GP. The GA research tradition has over two decades of theoretical work; theoretical work in GP

Fernandez, Thomas

26

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

27

nature genetics advance online publication 1 Identifying regulatory networks by  

E-print Network

article nature genetics · advance online publication 1 Identifying regulatory networks the combinatorial nature of transcription, a well-established phe- nomenon in eukaryotes. Here we describe a new­11 does not explicitly address the combinatorial nature of transcriptional regulation. Here, however, we

Church, George M.

28

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

2015-02-01

29

Genetic Essentialism: On the Deceptive Determinism of DNA  

PubMed Central

This paper introduces the notion of genetic essentialist biases: cognitive biases associated with essentialist thinking that are elicited when people encounter arguments that genes are relevant for a behavior, condition, or social group. Learning about genetic attributions for various human conditions leads to a particular set of thoughts regarding those conditions: they are more likely to be perceived as a) immutable and determined, b) having a specific etiology, c) homogeneous and discrete, and, d) natural, which can lead to the naturalistic fallacy. There are rare cases of “strong genetic explanation” when such responses to genetic attributions may be appropriate, however people tend to over-weigh genetic attributions compared with competing attributions even in cases of “weak genetic explanation,” which are far more common. Research on people’s understanding of race, gender, sexual orientation, criminality, mental illness and obesity is reviewed through a genetic essentialism lens, highlighting attitudinal, cognitive and behavioral changes that stem from consideration of genetic attributions as bases of these categories. Scientists and media portrayals of genetic discoveries are discussed with respect to genetic essentialism, as is the role that genetic essentialism has played (and continues to play) in various public policies, legislation, scientific endeavors, and ideological movements in recent history. Last, moderating factors and interventions to reduce the magnitude of genetic essentialism are discussed that identify promising directions to explore in order to reduce these biases. PMID:21142350

Dar-Nimrod, Ilan; Heine, Steven J.

2012-01-01

30

Genetics might determine which smokers get hooked  

Cancer.gov

Researchers have identified genetic risk factors that may accelerate a teen's progression to becoming a lifelong heavy smoker. The team of scientists from the U.S., the U.K., and New Zealand examined earlier studies by other research teams to develop a genetic risk profile for heavy smoking. Then they looked at their own long-term study of 1,000 New Zealanders from birth to age 38 to identify whether individuals at high genetic risk got hooked on cigarettes more quickly as teens and whether, as adults, they had a harder time quitting. Duke University researchers developed a new "genetic risk score" for the study by examining prior genome-wide associations (GWAS) of adult smokers. Duke is home to the Duke Cancer Institute.

31

Unconventional P-35S sequence identified in genetically modified maize.  

PubMed

The Cauliflower Mosaic Virus 35S promoter sequence, CaMV P-35S, is one of several commonly used genetic targets to detect genetically modified maize and is found in most GMOs. In this research we report the finding of an alternative P-35S sequence and its incidence in GM maize marketed in Jordan. The primer pair normally used to amplify a 123 bp DNA fragment of the CaMV P-35S promoter in GMOs also amplified a previously undetected alternative sequence of CaMV P-35S in GM maize samples which we term V3. The amplified V3 sequence comprises 386 base pairs and was not found in the standard wild-type maize, MON810 and MON 863 GM maize. The identified GM maize samples carrying the V3 sequence were found free of CaMV when compared with CaMV infected brown mustard sample. The data of sequence alignment analysis of the V3 genetic element showed 90% similarity with the matching P-35S sequence of the cauliflower mosaic virus isolate CabbB-JI and 99% similarity with matching P-35S sequences found in several binary plant vectors, of which the binary vector locus JQ693018 is one example. The current study showed an increase of 44% in the incidence of the identified 386 bp sequence in GM maize sold in Jordan's markets during the period 2009 and 2012. PMID:24495911

Al-Hmoud, Nisreen; Al-Husseini, Nawar; Ibrahim-Alobaide, Mohammed A; Kübler, Eric; Farfoura, Mahmoud; Alobydi, Hytham; Al-Rousan, Hiyam

2014-01-01

32

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

33

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

34

Proteomic and Genetic Approaches Identify Syk as an AML Target  

PubMed Central

SUMMARY Cell-based screening can facilitate rapid identification of compounds inducing complex cellular phenotypes. Advancing a compound toward the clinic, however, generally requires identification of precise mechanisms of action. We previously found that epidermal growth factor receptor (EGFR) inhibitors induce acute myeloid leukemia (AML) differentiation via a non-EGFR mechanism. In this report, we integrated proteomic and RNAi-based strategies to identify their off-target anti-AML mechanism. These orthogonal approaches identified Syk as a target in AML. Genetic and pharmacological inactivation of Syk with a drug in clinical trial for other indications promoted differentiation of AML cells and attenuated leukemia growth in vivo. These results demonstrate the power of integrating diverse chemical, proteomic, and genomic screening approaches to identify therapeutic strategies for cancer. PMID:19800574

Hahn, Cynthia K.; Berchuck, Jacob E.; Ross, Kenneth N.; Kakoza, Rose M.; Clauser, Karl; Schinzel, Anna C.; Ross, Linda; Galinsky, Ilene; Davis, Tina N.; Silver, Serena J.; Root, David E.; Stone, Richard M.; DeAngelo, Daniel J.; Carroll, Martin; Hahn, William C.; Carr, Steven A.; Golub, Todd R.; Kung, Andrew L.; Stegmaier, Kimberly

2009-01-01

35

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

36

Using Epidemiological Models and Genetic Selection to Identify Theoretical Opportunities to Reduce Disease Impact  

Technology Transfer Automated Retrieval System (TEKTRAN)

Selection for disease resistance is a contemporary topic with developing approaches for genetic improvement. Merging the sciences of genetic selection and epidemiology is essential to identify selection schemes to enhance disease resistance. Epidemiological models can identify theoretical opportuni...

37

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

38

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

39

Host genetic determinants of influenza pathogenicity  

PubMed Central

Despite effective vaccines, influenza remains a major global health threat due to the morbidity and mortality caused by seasonal epidemics, as well as the 2009 pandemic. Also of profound concern are the rare but potentially catastrophic transmissions of avian influenza to humans, highlighted by a recent H7N9 influenza outbreak. Murine and human studies reveal that the clinical course of influenza is the result of a combination of both host and viral genetic determinants. While viral pathogenicity has long been the subject of intensive efforts, research to elucidate host genetic determinants, particularly human, is now in the ascendant, and the goal of this review is to highlight these recent insights. PMID:23933004

Lin, Tsai-Yu; Brass, Abraham L.

2014-01-01

40

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

41

Evaluation of an efficient approach for identifying genetic disease loci  

SciTech Connect

Identification of disease loci by genetic linkage analysis has been enhanced by the availability of highly polymorphic short tandem repeat polymorphic markers (STRPs). The development of high quality tri- and tetranucleotide STRPs allows new strategies to increase the efficiency of genotyping resulting in streamlined linkage studies. We have tested a strategy using pooled DNA samples from affected individuals from large Bedouin pedigrees segregating recessive disorders. Equal molar amounts of DNA from affected individuals are pooled and used as a template for PCR of STRPs. Pooled DNA from unaffected siblings are used as controls. STRPS linked to the disorder show a shift in allele frequency in the affected compared to the control pool, whereas unlinked markers show an identical allele distribution in affected and control pools. We have demonstrated the sensitivity of this approach for identifying STRPs giving positive lod scores in recessive kindreds. We have also modelled this approach with dominant pedigrees. Application of this approach to polygenic disorders should be possible by using methods to quantitate allele frequencies in pooled samples. The high quality tri- and tetranucleotide repeat markers developed by the Cooperative Human Linkage Center (CHLC) facilitate the use of this method.

Sheffield, V.C.; Kwitek-Black, A.E.; Rokhlina, T. [Univ. of Iowa, Iowa City, IA (United States)] [and others

1994-09-01

42

Heritability Estimates Identify a Substantial Genetic Contribution to Risk and Outcome of Intracerebral Hemorrhage  

PubMed Central

Background and Purpose Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome. Methods We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality. Results ICH risk heritability was estimated at 29% (SE, 11%) for non-APOE loci and at 15% (SE, 10%) for APOE. Heritability for 90-day ICH mortality was 41% for non-APOE loci and 10% (SE, 9%) for APOE. Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non-APOE loci and at 12% (SE, 4%) for APOE. Conclusions Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified. PMID:23559261

Devan, William J.; Falcone, Guido J.; Anderson, Christopher D.; Jagiella, Jeremiasz M.; Schmidt, Helena; Hansen, Björn M.; Jimenez-Conde, Jordi; Giralt-Steinhauer, Eva; Cuadrado-Godia, Elisa; Soriano, Carolina; Ayres, Alison M.; Schwab, Kristin; Kassis, Sylvia Baedorf; Valant, Valerie; Pera, Joanna; Urbanik, Andrzej; Viswanathan, Anand; Rost, Natalia S.; Goldstein, Joshua N.; Freudenberger, Paul; Stögerer, Eva-Maria; Norrving, Bo; Tirschwell, David L.; Selim, Magdy; Brown, Devin L.; Silliman, Scott L.; Worrall, Bradford B.; Meschia, James F.; Kidwell, Chelsea S.; Montaner, Joan; Fernandez-Cadenas, Israel; Delgado, Pilar; Greenberg, Steven M.; Roquer, Jaume; Lindgren, Arne; Slowik, Agnieszka; Schmidt, Reinhold; Woo, Daniel; Rosand, Jonathan; Biffi, Alessandro

2013-01-01

43

Population differences in platinum toxicity as a means to identify novel genetic susceptibility variants  

PubMed Central

Objectives Clinical studies show that Asians (ASN) are more susceptible to toxicities associated with platinum-containing regimens. We hypothesized that studying ASN as an `enriched phenotype' population could enable the discovery of novel genetic determinants of platinum susceptibility. Methods Using well-genotyped lymphoblastoid cell lines from the HapMap, we determined cisplatin and carboplatin cytotoxicity phenotypes (IC50s) for ASN, Caucasians (CEU), and Africans (YRI). IC50s were used in genome-wide association studies. Results ASN were most sensitive to platinums, corroborating clinical findings. ASN genome-wide association studies produced 479 single-nucleotide polymorphisms (SNPs) associating with cisplatin susceptibility and 199 with carboplatin susceptibility (P<10?4). Considering only the most significant variants (P< 9.99 × 10?6), backwards elimination was then used to identify reduced-model SNPs, which robustly described the drug phenotypes within ASN. These SNPs comprised highly descriptive genetic signatures of susceptibility, with 12 SNPs explaining more than 95% of the susceptibility phenotype variation for cisplatin, and eight SNPs approximately 75% for carboplatin. To determine the possible function of these variants in ASN, the SNPs were tested for association with differential expression of target genes. SNPs were highly associated with the expression of multiple target genes, and notably, the histone H3 family was implicated for both drugs, suggesting a platinum-class mechanism. Histone H3 has repeatedly been described as regulating the formation of platinum-DNA adducts, but this is the first evidence that specific genetic variants might mediate these interactions in a pharmacogenetic manner. Finally, to determine whether any ASN-identified SNPs might also be important in other human populations, we interrogated all 479/199 SNPs for association with platinum susceptibility in an independent combined CEU/YRI population. Three unique SNPs for cisplatin and 10 for carboplatin replicated in CEU/YRI. Conclusion Enriched `platinum susceptible' populations can be used to discover novel genetic determinants governing interindividual platinum chemotherapy susceptibility. PMID:20393316

O'Donnell, Peter H.; Gamazon, Eric; Zhang, Wei; Stark, Amy L.; Kistner-Griffin, Emily O.; Huang, R. Stephanie; Dolan, M. Eileen

2010-01-01

44

Using Genetic Markers to Identify Lung Cancer in Fine Needle Aspiration Samples  

PubMed Central

Purpose We seek to establish a genetic test to identify lung cancer using cells obtained through CT guided fine needle aspiration (FNA). Experimental Design We selected regions of frequent copy number gains in chromosomes 1q32, 3q26, 5p15, and 8q24 in non-small cell lung cancer (NSCLC) and tested their ability to determine the neoplastic state of cells obtained by FNA using fluorescent in situ hybridization (FISH). Two sets of samples were included. The pilot set included six paraffin-embedded non-cancerous lung tissues and 33 formalin-fixed FNA specimens. These 39 samples were used to establish the optimal fixation and single scoring criteria for the samples. The test set included 40 FNA samples. The results of the genetic test were compared with the cytology, pathology, and clinical follow up for each case to assess the sensitivity and specificity of the genetic test. Results Non-tumor lung tissues had ?4 signals per nuclei for all tested markers while tumor samples had ?5 signals per nucleus in five or more cells for at least one marker. Among the 40 testing cases, 36 of 40 (90%) FNA samples were analyzable. Genetic analysis identified 15 cases as tumor and 21 as non-tumor. Clinical and pathological diagnoses confirmed the genetic test in 15 of 16 lung cancer cases regardless of tumor subtype, stage, or size and in 20 of 20 cases diagnosed as benign lung diseases. Conclusions A set of only four genetic markers can distinguish the neoplastic state of lung lesion using small samples obtained through CT guided FNA. PMID:19010865

Gill, Rajbir K.; Vazquez, Madeline F.; Kramer, Arin; Hames, Megan; Zhang, Lijuan; Heselmeyer-Haddad, Kerstin; Ried, Thomas; Shilo, Konstantin; Henschke, Claudia; Yankelevitz, David; Jen, Jin

2008-01-01

45

The borderline diagnosis III: identifying endophenotypes for genetic studies.  

PubMed

Although it is generally acknowledged that borderline personality disorder (BPD) has a complex, multifactorial etiology with interacting genetic and environmental substrates, the specific genetic underpinnings of this disorder have not been extensively investigated. Family aggregation studies suggest the heritability for BPD as a diagnosis, but the genetic basis for this disorder may be stronger for dimensions such as impulsivity/aggression and affective instability than for the diagnostic criteria itself. Family, adoptive, and twin studies also converge to support an underlying genetic component to the disorder. An endophenotypic approach to defining the genetics of this complex disorder may be called for. Twin studies in an epidemiologic, non-clinically ascertained sample using both diagnostic measures and laboratory measures that can be operationalized, including neuropsychologic, psychophysiologic, and operationalized behavioral tests, may be useful. Large-scale family studies of clinically ascertained samples with careful diagnostic demarcation and measurement of endophenotypes in probands and relatives may also prove to be a promising approach. The use of laboratory paradigms for measures of aggression and affective instability are discussed in the context of such endophenotypic approaches. PMID:12062879

Siever, Larry J; Torgersen, Svenn; Gunderson, John G; Livesley, W John; Kendler, Kenneth S

2002-06-15

46

Method of detecting genetic translocations identified with chromosomal abnormalities  

DOEpatents

Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyses. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acid probes are typically of a complexity greater than 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML) and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar but genetically different diseases, and for many prognostic and diagnostic applications.

Gray, Joe W. (Livermore, CA); Pinkel, Daniel (Walnut Creek, CA); Tkachuk, Douglas (Livermore, CA)

2001-01-01

47

Method of detecting genetic deletions identified with chromosomal abnormalities  

DOEpatents

Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyzes. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acids probes are typically of a complexity greater tha 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particlularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML) and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar ut genetically different diseases, and for many prognostic and diagnostic applications.

Gray, Joe W; Pinkel, Daniel; Tkachuk, Douglas

2013-11-26

48

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

49

Automatic Relevance Determination for Identifying Thalamic Regions Implicated in Schizophrenia  

E-print Network

Automatic Relevance Determination for Identifying Thalamic Regions Implicated in Schizophrenia of schizophrenia. Several studies have found the thalamus to be altered in schizophrenia, and the thalamus has and mediodorsal nucleus, underscoring the importance of examining thalamic subregions in schizophrenia. A. Browne

Browne, Antony

50

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

51

Riverscape genetics identifies replicated ecological divergence across an Amazonian ecotone.  

PubMed

Ecological speciation involves the evolution of reproductive isolation and niche divergence in the absence of a physical barrier to gene flow. The process is one of the most controversial topics of the speciation debate, particularly in tropical regions. Here, we investigate ecologically based divergence across an Amazonian ecotone in the electric fish, Steatogenys elegans. We combine phylogenetics, genome scans, and population genetics with a recently developed individual-based evolutionary landscape genetics approach that incorporates selection. This framework is used to assess the relative contributions of geography and divergent natural selection between environments as biodiversity drivers. We report on two closely related and sympatric lineages that exemplify how divergent selection across a major Amazonian aquatic ecotone (i.e., between rivers with markedly different hydrochemical properties) may result in replicated ecologically mediated speciation. The results link selection across an ecological gradient with reproductive isolation and we propose that assortative mating based on water color may be driving the divergence. Divergence resulting from ecologically driven selection highlights the importance of considering environmental heterogeneity in studies of speciation in tropical regions. Furthermore, we show that framing ecological speciation in a spatially explicit evolutionary landscape genetics framework provides an important first step in exploring a wide range of the potential effects of spatial dependence in natural selection. PMID:24641091

Cooke, Georgina M; Landguth, Erin L; Beheregaray, Luciano B

2014-07-01

52

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

53

Genetic modifier screens to identify components of a redox-regulated cell adhesion and migration pathway.  

PubMed

Under normal physiological conditions, cells use oxidants, particularly H2O2, for signal transduction during processes such as proliferation and migration. Though recent progress has been made in determining the precise role H2O2 plays in these processes, many gaps still remain. To further understand this, we describe the use of a dominant enhancer screen to identify novel components of a redox-regulated cell migration and adhesion pathway in Drosophila melanogaster. Here, we discuss our methodology and progress as well as the benefits and limitations of applying such an approach to study redox-regulated pathways. Depending on the nature of these pathways, unbiased genetic modifier screens may prove a productive way to identify novel redox-regulated signaling components. PMID:23849867

Hurd, Thomas Ryan; Leblanc, Michelle Gail; Jones, Leonard Nathaniel; DeGennaro, Matthew; Lehmann, Ruth

2013-01-01

54

Identifying the genetic relatedness of poa utilizing PAL-PCR  

Technology Transfer Automated Retrieval System (TEKTRAN)

Plant genomes maintain a vast array of chromosomal arrangements ranging from miniature inverted repeat tandem elements and short interspersed regions; to larger genome rearrangements containing inverted repeats. Such regions may be randomly identified by utilizing single primer PCR, also called pal...

55

Large-Scale Pooled Next-Generation Sequencing of 1077 Genes to Identify Genetic Causes of Short Stature  

PubMed Central

Context: The majority of patients presenting with short stature do not receive a definitive diagnosis. Advances in genetic sequencing allow for large-scale screening of candidate genes, potentially leading to genetic diagnoses. Objectives: The purpose of this study was to discover genetic variants that contribute to short stature in a cohort of children with no known genetic etiology. Design: This was a prospective cohort study of subjects with short stature. Setting: The setting was a pediatric endocrinology and genetics clinics at an academic center. Patients: A total of 192 children with short stature with no defined genetic etiology and 192 individuals of normal stature from the Framingham Heart Study were studied. Intervention: Pooled targeted sequencing using next-generation DNA sequencing technology of the exons of 1077 candidate genes was performed. Main Outcome Measures: The numbers of rare nonsynonymous genetic variants found in case patients but not in control subjects, known pathogenic variants in case patients, and potentially pathogenic variants in IGF1R were determined. Results: We identified 4928 genetic variants in 1077 genes that were present in case patients but not in control subjects. Of those, 1349 variants were novel (898 nonsynonymous). False-positive rates from pooled sequencing were 4% to 5%, and the false-negative rate was 0.1% in regions covered well by sequencing. We identified 3 individuals with known pathogenic variants in PTPN11 causing undiagnosed Noonan syndrome. There were 9 rare potentially nonsynonymous variants in IGF1R, one of which is a novel, probably pathogenic, frameshift mutation. A previously reported pathogenic variant in IGF1R was present in a control subject. Conclusions: Large-scale sequencing efforts have the potential to rapidly identify genetic etiologies of short stature, but data interpretation is complex. Noonan syndrome may be an underdiagnosed cause of short stature. PMID:23771920

Wang, Sophie R.; Carmichael, Heather; Andrew, Shayne F.; Miller, Timothy C.; Moon, Jennifer E.; Derr, Michael A.; Hwa, Vivian; Hirschhorn, Joel N.

2013-01-01

56

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

57

Multiple Genetically Distinct Groups Revealed among Clinical Isolates Identified as Atypical Aspergillus fumigatus  

Microsoft Academic Search

To investigate whether genetic variants of A. fumigatus are found among clinical isolates, four isolates that were originally identified as poorly sporulating strains of Aspergillus fumigatus were subjected to molecular analysis. DNA sequence analysis of the alkaline protease genes of these isolates showed that each is genetically distinct and each shows substantial variation (7 to 11%) from the A. fumigatus

Margaret E. Katz; Annette M. Dougall; Brian F. Cheetham

2005-01-01

58

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...

59

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.

60

Identifying Promising Compounds in Drug Discovery: Genetic Algorithms and Some New Statistical Techniques  

E-print Network

Identifying Promising Compounds in Drug Discovery: Genetic Algorithms and Some New Statistical Techniques Abhyuday Mandal* Department of Statistics, University of Georgia, Athens, Georgia 30602-1952 Kjell, Michigan 48105 Received December 14, 2006 Throughout the drug discovery process, discovery teams

Wu, Jeff

61

Two newly identified genetic determinants of pigmentation in Europeans.  

PubMed

We present results from a genome-wide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. Two coding variants in TPCN2 are associated with hair color, and a variant at the ASIP locus shows strong association with skin sensitivity to sun, freckling and red hair, phenotypic characteristics similar to those affected by well-known mutations in MC1R. PMID:18488028

Sulem, Patrick; Gudbjartsson, Daniel F; Stacey, Simon N; Helgason, Agnar; Rafnar, Thorunn; Jakobsdottir, Margret; Steinberg, Stacy; Gudjonsson, Sigurjon A; Palsson, Arnar; Thorleifsson, Gudmar; Pálsson, Snaebjörn; Sigurgeirsson, Bardur; Thorisdottir, Kristin; Ragnarsson, Rafn; Benediktsdottir, Kristrun R; Aben, Katja K; Vermeulen, Sita H; Goldstein, Alisa M; Tucker, Margaret A; Kiemeney, Lambertus A; Olafsson, Jon H; Gulcher, Jeffrey; Kong, Augustine; Thorsteinsdottir, Unnur; Stefansson, Kari

2008-07-01

62

Population genetics identifies challenges in analyzing rare variants.  

PubMed

Geneticists have, for years, understood the nature of genome-wide association studies using common genomic variants. Recently, however, focus has shifted to the analysis of rare variants. This presents potential problems for researchers, as rare variants do not always behave in the same way common variants do, sometimes rendering decades of solid intuition moot. In this paper, we present examples of the differences between common and rare variants. We show why one must be significantly more careful about the origin of rare variants, and how failing to do so can lead to highly inflated type I error. We then explain how to best avoid such concerns with careful understanding and study design. Additionally, we demonstrate that a seemingly low error rate in next-generation sequencing can dramatically impact the false-positive rate for rare variants. This is due to the fact that rare variants are, by definition, seen infrequently, making it hard to distinguish between errors and real variants. Compounding this problem is the fact that the proportion of errors is likely to get worse, not better, with increasing sample size. One cannot simply scale their way up in order to solve this problem. Understanding these potential pitfalls is a key step in successfully identifying true associations between rare variants and diseases. PMID:25640419

Johnston, Henry Richard; Hu, Yijuan; Cutler, David J

2015-03-01

63

Genetical genomic determinants of alcohol consumption in rats and humans  

Microsoft Academic Search

BACKGROUND: We have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB\\/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs).

Boris Tabakoff; Laura Saba; Morton Printz; Pam Flodman; Colin Hodgkinson; David Goldman; George Koob; Heather N Richardson; Katerina Kechris; Richard L Bell; Norbert Hübner; Matthias Heinig; Michal Pravenec; Jonathan Mangion; Lucie Legault; Maurice Dongier; Katherine M Conigrave; John B Whitfield; John Saunders; Bridget Grant; Paula L Hoffman

2009-01-01

64

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...

65

Systematic Genetic Analysis Identifies Cis-eQTL Target Genes Associated with Glioblastoma Patient Survival  

PubMed Central

Prior expression quantitative trait locus (eQTL) studies have demonstrated heritable variation determining differences in gene expression. The majority of eQTL studies were based on cell lines and normal tissues. We performed cis-eQTL analysis using glioblastoma multiforme (GBM) data sets obtained from The Cancer Genome Atlas (TCGA) to systematically investigate germline variation’s contribution to tumor gene expression levels. We identified 985 significant cis-eQTL associations (FDR<0.05) mapped to 978 SNP loci and 159 unique genes. Approximately 57% of these eQTLs have been previously linked to the gene expression in cell lines and normal tissues; 43% of these share cis associations known to be associated with functional annotations. About 25% of these cis-eQTL associations are also common to those identified in Breast Cancer from a recent study. Further investigation of the relationship between gene expression and patient clinical information identified 13 eQTL genes whose expression level significantly correlates with GBM patient survival (p<0.05). Most of these genes are also differentially expressed in tumor samples and organ-specific controls (p<0.05). Our results demonstrated a significant relationship of germline variation with gene expression levels in GBM. The identification of eQTLs-based expression associated survival might be important to the understanding of genetic contribution to GBM cancer prognosis. PMID:25133526

Chen, Qing-Rong; Hu, Ying; Yan, Chunhua; Buetow, Kenneth; Meerzaman, Daoud

2014-01-01

66

Advancements in identifying biomechanical determinants for abdominal aortic aneurysm rupture.  

PubMed

Abdominal aortic aneurysms are a common health problem and currently the need for surgical intervention is determined based on maximum diameter and growth rate criteria. Since these universal variables often fail to predict accurately every abdominal aortic aneurysms evolution, there is a considerable effort in the literature for other markers to be identified towards individualized rupture risk estimations and growth rate predictions. To this effort, biomechanical tools have been extensively used since abdominal aortic aneurysm rupture is in fact a material failure of the diseased arterial wall to compensate the stress acting on it. The peak wall stress, the role of the unique geometry of every individual abdominal aortic aneurysm as well as the mechanical properties and the local strength of the degenerated aneurysmal wall, all confer to rupture risk. In this review article, the assessment of these variables through mechanical testing, advanced imaging and computational modeling is reviewed and the clinical perspective is discussed. PMID:24757027

Kontopodis, Nikolaos; Metaxa, Eleni; Papaharilaou, Yannis; Tavlas, Emmanouil; Tsetis, Dimitrios; Ioannou, Christos

2015-02-01

67

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...

68

Determining the genetic heritability of wood properties  

E-print Network

.49 0.62 Specific gravity 0.71 0.73 Density (pilodyn) 0.62 0.67 Microfibril angle 0.52 0.47 #12;Genetic gain relative to QCI Gain % Gain MOE (MPa) 1049.43 15 MOR (MPa) 10.37 18 Specific gravity 0.038 10 MFA

69

Methods for determining the genetic affinity of microorganisms and viruses  

NASA Technical Reports Server (NTRS)

Selecting which sub-sequences in a database of nucleic acid such as 16S rRNA are highly characteristic of particular groupings of bacteria, microorganisms, fungi, etc. on a substantially phylogenetic tree. Also applicable to viruses comprising viral genomic RNA or DNA. A catalogue of highly characteristic sequences identified by this method is assembled to establish the genetic identity of an unknown organism. The characteristic sequences are used to design nucleic acid hybridization probes that include the characteristic sequence or its complement, or are derived from one or more characteristic sequences. A plurality of these characteristic sequences is used in hybridization to determine the phylogenetic tree position of the organism(s) in a sample. Those target organisms represented in the original sequence database and sufficient characteristic sequences can identify to the species or subspecies level. Oligonucleotide arrays of many probes are especially preferred. A hybridization signal can comprise fluorescence, chemiluminescence, or isotopic labeling, etc.; or sequences in a sample can be detected by direct means, e.g. mass spectrometry. The method's characteristic sequences can also be used to design specific PCR primers. The method uniquely identifies the phylogenetic affinity of an unknown organism without requiring prior knowledge of what is present in the sample. Even if the organism has not been previously encountered, the method still provides useful information about which phylogenetic tree bifurcation nodes encompass the organism.

Fox, George E. (Inventor); Willson, III, Richard C. (Inventor); Zhang, Zhengdong (Inventor)

2012-01-01

70

Genetic determinants and potential therapeutic targets for pancreatic adenocarcinoma  

PubMed Central

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in both men and women in the United States, carrying a 5-year survival rate of approximately 5%, which is the poorest prognosis of any solid tumor type. Given the dismal prognosis associated with PDAC, a more thorough understanding of risk factors and genetic predisposition has important implications not only for cancer prevention, but also for screening techniques and the development of personalized therapies. While screening of the general population is not recommended or practicable with current diagnostic methods, studies are ongoing to evaluate its usefulness in people with at least 5- to 10-fold increased risk of PDAC. In order to help identify high-risk populations who would be most likely to benefit from early detection screening tests for pancreatic cancer, discovery of additional pancreatic cancer susceptibility genes is crucial. Thus, specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. The goal of this review is to provide an overview of the genetic basis for PDAC with a focus on germline and familial determinants. A discussion of potential therapeutic targets and future directions in screening and treatment is also provided. PMID:24624093

Reznik, Robert; Hendifar, Andrew E.; Tuli, Richard

2014-01-01

71

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

E-print Network

Program, Institute of Health and Biomedical Innovation, Brisbane, Australia. 2Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Australia. 3Department of Public Health and Primary Care, University of Cambridge... ) generally carries a good prog- nosis, some patients with this tumour subtype relapse within two years. Identifying genetic variants associated with prognosis could inform clinical decision-making for management at diagnosis, and inform development...

2012-04-12

72

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.

73

Genetic mapping of the determinants of plaque morphology of coxsackievirus B4  

Microsoft Academic Search

Summary The genetic determinants of plaque size of two variants of coxsackievirus B4, CB4-P and CB4-V, were identified using a panel of recombinant, chimeric viruses. When grown in monkey kidney cells, CB4-V yielded large plaques with an average size of 1.0 cm while CB4-P yielded small plaques with an average size of 0.4 cm. Two genetic domains, the 5' untranslated

A. I. Ramsingh; M. Caggana; S. Ronstrom

1995-01-01

74

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

75

Genome-wide approaches for identifying genetic risk factors for osteoporosis  

PubMed Central

Osteoporosis, the most common type of bone disease worldwide, is clinically characterized by low bone mineral density (BMD) and increased susceptibility to fracture. Multiple genetic and environmental factors and gene-environment interactions have been implicated in its pathogenesis. Osteoporosis has strong genetic determination, with the heritability of BMD estimated to be as high as 60%. More than 80 genes or genetic variants have been implicated in risk of osteoporosis by hypothesis-free genome-wide studies. However, these genes or genetic variants can only explain a small portion of BMD variation, suggesting that many other genes or genetic variants underlying osteoporosis risk await discovery. Here, we review recent progress in genome-wide studies of osteoporosis and discuss their implications for medicine and the major challenges in the field. PMID:23731620

2013-01-01

76

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

77

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

PubMed

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

78

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

79

A screen of zebrafish mutants identifies ethanol-sensitive genetic loci  

PubMed Central

Background Fetal Alcohol Spectrum Disorders (FASD) are a highly variable set of phenotypes caused by fetal alcohol exposure. Numerous factors influence FASD phenotypes, including genetics. The zebrafish is a powerful vertebrate model system with which to identify these genetic factors. Many zebrafish mutants are housed at the Zebrafish International Resource Center (ZIRC). These mutants are readily accessible and an excellent source to screen for ethanol-sensitive developmental structural mutants. Methods We screened mutants obtained from ZIRC for sensitivity to ethanol teratogenesis. Embryos were treated with 1% ethanol (41 mM tissue levels) from 6 hours post fertilization onward. Levels of apoptosis were evaluated at 24 hpf. At 5 days post fertilization, the craniofacial skeleton, peripheral axon projections and sensory neurons of neuromasts were examined. Fish were genotyped to determine if there were phenotype/genotype correlations. Results Five of twenty loci interacted with ethanol. Notable among these was that vangl2, involved in convergent/extension movements of the embryonic axis, interacted strongly with ethanol. Untreated vangl2 mutants had normal craniofacial morphology while severe midfacial defects including synophthalmia and narrowing of the palatal skeleton were found in all ethanol-treated mutants and a low percentage of heterozygotes. The cell cycle gene, plk1, also interacted strongly with ethanol. Untreated mutants have slightly elevated levels of apoptosis and loss of ventral craniofacial elements. Exposure to ethanol results in extensive apoptosis along with loss of neural tissue and the entire craniofacial skeleton. Phenotypes of hinfp, mars and foxi1 mutants were also exacerbated by ethanol. Conclusions Our results provide insight into the gene/ethanol interactions that may underlie ethanol teratogenesis. They support previous findings that ethanol disrupts elongation of the embryonic axis. Importantly, these results show that the zebrafish is an efficient model with which to test for gene/ethanol interactions. Understanding these interactions will be crucial to understanding of the FASD variation. PMID:24164477

Swartz, Mary E.; Wells, M. Ben; Griffin, Melissa; McCarthy, Neil; Lovely, C. Ben; McGurk, Patrick; Rozacky, Jenna; Eberhart, Johann K.

2013-01-01

80

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

81

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...

82

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.

83

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.

84

Genome-wide association study to identify genetic variants present in Japanese patients harboring intracranial aneurysms  

Microsoft Academic Search

An intracranial aneurysm (IA), which results in a subarachnoid hemorrhage with a high mortality on rupture, is a major public health concern. To identify genetic susceptibility loci for IA, we carried out a multistage association study using genome-wide single nucleotide polymorphisms (SNPs) in Japanese case–control subjects. In this study, we assessed evidence for association in standard approaches, and additional tests

Koichi Akiyama; Akira Narita; Hirofumi Nakaoka; Tailin Cui; Tomoko Takahashi; Katsuhito Yasuno; Atsushi Tajima; Boris Krischek; Ken Yamamoto; Hidetoshi Kasuya; Akira Hata; Ituro Inoue

2010-01-01

85

Genome-Wide Linkage Analysis to Identify Genetic Modifiers of ALK Mutation Penetrance in Familial Neuroblastoma  

Microsoft Academic Search

Background: Neuroblastoma (NB) is an important childhood cancer with a strong genetic component related to disease susceptibility. Approximately 1% of NB cases have a positive family history. Following a genome-wide linkage analysis and sequencing of candidate genes in the critical region, we identified ALK as the major familial NB gene. Dominant mutations in ALK are found in more than 50%

Marcella Devoto; Claudia Specchia; Marci Laudenslager; Luca Longo; Hakon Hakonarson; John Maris; Yael Mossé

2011-01-01

86

Network analysis of skin tumor progression identifies a rewired genetic architecture affecting inflammation and tumor susceptibility  

Microsoft Academic Search

BACKGROUND: Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits, including inflammation and cancer susceptibility. Whether germline variants affect gene expression in tumors that have undergone somatic alterations, and the extent

David A Quigley; Minh D To; Il Jin Kim; Kevin K Lin; Donna G Albertson; Jonas Sjolund; Jesús Pérez-Losada; Allan Balmain

2011-01-01

87

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.

88

Evolutionary Analyses of Staphylococcus aureus Identify Genetic Relationships between Nasal Carriage and  

E-print Network

Evolutionary Analyses of Staphylococcus aureus Identify Genetic Relationships between Nasal of America Abstract Nasal carriage of Staphylococcus aureus has long been hypothesized to be a major vector, Stinnett JW, Muthukrishnan G, Parkinson CL, Cole AM (2011) Evolutionary Analyses of Staphylococcus aureus

Parkinson, Christopher L.

89

nature genetics volume 29 october 2001 1 Identifying regulatory networks by  

E-print Network

article nature genetics · volume 29 · october 2001 1 Identifying regulatory networks the combinatorial nature of transcription, a well-established phe- nomenon in eukaryotes. Here we describe a new­11 does not explicitly address the combinatorial nature of transcriptional regulation. Here, however, we

Church, George M.

90

Genetic Association and Gene Expression Analysis Identify FGFR1 as a New Susceptibility Gene for  

E-print Network

Genetic Association and Gene Expression Analysis Identify FGFR1 as a New Susceptibility Gene.8 10 6 , which was P 7.0 10 8 in the recessive model. rs7012413*T was associated with FGFR1 expression ]0.001) and increased after diet-induced obesity (P 0.05). Conclusions: FGFR1 is a novel obesity gene

Paris-Sud XI, Université de

91

Genetic determinants of virulence - Candida parapsilosis.  

PubMed

The global epidemiology of fungal infections is changing. While overall, Candida albicans remains the most common pathogen; several institutions in Europe, Asia and South America have reported the rapid emergence to predominance of Candida parapsilosis. This mini-review examines the impact of gene deletions achieved in C. parapsilosis that have been published to date. The molecular approaches to gene disruption in C. parapsilosis and the molecularly characterized genes to date are reviewed. Similar to C. albicans, factors influencing virulence in C. parapsilosis include adherence, biofilm formation, lipid metabolism, and secretion of hydrolytic enzymes such as lipases, phospholipases and secreted aspartyl proteinases. Development of a targeted gene deletion method has enabled the identification of several unique aspects of C. parapsilosis genes that play a role in host-pathogen interactions - CpLIP1, CpLIP2, SAPP1a, SAPP1b, BCR1, RBT1, CpFAS2, OLE1, FIT-2. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012). PMID:24257473

Singaravelu, Kumara; Gácser, Attila; Nosanchuk, Joshua D

2014-01-01

92

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...

93

Chemical Genetics Identify eIF2? Kinase Heme Regulated Inhibitor as Anti-Cancer Target  

PubMed Central

Translation initiation plays a critical role in cellular homeostasis, proliferation, differentiation and malignant transformation. Consistently, increasing the abundance of the eIF2·GTP·Met-tRNAi translation initiation complex transforms normal cells and contributes to cancer initiation and the severity of some anemia. The chemical modifiers of the eIF2·GTP·Met-tRNAi ternary complex are therefore invaluable tools for studying its role in the pathobiology of human disorders and for determining if this complex can be pharmacologically targeted for therapeutic purposes. Using a cell based assay, we identified N,N’-diarylureas as novel inhibitors of the ternary complex abundance. Direct functional-genetics and biochemical evidence demonstrated that the N,N’-diarylureas activate heme regulated inhibitor kinase, thereby phosphorylate eIF2? and reduce abundance of the ternary complex. Using tumor cell proliferation in vitro and tumor growth in vivo as paradigms, we demonstrate that N,N’-diarylureas are potent and specific tools for studying the role eIF2·GTP·Met-tRNAi ternary complex in the pathobiology of human disorders. PMID:21765405

Chen, Ting; Ozel, Duygu; Qiao, Yuan; Harbinski, Fred; Chen, Limo; Denoyelle, Séverine; He, Xiaoying; Zvereva, Nela; Supko, Jeffrey G.; Chorev, Michael; Halperin, Jose A.; Aktas, Bertal H.

2013-01-01

94

Genetic Determinants of Reutericyclin Biosynthesis in Lactobacillus reuteri.  

PubMed

Reutericyclin is a unique antimicrobial tetramic acid produced by some strains of Lactobacillus reuteri. This study aimed to identify the genetic determinants of reutericyclin biosynthesis. Comparisons of the genomes of reutericyclin-producing L. reuteri strains with those of non-reutericyclin-producing strains identified a genomic island of 14 open reading frames (ORFs) including genes coding for a nonribosomal peptide synthetase (NRPS), a polyketide synthase (PKS), homologues of PhlA, PhlB, and PhlC, and putative transport and regulatory proteins. The protein encoded by rtcN is composed of a condensation domain, an adenylation domain likely specific for d-leucine, and a thiolation domain. rtcK codes for a PKS that is composed of a ketosynthase domain, an acyl-carrier protein domain, and a thioesterase domain. The products of rtcA, rtcB, and rtcC are homologous to the diacetylphloroglucinol-biosynthetic proteins PhlABC and may acetylate the tetramic acid moiety produced by RtcN and RtcK, forming reutericyclin. Deletion of rtcN or rtcABC in L. reuteri TMW1.656 abrogated reutericyclin production but did not affect resistance to reutericyclin. Genes coding for transport and regulatory proteins could be deleted only in the reutericyclin-negative L. reuteri strain TMW1.656?rtcN, and these deletions eliminated reutericyclin resistance. The genomic analyses suggest that the reutericyclin genomic island was horizontally acquired from an unknown source during a unique event. The combination of PhlABC homologues with both an NRPS and a PKS has also been identified in the lactic acid bacteria Streptococcus mutans and Lactobacillus plantarum, suggesting that the genes in these organisms and those in L. reuteri share an evolutionary origin. PMID:25576609

Lin, Xiaoxi B; Lohans, Christopher T; Duar, Rebbeca; Zheng, Jinshui; Vederas, John C; Walter, Jens; Gänzle, Michael

2015-03-15

95

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

96

Pleiotropy among Common Genetic Loci Identified for Cardiometabolic Disorders and C-Reactive Protein  

PubMed Central

Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS). We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463) as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10) appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18) had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes. PMID:25768928

Ligthart, Symen; de Vries, Paul S.; Uitterlinden, André G.; Hofman, Albert; Franco, Oscar H.; Chasman, Daniel I.; Dehghan, Abbas

2015-01-01

97

Harnessing genomics to identify environmental determinants of heritable disease  

PubMed Central

Next-generation sequencing technologies can now be used to directly measure heritable de novo DNA sequence mutations in humans. However, these techniques have not been used to examine environmental factors that induce such mutations and their associated diseases. To address this issue, a working group on environmentally induced germline mutation analysis (ENIGMA) met in October 2011 to propose the necessary foundational studies, which include sequencing of parent–offspring trios from highly exposed human populations, and controlled dose–response experiments in animals. These studies will establish background levels of variability in germline mutation rates and identify environmental agents that influence these rates and heritable disease. Guidance for the types of exposures to examine come from rodent studies that have identified agents such as cancer chemotherapeutic drugs, ionizing radiation, cigarette smoke, and air pollution as germ-cell mutagens. Research is urgently needed to establish the health consequences of parental exposures on subsequent generations. PMID:22935230

Yauk, Carole Lyn; Argueso, J. Lucas; Auerbach, Scott S.; Awadalla, Philip; Davis, Sean R.; DeMarini, David M.; Douglas, George R.; Dubrova, Yuri E.; Elespuru, Rosalie K.; Glover, Thomas W.; Hales, Barbara F.; Hurles, Matthew E.; Klein, Catherine B.; Lupski, James R.; Manchester, David K.; Marchetti, Francesco; Montpetit, Alexandre; Mulvihill, John J.; Robaire, Bernard; Robbins, Wendie A.; Rouleau, Guy A.; Shaughnessy, Daniel T.; Somers, Christopher M.; Taylor, James G.; Trasler, Jacquetta; Waters, Michael D.; Wilson, Thomas E.; Witt, Kristine L.; Bishop, Jack B.

2012-01-01

98

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

99

Genetic Determinants of Trabecular and Cortical Volumetric Bone Mineral Densities and Bone Microstructure  

PubMed Central

Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n?=?5,878) followed by replication (n?=?1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p?=?3.6×10?14; LOC285735, rs271170, p?=?2.7×10?12; OPG, rs7839059, p?=?1.2×10?10; and ESR1/C6orf97, rs6909279, p?=?1.1×10?9). The trabecular vBMD GWA meta-analysis (n?=?2,500) followed by replication (n?=?1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p?=?1.9×10?9). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n?=?729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60–0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk. PMID:23437003

Kähönen, Mika; Raitakari, Olli; Laaksonen, Marika; Sievänen, Harri; Viikari, Jorma; Lyytikäinen, Leo-Pekka; Mellström, Dan; Karlsson, Magnus; Ljunggren, Östen; Grundberg, Elin; Kemp, John P.; Sayers, Adrian; Nethander, Maria; Evans, David M.; Vandenput, Liesbeth; Tobias, Jon H.; Ohlsson, Claes

2013-01-01

100

Disposition and determinism - genetic diagnostics in risk society  

Microsoft Academic Search

This article investigates the relationship between genetic determinism and the dis- course of risk by making use of an elaboration of the concept of governmentality developed by Michel Foucault. After a short outline of the theoretical profile of the employed risk analysis, the main part of the text distinguishes three core level of analysis. With a view to illustrating several

Thomas Lemke

2004-01-01

101

Genetic screens to identify elements of the decapentaplegic signaling pathway in Drosophila.  

PubMed

Pathways for regulation of signaling by transforming growth factor-beta family members are poorly understood at present. The best genetically characterized member of this family is encoded by the Drosophila gene decapentaplegic (dpp), which is required for multiple events during fly development. We describe here the results of screens for genes required to maximize dpp signaling during embryonic dorsal-ventral patterning. Screens for genetic interactions in the zygote have identified an allele of tolloid, as well as two novel alleles of screw, a gene recently shown to encode another bone morphogenetic protein-like polypeptide. Both genes are required for patterning the dorsalmost tissues of the embryo. Screens for dpp interactions with maternally expressed genes have identified loss of function mutations in Mothers against dpp and Medea. These mutations are homozygous pupal lethal, engendering gut defects and severely reduced imaginal disks, reminiscent of dpp mutant phenotypes arising during other dpp-dependent developmental events. Genetic interaction phenotypes are consistent with reduction of dpp activity in the early embryo and in the imaginal disks. We propose that the novel screw mutations identified here titrate out some component(s) of the dpp signaling pathway. We propose that Mad and Medea encode rate-limiting components integral to dpp pathways throughout development. PMID:7705627

Raftery, L A; Twombly, V; Wharton, K; Gelbart, W M

1995-01-01

102

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

103

Inferring Genetic Networks and Identifying Compound Mode of Action via Expression Profiling  

NASA Astrophysics Data System (ADS)

The complexity of cellular gene, protein, and metabolite networks can hinder attempts to elucidate their structure and function. To address this problem, we used systematic transcriptional perturbations to construct a first-order model of regulatory interactions in a nine-gene subnetwork of the SOS pathway in Escherichia coli. The model correctly identified the major regulatory genes and the transcriptional targets of mitomycin C activity in the subnetwork. This approach, which is experimentally and computationally scalable, provides a framework for elucidating the functional properties of genetic networks and identifying molecular targets of pharmacological compounds.

Gardner, Timothy S.; di Bernardo, Diego; Lorenz, David; Collins, James J.

2003-07-01

104

Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery  

PubMed Central

Background Atherosclerosis, the underlying cause of cardiovascular disease, results from both genetic and environmental factors. Methods In the current study we take a systems-based approach using weighted gene co-expression analysis to identify a candidate pathway of genes related to atherosclerosis. Bioinformatic analyses are performed to identify candidate genes and interactions and several novel genes are characterized using in-vitro studies. Results We identify 1 coexpression module associated with innominate artery atherosclerosis that is also enriched for inflammatory and macrophage gene signatures. Using a series of bioinformatics analysis, we further prioritize the genes in this pathway and identify Cd44 as a critical mediator of the atherosclerosis. We validate our predictions generated by the network analysis using Cd44 knockout mice. Conclusion These results indicate that alterations in Cd44 expression mediate inflammation through a complex transcriptional network involving a number of previously uncharacterized genes. PMID:25115202

2014-01-01

105

A High Through-Put Reverse Genetic Screen Identifies Two Genes Involved in Remote Memory in Mice  

E-print Network

A High Through-Put Reverse Genetic Screen Identifies Two Genes Involved in Remote Memory in Mice Through-Put Reverse Genetic Screen Identifies Two Genes Involved in Remote Memory in Mice. PLoS ONE 3 required for remote memory, we screened randomly selected mouse strains harboring known mutations. In our

Anagnostaras, Stephan

106

Functional genomics complements quantitative genetics in identifying disease-gene associations.  

PubMed

An ultimate goal of genetic research is to understand the connection between genotype and phenotype in order to improve the diagnosis and treatment of diseases. The quantitative genetics field has developed a suite of statistical methods to associate genetic loci with diseases and phenotypes, including quantitative trait loci (QTL) linkage mapping and genome-wide association studies (GWAS). However, each of these approaches have technical and biological shortcomings. For example, the amount of heritable variation explained by GWAS is often surprisingly small and the resolution of many QTL linkage mapping studies is poor. The predictive power and interpretation of QTL and GWAS results are consequently limited. In this study, we propose a complementary approach to quantitative genetics by interrogating the vast amount of high-throughput genomic data in model organisms to functionally associate genes with phenotypes and diseases. Our algorithm combines the genome-wide functional relationship network for the laboratory mouse and a state-of-the-art machine learning method. We demonstrate the superior accuracy of this algorithm through predicting genes associated with each of 1157 diverse phenotype ontology terms. Comparison between our prediction results and a meta-analysis of quantitative genetic studies reveals both overlapping candidates and distinct, accurate predictions uniquely identified by our approach. Focusing on bone mineral density (BMD), a phenotype related to osteoporotic fracture, we experimentally validated two of our novel predictions (not observed in any previous GWAS/QTL studies) and found significant bone density defects for both Timp2 and Abcg8 deficient mice. Our results suggest that the integration of functional genomics data into networks, which itself is informative of protein function and interactions, can successfully be utilized as a complementary approach to quantitative genetics to predict disease risks. All supplementary material is available at http://cbfg.jax.org/phenotype. PMID:21085640

Guan, Yuanfang; Ackert-Bicknell, Cheryl L; Kell, Braden; Troyanskaya, Olga G; Hibbs, Matthew A

2010-01-01

107

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

108

Large genetic screens for gynogenesis and androgenesis haploid inducers in Arabidopsis thaliana failed to identify mutants  

PubMed Central

Gynogenesis is a process in which the embryo genome originates exclusively from female origin, following embryogenesis stimulation by a male gamete. In contrast, androgenesis is the development of embryos that contain only the male nuclear genetic background. Both phenomena are of great interest in plant breeding as haploidization is an efficient tool to reduce the length of breeding schemes to create varieties. Although few inducer lines have been described, the genetic control of these phenomena is poorly understood. We developed genetic screens to identify mutations that would induce gynogenesis or androgenesis in Arabidopsis thaliana. The ability of mutant pollen to induce either gynogenesis or androgenesis was tested by crossing mutagenized plants as males. Seedlings from these crosses were screened with recessive phenotypic markers, one genetically controlled by the female genome and another by the male genome. Positive and negative controls confirmed the unambiguous detection of both gynogenesis and androgenesis events. This strategy was applied to 1,666 EMS-mutagenised lines and 47 distant Arabidopsis strains. While an internal control suggested that the mutagenesis reached saturation, no gynogenesis or androgenesis inducer was found. However, spontaneous gynogenesis was observed at a frequency of 1/10,800. Altogether, these results suggest that no simple EMS-induced mutation in the male genome is able to induce gynogenesis or androgenesis in Arabidopsis. PMID:25814999

Portemer, Virginie; Renne, Charlotte; Guillebaux, Alexia; Mercier, Raphael

2015-01-01

109

Large genetic screens for gynogenesis and androgenesis haploid inducers in Arabidopsis thaliana failed to identify mutants.  

PubMed

Gynogenesis is a process in which the embryo genome originates exclusively from female origin, following embryogenesis stimulation by a male gamete. In contrast, androgenesis is the development of embryos that contain only the male nuclear genetic background. Both phenomena are of great interest in plant breeding as haploidization is an efficient tool to reduce the length of breeding schemes to create varieties. Although few inducer lines have been described, the genetic control of these phenomena is poorly understood. We developed genetic screens to identify mutations that would induce gynogenesis or androgenesis in Arabidopsis thaliana. The ability of mutant pollen to induce either gynogenesis or androgenesis was tested by crossing mutagenized plants as males. Seedlings from these crosses were screened with recessive phenotypic markers, one genetically controlled by the female genome and another by the male genome. Positive and negative controls confirmed the unambiguous detection of both gynogenesis and androgenesis events. This strategy was applied to 1,666 EMS-mutagenised lines and 47 distant Arabidopsis strains. While an internal control suggested that the mutagenesis reached saturation, no gynogenesis or androgenesis inducer was found. However, spontaneous gynogenesis was observed at a frequency of 1/10,800. Altogether, these results suggest that no simple EMS-induced mutation in the male genome is able to induce gynogenesis or androgenesis in Arabidopsis. PMID:25814999

Portemer, Virginie; Renne, Charlotte; Guillebaux, Alexia; Mercier, Raphael

2015-01-01

110

Expression quantitative trait analyses to identify causal genetic variants for type 2 diabetes susceptibility  

PubMed Central

Type 2 diabetes (T2D) is a common metabolic disorder which is caused by multiple genetic perturbations affecting different biological pathways. Identifying genetic factors modulating the susceptibility of this complex heterogeneous metabolic phenotype in different ethnic and racial groups remains challenging. Despite recent success, the functional role of the T2D susceptibility variants implicated by genome-wide association studies (GWAS) remains largely unknown. Genetic dissection of transcript abundance or expression quantitative trait (eQTL) analysis unravels the genomic architecture of regulatory variants. Availability of eQTL information from tissues relevant for glucose homeostasis in humans opens a new avenue to prioritize GWAS-implicated variants that may be involved in triggering a causal chain of events leading to T2D. In this article, we review the progress made in the field of eQTL research and knowledge gained from those studies in understanding transcription regulatory mechanisms in human subjects. We highlight several novel approaches that can integrate eQTL analysis with multiple layers of biological information to identify ethnic-specific causal variants and gene-environment interactions relevant to T2D pathogenesis. Finally, we discuss how the eQTL analysis mediated search for “missing heritability” may lead us to novel biological and molecular mechanisms involved in susceptibility to T2D. PMID:24748924

Das, Swapan Kumar; Sharma, Neeraj Kumar

2014-01-01

111

Identifying genetic associations with MRI-derived measures via tree-guided sparse learning.  

PubMed

In recent imaging genetic studies, much work has been focused on regression analysis that treats large-scale single nucleotide polymorphisms (SNPs) and quantitative traits (QTs) as association variables. To deal with the weak detection and high-throughput data problem, feature selection methods such as the least absolute shrinkage and selection operator (Lasso) are often used for selecting the most relevant SNPs associated with QTs. However, one problem of Lasso as well as many other feature selection methods for imaging genetics is that some useful prior information, i.e., the hierarchical structure among SNPs throughout the whole genome, are rarely used for designing more powerful model. In this paper, we propose to identify the associations between candidate genetic features (i.e., SNPs) and magnetic resonance imaging (MRI)-derived measures using a tree-guided sparse learning (TGSL) method. The advantage of our method is that it explicitly models the priori hierarchical grouping structure among the SNPs in the objective function for feature selection. Specifically, two kinds of hierarchical structures, i.e., group by gene and group by linkage disequilibrium (LD) clusters, are imposed as a tree-guided regularization term in our sparse learning model. Experimental results on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database show that our method not only achieves better predictions on the two MRI measures (i.e., left and right hippocampal formation), but also identifies the informative SNPs to guide the disease-induced interpretation compared with other reference methods. PMID:25485448

Hao, Xiaoke; Yu, Jintai; Zhang, Daoqiang

2014-01-01

112

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

113

Genetic interactions affecting human gene expression identified by variance association mapping  

PubMed Central

Non-additive interaction between genetic variants, or epistasis, is a possible explanation for the gap between heritability of complex traits and the variation explained by identified genetic loci. Interactions give rise to genotype dependent variance, and therefore the identification of variance quantitative trait loci can be an intermediate step to discover both epistasis and gene by environment effects (GxE). Using RNA-sequence data from lymphoblastoid cell lines (LCLs) from the TwinsUK cohort, we identify a candidate set of 508 variance associated SNPs. Exploiting the twin design we show that GxE plays a role in ?70% of these associations. Further investigation of these loci reveals 57 epistatic interactions that replicated in a smaller dataset, explaining on average 4.3% of phenotypic variance. In 24 cases, more variance is explained by the interaction than their additive contributions. Using molecular phenotypes in this way may provide a route to uncovering genetic interactions underlying more complex traits. DOI: http://dx.doi.org/10.7554/eLife.01381.001 PMID:24771767

Brown, Andrew Anand; Buil, Alfonso; Viñuela, Ana; Lappalainen, Tuuli; Zheng, Hou-Feng; Richards, J Brent; Small, Kerrin S; Spector, Timothy D; Dermitzakis, Emmanouil T; Durbin, Richard

2014-01-01

114

Network-based SNP meta-analysis identifies joint and disjoint genetic features across common human diseases  

PubMed Central

Background Genome-wide association studies (GWAS) have provided a large set of genetic loci influencing the risk for many common diseases. Association studies typically analyze one specific trait in single populations in an isolated fashion without taking into account the potential phenotypic and genetic correlation between traits. However, GWA data can be efficiently used to identify overlapping loci with analogous or contrasting effects on different diseases. Results Here, we describe a new approach to systematically prioritize and interpret available GWA data. We focus on the analysis of joint and disjoint genetic determinants across diseases. Using network analysis, we show that variant-based approaches are superior to locus-based analyses. In addition, we provide a prioritization of disease loci based on network properties and discuss the roles of hub loci across several diseases. We demonstrate that, in general, agonistic associations appear to reflect current disease classifications, and present the potential use of effect sizes in refining and revising these agonistic signals. We further identify potential branching points in disease etiologies based on antagonistic variants and describe plausible small-scale models of the underlying molecular switches. Conclusions The observation that a surprisingly high fraction (>15%) of the SNPs considered in our study are associated both agonistically and antagonistically with related as well as unrelated disorders indicates that the molecular mechanisms influencing causes and progress of human diseases are in part interrelated. Genetic overlaps between two diseases also suggest the importance of the affected entities in the specific pathogenic pathways and should be investigated further. PMID:22988944

2012-01-01

115

A novel method of identifying genetic mutations using an electrochemical DNA array  

PubMed Central

We describe the development of a new type of DNA array chip that utilizes electrochemical reactions and a novel method of simultaneously identifying multiple genetic mutations on an array chip. The electrochemical array (ECA) uses a threading intercalator specific to double-stranded nucleotides, ferrocenylnaphthalene diimide (FND), as the indicator. ECA does not require target labeling, and the equipment is simple, durable and less expensive. The simultaneous multiple mutation detection (SMMD) system using an ECA chip and FND utilizes an enzyme to simultaneously distinguish several genetic mutations such as single nucleotide polymorphism (SNP), insertion, deletion, translocation and short tandem repeat. We examined this SMMD system using an ECA chip, by detecting seven different mutations on the lipoprotein lipase (LPL) gene for 50 patients in a blind test. It turned out that all the results obtained were concordant with the sequencing results, demonstrating that this system is a powerful tool for clinical applications. PMID:15498924

Wakai, Junko; Takagi, Atsuko; Nakayama, Masato; Miya, Takahito; Miyahara, Takatoshi; Iwanaga, Tsuyoshi; Takenaka, Shigeori; Ikeda, Yasuyuki; Amano, Masahiko

2004-01-01

116

A novel method of identifying genetic mutations using an electrochemical DNA array.  

PubMed

We describe the development of a new type of DNA array chip that utilizes electrochemical reactions and a novel method of simultaneously identifying multiple genetic mutations on an array chip. The electrochemical array (ECA) uses a threading intercalator specific to double-stranded nucleotides, ferrocenylnaphthalene diimide (FND), as the indicator. ECA does not require target labeling, and the equipment is simple, durable and less expensive. The simultaneous multiple mutation detection (SMMD) system using an ECA chip and FND utilizes an enzyme to simultaneously distinguish several genetic mutations such as single nucleotide polymorphism (SNP), insertion, deletion, translocation and short tandem repeat. We examined this SMMD system using an ECA chip, by detecting seven different mutations on the lipoprotein lipase (LPL) gene for 50 patients in a blind test. It turned out that all the results obtained were concordant with the sequencing results, demonstrating that this system is a powerful tool for clinical applications. PMID:15498924

Wakai, Junko; Takagi, Atsuko; Nakayama, Masato; Miya, Takahito; Miyahara, Takatoshi; Iwanaga, Tsuyoshi; Takenaka, Shigeori; Ikeda, Yasuyuki; Amano, Masahiko; Urata, Tomohiro

2004-01-01

117

Mapping genetic determinants of coronary microvascular remodeling in the spontaneously hypertensive rat.  

PubMed

The mechanisms underlying coronary microvascular remodeling and dysfunction, which are critical determinants of abnormal myocardial blood flow regulation in human hypertension, are poorly understood. The spontaneously hypertensive rat (SHR) exhibits many features of human hypertensive cardiomyopathy. We demonstrate that remodeling of intramural coronary arterioles is apparent in the SHR already at 4 weeks of age, i.e. before the onset of systemic hypertension. To uncover possible genetic determinants of coronary microvascular remodeling, we carried out detailed histological and histomorphometric analysis of the heart and coronary vasculature in 30 weeks old SHR, age-matched Brown Norway (BN-Lx) parentals and BXH/HXB recombinant inbred (RI) strains. Using previously mapped expression quantitative trait loci (eQTLs), we carried out a genome-wide association analysis between genetic determinants of cardiac gene expression and histomorphometric traits. This identified 36 robustly mapped eQTLs in the heart which were associated with medial area of intramural coronary arterioles [false discovery rate (FDR) ~5%]. Transcripts, which were both under cis-acting genetic regulation and significantly correlated with medial area (FDR <5%), but not with blood pressure indices, were prioritized and four candidate genes were identified (Rtel1, Pla2g5, Dnaja4 and Rcn2) according to their expression levels and biological functions. Our results demonstrate that genetic factors play a role in the development of coronary microvascular remodeling and suggest blood pressure independent candidate genes for further functional experiments. PMID:23197152

Mancini, Massimiliano; Petretto, Enrico; Kleinert, Christina; Scavone, Angela; De, Tisham; Cook, Stuart; Silhavy, Jan; Zidek, Vaclav; Pravenec, Michal; d'Amati, Giulia; Camici, Paolo G

2013-01-01

118

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

119

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

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

2013-01-01

120

Non-genetic determinants of mosquito competence for malaria parasites.  

PubMed

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

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

2013-01-01

121

Neural Basis of Genetically Determined Visuospatial Construction Deficit in Williams Syndrome  

Microsoft Academic Search

A unique opportunity to understand genetic determinants of cognition is offered by Williams syndrome (WS), a well-characterized hemideletion on chromosome 7q11.23 that causes extreme, specific weakness in visuospatial construction (the ability to visualize an object as a set of parts or construct a replica). Using multimodal neuroimaging, we identified a neural mechanism underlying the WS visuoconstructive deficit. Hierarchical assessment of

Andreas Meyer-Lindenberg; Philip Kohn; Carolyn B. Mervis; J. Shane Kippenhan; Rosanna K. Olsen; Colleen A. Morris; Karen Faith Berman

2004-01-01

122

Genetically Determined Protein Polymorphism in the Rabbit Nervous System  

Microsoft Academic Search

One of the polypeptides (H1) of the rabbit nervous system occurs in an altered form (H2) in some rabbits. The electrophoretic mobility of H2 on sodium dodecyl sulfate-polyacrylamide gels is about 6% greater than that of H1, suggesting that the two polypeptides differ in molecular weight by about 10,000. The alteration is genetically determined since (i) rabbit phenotypes corresponding to

Mark B. Willard

1976-01-01

123

Genetic associations with micronutrient levels identified in immune and gastrointestinal networks.  

PubMed

The discovery of vitamins and clarification of their role in preventing frank essential nutrient deficiencies occurred in the early 1900s. Much vitamin research has understandably focused on public health and the effects of single nutrients to alleviate acute conditions. The physiological processes for maintaining health, however, are complex systems that depend upon interactions between multiple nutrients, environmental factors, and genetic makeup. To analyze the relationship between these factors and nutritional health, data were obtained from an observational, community-based participatory research program of children and teens (age 6-14) enrolled in a summer day camp in the Delta region of Arkansas. Assessments of erythrocyte S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), plasma homocysteine (Hcy) and 6 organic micronutrients (retinol, 25-hydroxy vitamin D3, pyridoxal, thiamin, riboflavin, and vitamin E), and 1,129 plasma proteins were performed at 3 time points in each of 2 years. Genetic makeup was analyzed with 1 M SNP genotyping arrays, and nutrient status was assessed with 24-h dietary intake questionnaires. A pattern of metabolites (met_PC1) that included the ratio of erythrocyte SAM/SAH, Hcy, and 5 vitamins were identified by principal component analysis. Met_PC1 levels were significantly associated with (1) single-nucleotide polymorphisms, (2) levels of plasma proteins, and (3) multilocus genotypes coding for gastrointestinal and immune functions, as identified in a global network of metabolic/protein-protein interactions. Subsequent mining of data from curated pathway, network, and genome-wide association studies identified genetic and functional relationships that may be explained by gene-nutrient interactions. The systems nutrition strategy described here has thus associated a multivariate metabolite pattern in blood with genes involved in immune and gastrointestinal functions. PMID:24879315

Morine, Melissa J; Monteiro, Jacqueline Pontes; Wise, Carolyn; Teitel, Candee; Pence, Lisa; Williams, Anna; Ning, Baitang; McCabe-Sellers, Beverly; Champagne, Catherine; Turner, Jerome; Shelby, Beatrice; Bogle, Margaret; Beger, Richard D; Priami, Corrado; Kaput, Jim

2014-07-01

124

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.

125

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.

126

Use of a twin dataset to identify AMD-related visual patterns controlled by genetic factors  

NASA Astrophysics Data System (ADS)

The mapping of genotype to the phenotype of age-related macular degeneration (AMD) is expected to improve the diagnosis and treatment of the disease in a near future. In this study, we focused on the first step to discover this mapping: we identified visual patterns related to AMD which seem to be controlled by genetic factors, without explicitly relating them to the genes. For this purpose, we used a dataset of eye fundus photographs from 74 twin pairs, either monozygotic twins, who have the same genotype, or dizygotic twins, whose genes responsible for AMD are less likely to be identical. If we are able to differentiate monozygotic twins from dizygotic twins, based on a given visual pattern, then this pattern is likely to be controlled by genetic factors. The main visible consequence of AMD is the apparition of drusen between the retinal pigment epithelium and Bruch's membrane. We developed two automated drusen detectors based on the wavelet transform: a shape-based detector for hard drusen, and a texture- and color- based detector for soft drusen. Forty visual features were evaluated at the location of the automatically detected drusen. These features characterize the texture, the shape, the color, the spatial distribution, or the amount of drusen. A distance measure between twin pairs was defined for each visual feature; a smaller distance should be measured between monozygotic twins for visual features controlled by genetic factors. The predictions of several visual features (75.7% accuracy) are comparable or better than the predictions of human experts.

Quellec, Gwénolé; Abràmoff, Michael D.; Russell, Stephen R.

2010-03-01

127

Using multilevel models to identify drivers of landscape-genetic structure among management areas.  

PubMed

Landscape genetics offers a powerful approach to understanding species' dispersal patterns. However, a central obstacle is to account for ecological processes operating at multiple spatial scales, while keeping research outcomes applicable to conservation management. We address this challenge by applying a novel multilevel regression approach to model landscape drivers of genetic structure at both the resolution of individuals and at a spatial resolution relevant to management (i.e. local government management areas: LGAs) for the koala (Phascolartos cinereus) in Australia. Our approach allows for the simultaneous incorporation of drivers of landscape-genetic relationships operating at multiple spatial resolutions. Using microsatellite data for 1106 koalas, we show that, at the individual resolution, foliage projective cover (FPC) facilitates high gene flow (i.e. low resistance) until it falls below approximately 30%. Out of six additional land-cover variables, only highways and freeways further explained genetic distance after accounting for the effect of FPC. At the LGA resolution, there was significant variation in isolation-by-resistance (IBR) relationships in terms of their slopes and intercepts. This was predominantly explained by the average resistance distance among LGAs, with a weaker effect of historical forest cover. Rates of recent landscape change did not further explain variation in IBR relationships among LGAs. By using a novel multilevel model, we disentangle the effect of landscape resistance on gene flow at the fine resolution (i.e. among individuals) from effects occurring at coarser resolutions (i.e. among LGAs). This has important implications for our ability to identify appropriate scale-dependent management actions. PMID:23730800

Dudaniec, Rachael Y; Rhodes, Jonathan R; Worthington Wilmer, Jessica; Lyons, Mitchell; Lee, Kristen E; McAlpine, Clive A; Carrick, Frank N

2013-07-01

128

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

129

Genetic Mapping and Exome Sequencing Identify Variants Associated with Five Novel Diseases  

PubMed Central

The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean?=?4.4 Mb) that contain many genes (mean?=?79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data. PMID:22279524

Puffenberger, Erik G.; Jinks, Robert N.; Sougnez, Carrie; Cibulskis, Kristian; Willert, Rebecca A.; Achilly, Nathan P.; Cassidy, Ryan P.; Fiorentini, Christopher J.; Heiken, Kory F.; Lawrence, Johnny J.; Mahoney, Molly H.; Miller, Christopher J.; Nair, Devika T.; Politi, Kristin A.; Worcester, Kimberly N.; Setton, Roni A.; DiPiazza, Rosa; Sherman, Eric A.; Eastman, James T.; Francklyn, Christopher; Robey-Bond, Susan; Rider, Nicholas L.; Gabriel, Stacey; Morton, D. Holmes; Strauss, Kevin A.

2012-01-01

130

Identifying Host Genetic Risk Factors in the Context of Public Health Surveillance for Invasive Pneumococcal Disease  

PubMed Central

Host genetic factors that modify risk of pneumococcal disease may help target future public health interventions to individuals at highest risk of disease. We linked data from population-based surveillance for invasive pneumococcal disease (IPD) with state-based newborn dried bloodspot repositories to identify biological samples from individuals who developed invasive pneumococcal disease. Genomic DNA was extracted from 366 case and 732 anonymous control samples. TagSNPs were selected in 34 candidate genes thought to be associated with host response to invasive pneumococcal disease, and a total of 326 variants were successfully genotyped. Among 543 European Americans (EA) (182 cases and 361 controls), and 166 African Americans (AA) (53 cases and 113 controls), common variants in surfactant protein D (SFTPD) are consistently underrepresented in IPD. SFTPD variants with the strongest association for IPD are intronic rs17886286 (allelic OR 0.45, 95% confidence interval (CI) [0.25, 0.82], with p?=?0.007) in EA and 5? flanking rs12219080 (allelic OR 0.32, 95%CI [0.13, 0.78], with p?=?0.009) in AA. Variants in CD46 and IL1R1 are also associated with IPD in both EA and AA, but with effects in different directions; FAS, IL1B, IL4, IL10, IL12B, SFTPA1, SFTPB, and PTAFR variants are associated (p?0.05) with IPD in EA or AA. We conclude that variants in SFTPD may protect against IPD in EA and AA and genetic variation in other host response pathways may also contribute to risk of IPD. While our associations are not corrected for multiple comparisons and therefore must be replicated in additional cohorts, this pilot study underscores the feasibility of integrating public health surveillance with existing, prospectively collected, newborn dried blood spot repositories to identify host genetic factors associated with infectious diseases. PMID:21858107

Zimmer, Shanta M.; Lynfield, Ruth; McNicholl, Janet M.; Messonnier, Nancy E.; Whitney, Cynthia G.; Crawford, Dana C.

2011-01-01

131

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

132

Genetic determinants of aggression and impulsivity in humans.  

PubMed

Human aggression/impulsivity-related traits have a complex background that is greatly influenced by genetic and non-genetic factors. The relationship between aggression and anxiety is regulated by highly conserved brain regions including amygdala, which controls neural circuits triggering defensive, aggressive, or avoidant behavioral models. The dysfunction of neural circuits responsible for emotional control was shown to represent an etiological factor of violent behavior. In addition to the amygdala, these circuits also involve the anterior cingulated cortex and regions of the prefrontal cortex. Excessive reactivity in the amygdala coupled with inadequate prefrontal regulation serves to increase the likelihood of aggressive behavior. Developmental alterations in prefrontal-subcortical circuitry as well as neuromodulatory and hormonal abnormality appear to play a role. Imbalance in testosterone/serotonin and testosterone/cortisol ratios (e.g., increased testosterone levels and reduced cortisol levels) increases the propensity toward aggression because of reduced activation of the neural circuitry of impulse control and self-regulation. Serotonin facilitates prefrontal inhibition, and thus insufficient serotonergic activity can enhance aggression. Genetic predisposition to aggression appears to be deeply affected by the polymorphic genetic variants of the serotoninergic system that influences serotonin levels in the central and peripheral nervous system, biological effects of this hormone, and rate of serotonin production, synaptic release and degradation. Among these variants, functional polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (5-HTT) may be of particular importance due to the relationship between these polymorphic variants and anatomical changes in the limbic system of aggressive people. Furthermore, functional variants of MAOA and 5-HTT are capable of mediating the influence of environmental factors on aggression-related traits. In this review, we consider genetic determinants of human aggression, with special emphasis on genes involved in serotonin and dopamine metabolism and function. PMID:21994088

Pavlov, Konstantin A; Chistiakov, Dimitry A; Chekhonin, Vladimir P

2012-02-01

133

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.

134

Release of genetically engineered insects: a framework to identify potential ecological effects  

PubMed Central

Genetically engineered (GE) insects have the potential to radically change pest management worldwide. With recent approvals of GE insect releases, there is a need for a synthesized framework to evaluate their potential ecological and evolutionary effects. The effects may occur in two phases: a transitory phase when the focal population changes in density, and a steady state phase when it reaches a new, constant density. We review potential effects of a rapid change in insect density related to population outbreaks, biological control, invasive species, and other GE organisms to identify a comprehensive list of potential ecological and evolutionary effects of GE insect releases. We apply this framework to the Anopheles gambiae mosquito – a malaria vector being engineered to suppress the wild mosquito population – to identify effects that may occur during the transitory and steady state phases after release. Our methodology reveals many potential effects in each phase, perhaps most notably those dealing with immunity in the transitory phase, and with pathogen and vector evolution in the steady state phase. Importantly, this framework identifies knowledge gaps in mosquito ecology. Identifying effects in the transitory and steady state phases allows more rigorous identification of the potential ecological effects of GE insect release. PMID:24198955

David, Aaron S; Kaser, Joe M; Morey, Amy C; Roth, Alexander M; Andow, David A

2013-01-01

135

Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome.  

PubMed

In many individuals suspected of the common cancer predisposition Lynch syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are identified in one of the DNA mismatch repair (MMR) genes. The uncertainty of whether such VUS inactivate MMR, and therefore are pathogenic, precludes targeted healthcare for both carriers and their relatives. To facilitate the identification of pathogenic VUS, we have developed an in cellulo genetic screen-based procedure for the large-scale mutagenization, identification, and cataloging of residues of MMR genes critical for MMR gene function. When a residue identified as mutated in an individual suspected of Lynch syndrome is listed as critical in such a reverse diagnosis catalog, there is a high probability that the corresponding human VUS is pathogenic. To investigate the applicability of this approach, we have generated and validated a prototypic reverse diagnosis catalog for the MMR gene MutS Homolog 2 (Msh2) by mutagenizing, identifying, and cataloging 26 deleterious mutations in 23 amino acids. Extensive in vivo and in vitro analysis of mutants listed in the catalog revealed both recessive and dominant-negative phenotypes. Nearly half of these critical residues match with VUS previously identified in individuals suspected of Lynch syndrome. This aids in the assignment of pathogenicity to these human VUS and validates the approach described here as a diagnostic tool. In a wider perspective, this work provides a model for the translation of personalized genomics into targeted healthcare. PMID:23690608

Drost, Mark; Lützen, Anne; van Hees, Sandrine; Ferreira, Daniel; Calléja, Fabienne; Zonneveld, José B M; Nielsen, Finn Cilius; Rasmussen, Lene Juel; de Wind, Niels

2013-06-01

136

Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome  

PubMed Central

In many individuals suspected of the common cancer predisposition Lynch syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are identified in one of the DNA mismatch repair (MMR) genes. The uncertainty of whether such VUS inactivate MMR, and therefore are pathogenic, precludes targeted healthcare for both carriers and their relatives. To facilitate the identification of pathogenic VUS, we have developed an in cellulo genetic screen-based procedure for the large-scale mutagenization, identification, and cataloging of residues of MMR genes critical for MMR gene function. When a residue identified as mutated in an individual suspected of Lynch syndrome is listed as critical in such a reverse diagnosis catalog, there is a high probability that the corresponding human VUS is pathogenic. To investigate the applicability of this approach, we have generated and validated a prototypic reverse diagnosis catalog for the MMR gene MutS Homolog 2 (Msh2) by mutagenizing, identifying, and cataloging 26 deleterious mutations in 23 amino acids. Extensive in vivo and in vitro analysis of mutants listed in the catalog revealed both recessive and dominant-negative phenotypes. Nearly half of these critical residues match with VUS previously identified in individuals suspected of Lynch syndrome. This aids in the assignment of pathogenicity to these human VUS and validates the approach described here as a diagnostic tool. In a wider perspective, this work provides a model for the translation of personalized genomics into targeted healthcare. PMID:23690608

Drost, Mark; Lützen, Anne; van Hees, Sandrine; Ferreira, Daniel; Calléja, Fabienne; Zonneveld, José B. M.; Nielsen, Finn Cilius; Rasmussen, Lene Juel; de Wind, Niels

2013-01-01

137

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

PubMed Central

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.

2014-01-01

138

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

139

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

140

Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density.  

PubMed

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

2014-06-01

141

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

142

Genetic determinants for methotrexate response in juvenile idiopathic arthritis  

PubMed Central

Juvenile idiopathic arthritis (JIAs) is the most common chronic rheumatic disease of childhood and is an important cause of disability. The folic acid analog methotrexate is the first choice disease-modifying anti-rheumatic drug in this disease, however, 35–45% of patients fail to respond. Molecular elements, such as variants in genes of pharmacological relevance, influencing response to methotrexate in JIA, would be important to individualize treatment strategies. Several studies have evaluated the effects of candidate genetic variants in the complex pathway of genes involved in methotrexate pharmacodynamics and pharmacokinetics, however, results are still contrasting and no definitive genetic marker of methotrexate response useful for the clinician to tailor therapy of children with JIA has been identified. Recently, genome-wide approaches have been applied, identifying new potential biological processes involved in methotrexate response in JIA such as TGF-beta signaling and calcium channels. If these genomic results are properly validated and integrated with innovative analyses comprising deep sequencing, epigenetics, and pharmacokinetics, they will greatly contribute to personalize therapy with methotrexate in children with JIA. PMID:25852556

Pastore, Serena; Stocco, Gabriele; Favretto, Diego; De Iudicibus, Sara; Taddio, Andrea; d’Adamo, Pio; Malusà, Noelia; Addobbati, Riccardo; Decorti, Giuliana; Lepore, Loredana; Ventura, Alessandro

2015-01-01

143

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

144

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

145

Genetic Determinism and the Innate-Acquired Distinction in Medicine  

PubMed Central

This article illustrates in which sense genetic determinism is still part of the contemporary interactionist consensus in medicine. Three dimensions of this consensus are discussed: kinds of causes, a continuum of traits ranging from monogenetic diseases to car accidents, and different kinds of determination due to different norms of reaction. On this basis, this article explicates in which sense the interactionist consensus presupposes the innate–acquired distinction. After a descriptive Part 1, Part 2 reviews why the innate–acquired distinction is under attack in contemporary philosophy of biology. Three arguments are then presented to provide a limited and pragmatic defense of the distinction: an epistemic, a conceptual, and a historical argument. If interpreted in a certain manner, and if the pragmatic goals of prevention and treatment (ideally specifying what medicine and health care is all about) are taken into account, then the innate–acquired distinction can be a useful epistemic tool. It can help, first, to understand that genetic determination does not mean fatalism, and, second, to maintain a system of checks and balances in the continuing nature–nurture debates. PMID:20234831

2009-01-01

146

Sensitization to Cockroach Allergen: Immune Regulation and Genetic Determinants  

PubMed Central

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. PMID:22272212

Gao, Peisong

2012-01-01

147

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

148

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

149

Molecular genetic approaches for identifying the basis of variation in resistance to tick infestation in cattle.  

PubMed

In recent years there has been renewed interest in the adaptation of cattle to challenging environments, largely driven by advances in genomic methods. The current interest in tick resistance is understandable given the major production and welfare implications of tick infestation in tropical and subtropical zones where around 70% of beef cattle are located. Heritability for tick burden in cattle has been shown to range about 0.30, which is sufficient to result in the success of some programs of selection for tick resistance in cattle. Gene-expression studies strongly indicate that both immune and non-immune mechanisms are associated with tick resistance in cattle. Recent quantitative-trait mapping studies have identified chromosome segments and single nucleotide polymorphisms associated with tick burden, but no causal variant has been identified so far. Most of the genetic markers identified for tick burden explain a relatively small proportion of the variance, which is typical of markers for quantitative traits. This leads to the conclusion that panels of multiple markers for tick resistance rather than a single marker will most likely be developed, possibly involving specific panels for zebu or taurine breeds, which could be used for future selection and breeding programs in cattle. PMID:21700395

Porto Neto, Laercio R; Jonsson, Nicholas N; D'Occhio, Michael J; Barendse, William

2011-08-25

150

A Novel Molecular Signature Identified by Systems Genetics Approach Predicts Prognosis in Oral Squamous Cell Carcinoma  

PubMed Central

Molecular methods for predicting prognosis in patients with oral cavity squamous cell carcinoma (OSCC) are urgently needed, considering its high recurrence rate and tendency for metastasis. The present study investigated the genetic basis of variations in gene expression associated with poor prognosis in OSCC using Affymetrix SNP 6.0 and Affymetrix GeneChip Human Gene 1.0 ST arrays. We identified recurrent DNA amplifications scattered from 8q22.2 to 8q24.3 in 112 OSCC specimens. These amplicons demonstrated significant associations with increased incidence of extracapsular spread, development of second primary malignancies, and poor survival. Fluorescence in situ hybridization, in a validation panel consisting of 295 cases, confirmed these associations. Assessment of the effects of copy number variations (CNVs) on genome-wide variations in gene expression identified a total of 85 CNV-associated transcripts enriched in the MYC-centered regulatory network. Twenty-four transcripts associated with increased risk of second primary malignancies, tumor relapse, and poor survival. Besides MYC itself, a novel dysregulated MYC module plays a key role in OSCC carcinogenesis. This study identified a candidate molecular signature associated with poor prognosis in OSCC patients, which may ultimately facilitate patient-tailored selection of therapeutic strategies. PMID:21853135

Peng, Shih-Chi; Chen, Yin-Ju; Cheng, Ann-Joy; Juang, Jyh-Lyh; Tsai, Chi-Ying; Chen, Tse-Ching; Chuang, Yung-Jen; Tang, Chuan-Yi; Hsieh, Wen-Ping; Yen, Tzu-Chen

2011-01-01

151

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

152

Psoriasis Regression Analysis of MHC Loci Identifies Shared Genetic Variants with Vitiligo  

PubMed Central

Psoriasis is a common inflammatory skin disease with genetic components of both immune system and the epidermis. PSOR1 locus (6q21) has been strongly associated with psoriasis; however, it is difficult to identify additional independent association due to strong linkage disequilibrium in the MHC region. We performed stepwise regression analyses of more than 3,000 SNPs in the MHC region genotyped using Human 610-Quad (Illumina) in 1,139 cases with psoriasis and 1,132 controls of Han Chinese population to search for additional independent association. With four regression models obtained, two SNPs rs9468925 in HLA-C/HLA-B and rs2858881 in HLA-DQA2 were repeatedly selected in all models, suggesting that multiple loci outside PSOR1 locus were associated with psoriasis. More importantly we find that rs9468925 in HLA-C/HLA-B is associated with both psoriasis and vitiligo, providing first important evidence that two major skin diseases share a common genetic locus in the MHC, and a basis for elucidating the molecular mechanism of skin disorders. PMID:22125590

Yin, Xian-Yong; Wang, Zai-Xing; Sun, Liang-Dan; He, Su-Min; Cheng, Hui; Hu, Da-Yan; Zhang, Zheng; Li, Yang; Zuo, Xian-Bo; Zhou, You-Wen; Yang, Sen; Fan, Xing; Zhang, Xue-Jun; Zhang, Feng-Yu

2011-01-01

153

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

154

Identifying Genetic Variants for Heart Rate Variability in the Acetylcholine Pathway  

PubMed Central

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; Muñoz, 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

155

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

156

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

157

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

158

Yeast Augmented Network Analysis (YANA): a new systems approach to identify therapeutic targets for human genetic diseases  

PubMed Central

Genetic interaction networks that underlie most human diseases are highly complex and poorly defined. Better-defined networks will allow identification of a greater number of therapeutic targets. Here we introduce our Yeast Augmented Network Analysis (YANA) approach and test it with the X-linked spinal muscular atrophy (SMA) disease gene UBA1. First, we express UBA1 and a mutant variant in fission yeast and use high-throughput methods to identify fission yeast genetic modifiers of UBA1. Second, we analyze available protein-protein interaction network databases in both fission yeast and human to construct UBA1 genetic networks. Third, from these networks we identified potential therapeutic targets for SMA. Finally, we validate one of these targets in a vertebrate (zebrafish) SMA model. This study demonstrates the power of combining synthetic and chemical genetics with a simple model system to identify human disease gene networks that can be exploited for treating human diseases. PMID:25075304

Wiley, David J.; Juan, Ilona; Le, Hao; Cai, Xiaodong; Baumbach, Lisa; Beattie, Christine; D'Urso, Gennaro

2014-01-01

159

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

160

Genetic and expression analysis of cattle identifies candidate genes in pathways responding to Trypanosoma congolense infection  

PubMed Central

African bovine trypanosomiasis caused by Trypanosoma sp., is a major constraint on cattle productivity in sub-Saharan Africa. Some African Bos taurus breeds are highly tolerant of infection, but the potentially more productive Bos indicus zebu breeds are much more susceptible. Zebu cattle are well adapted for plowing and haulage, and increasing their tolerance of trypanosomiasis could have a major impact on crop cultivation as well as dairy and beef production. We used three strategies to obtain short lists of candidate genes within QTL that were previously shown to regulate response to infection. We analyzed the transcriptomes of trypanotolerant N'Dama and susceptible Boran cattle after infection with Trypanosoma congolense. We sequenced EST libraries from these two breeds to identify polymorphisms that might underlie previously identified quantitative trait loci (QTL), and we assessed QTL regions and candidate loci for evidence of selective sweeps. The scan of the EST sequences identified a previously undescribed polymorphism in ARHGAP15 in the Bta2 trypanotolerance QTL. The polymorphism affects gene function in vitro and could contribute to the observed differences in expression of the MAPK pathway in vivo. The expression data showed that TLR and MAPK pathways responded to infection, and the former contained TICAM1, which is within a QTL on Bta7. Genetic analyses showed that selective sweeps had occurred at TICAM1 and ARHGAP15 loci in African taurine cattle, making them strong candidates for the genes underlying the QTL. Candidate QTL genes were identified in other QTL by their expression profile and the pathways in which they participate. PMID:21593421

Noyes, Harry; Brass, Andy; Obara, Isaiah; Anderson, Susan; Archibald, Alan L.; Bradley, Dan G.; Fisher, Paul; Freeman, Abigail; Gibson, John; Gicheru, Michael; Hall, Laurence; Hanotte, Olivier; Hulme, Helen; McKeever, Declan; Murray, Caitriona; Oh, Sung Jung; Tate, Catriona; Smith, Ken; Tapio, Miika; Wambugu, John; Williams, Diana J.; Agaba, Morris; Kemp, Stephen J.

2011-01-01

161

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

162

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, Tõnu; 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, Håkon 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, Guðny; Elderson, Martin F; Eriksson, Johan G; Evans, David M; Faul, Jessica D; Ferrucci, Luigi; Garcia, Melissa E; Grönberg, Henrik; Guðnason, 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

163

Genetic determinants influencing human serum metabolome among African Americans.  

PubMed

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

2014-03-01

164

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

165

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

166

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

167

A molecular genetic linkage map identifying the St and H subgenomes of Elymus (Poaceae: Triticeae) wheatgrass.  

PubMed

Elymus L. is the largest and most complex genus in the Triticeae tribe of grasses with approximately 150 polyploid perennial 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 River wheatgrass) and rhizomatous Elymus lanceolatus (EL) (thickspike wheatgrass) to produce F(1) interspecific hybrids that were then backcrossed to the same EL male to generate progeny with segregating phenotypes. EW and EL are both allotetraploid species (n = 14) containing the St (Pseudoroegneria) and H (Hordeum) genomes. A total of 387 backcross progeny from four populations were genotyped using 399 AFLP and 116 EST-based SSR and STS markers. The resulting consensus map was 2574 cM in length apportioned among the expected number of 14 linkage groups. EST-based SSR and STS markers with homology to rice genome sequences were used to identify Elymus linkage groups homoeologous to chromosomes 1-7 of wheat. The frequency of St-derived genome markers on each linkage group was used to assign genome designations to all linkage groups, resulting in the identification of the seven St and seven H linkage groups of Elymus. This map also confirms the alloploidy and disomic chromosome pairing and segregation of Elymus and will be useful in identifying QTLs controlling perennial grass traits in this genus. PMID:21942400

Mott, Ivan W; Larson, Steven R; Jones, Thomas A; Robins, Joseph G; Jensen, Kevin B; Peel, Michael D

2011-10-01

168

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

169

Genetic Determinants of Serum Testosterone Concentrations in Men  

PubMed Central

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n?=?871) and two de novo replication cohorts (n?=?4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p?=?1.2×10?41 and rs6258, p?=?2.3×10?22). Subjects with ?3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p?=?5.6×10?16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation. PMID:21998597

Maggio, Marcello; Coviello, Andrea D.; Ferrucci, Luigi; Heier, Margit; Hofman, Albert; Holliday, Kate L.; Jansson, John-Olov; Kähönen, Mika; Karasik, David; Karlsson, Magnus K.; Kiel, Douglas P.; Liu, Yongmei; Ljunggren, Östen; Lorentzon, Mattias; Lyytikäinen, Leo-Pekka; Meitinger, Thomas; Mellström, Dan; Melzer, David; Miljkovic, Iva; Nauck, Matthias; Nilsson, Maria; Penninx, Brenda; Pye, Stephen R.; Vasan, Ramachandran S.; Reincke, Martin; Rivadeneira, Fernando; Tajar, Abdelouahid; Teumer, Alexander; Uitterlinden, André G.; Ulloor, Jagadish; Viikari, Jorma; Völker, Uwe; Völzke, Henry; Wichmann, H. Erich; Wu, Tsung-Sheng; Zhuang, Wei Vivian; Ziv, Elad; Wu, Frederick C. W.; Raitakari, Olli; Eriksson, Anna; Bidlingmaier, Martin; Harris, Tamara B.; Murray, Anna; de Jong, Frank H.; Murabito, Joanne M.; Bhasin, Shalender; Vandenput, Liesbeth; Haring, Robin

2011-01-01

170

Genetic determinants of serum testosterone concentrations in men.  

PubMed

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n?=?871) and two de novo replication cohorts (n?=?4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p?=?1.2×10(-41) and rs6258, p?=?2.3×10(-22)). Subjects with ? 3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p?=?5.6×10(-16)). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation. PMID:21998597

Ohlsson, Claes; Wallaschofski, Henri; Lunetta, Kathryn L; Stolk, Lisette; Perry, John R B; Koster, Annemarie; Petersen, Ann-Kristin; Eriksson, Joel; Lehtimäki, Terho; Huhtaniemi, Ilpo T; Hammond, Geoffrey L; Maggio, Marcello; Coviello, Andrea D; Ferrucci, Luigi; Heier, Margit; Hofman, Albert; Holliday, Kate L; Jansson, John-Olov; Kähönen, Mika; Karasik, David; Karlsson, Magnus K; Kiel, Douglas P; Liu, Yongmei; Ljunggren, Osten; Lorentzon, Mattias; Lyytikäinen, Leo-Pekka; Meitinger, Thomas; Mellström, Dan; Melzer, David; Miljkovic, Iva; Nauck, Matthias; Nilsson, Maria; Penninx, Brenda; Pye, Stephen R; Vasan, Ramachandran S; Reincke, Martin; Rivadeneira, Fernando; Tajar, Abdelouahid; Teumer, Alexander; Uitterlinden, André G; Ulloor, Jagadish; Viikari, Jorma; Völker, Uwe; Völzke, Henry; Wichmann, H Erich; Wu, Tsung-Sheng; Zhuang, Wei Vivian; Ziv, Elad; Wu, Frederick C W; Raitakari, Olli; Eriksson, Anna; Bidlingmaier, Martin; Harris, Tamara B; Murray, Anna; de Jong, Frank H; Murabito, Joanne M; Bhasin, Shalender; Vandenput, Liesbeth; Haring, Robin

2011-10-01

171

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

172

Cellular and network mechanisms of genetically-determined absence seizures  

PubMed Central

The absence epilepsies are characterized by recurrent episodes of loss of consciousness associated with generalized spike-and-wave discharges, with an abrupt onset and offset, in the thalamocortical system. In the absence of detailed neurophysiological studies in humans, many of the concepts regarding the pathophysiological basis of absence seizures are based on studies in animal models. Each of these models has its particular strengths and limitations, and the validity of findings from these models for the human condition cannot be assumed. Consequently, studies in different models have produced some conflicting findings and conclusions. A long-standing concept, based primarily from studies in vivo in cats and in vitro brain slices, is that these paroxysmal electrical events develop suddenly from sleep-related spindle oscillations. More specifically, it is proposed that the initial mechanisms that underlie absence-related spike-and-wave discharges are located in the thalamus, involving especially the thalamic reticular nucleus. By contrast, more recent studies in well-established, genetic models of absence epilepsy in rats demonstrate that spike-and-wave discharges originate in a cortical focus and develop from a wake-related natural corticothalamic sensorimotor rhythm. In this review we integrate recent findings showing that, in both the thalamus and the neocortex, genetically-determined, absence-related spike-and-wave discharges are the manifestation of hypersynchronized, cellular, rhythmic excitations and inhibitions that result from a combination of complex, intrinsic, synaptic mechanisms. Arguments are put forward supporting the hypothesis that layer VI corticothalamic neurons act as ‘drivers’ in the generation of spike-and-wave discharges in the somatosensory thalamocortical system that result in corticothalamic resonances particularly initially involving the thalamic reticular nucleus. However an important unresolved question is: what are the cellular and network mechanisms responsible for the switch from physiological, wake-related, natural oscillations into pathological spike-and-wave discharges? We speculate on possible answers to this, building particularly on recent findings from genetic models in rats. PMID:21909233

Pinault, Didier; O'Brien, Terence J.

2005-01-01

173

Identifying Genetic Susceptibility to Sensitization to Cephalosporins in Health Care Workers  

PubMed Central

Exposure to cephalosporins could cause occupational allergic diseases in health care workers (HCWs). We evaluated the prevalence of serum specific IgE and IgG antibodies to cephalosporin-human serum albumin (HSA) conjugate and to identify potential genetic risk factors associated with sensitization to cephalosporins in exposed HCWs. The study population consisted of 153 HCWs who had been exposed to antibiotics in a single university hospital and 86 unexposed healthy controls. A questionnaire survey of work-related symptoms (WRS) was administered. A skin-prick test (SPT) was performed, and serum-specific IgE and IgG antibodies to 3 commonly prescribed cephalosporins were measured by ELISA. Four single-nucleotide polymorphisms of the candidate genes related to IgE sensitization were genotyped. The prevalence of WRS to cephalosporins was 2.6%. The prevalence rates of serum-specific IgE and IgG antibodies to cephalosporins were 20.3% and 14.7%, respectively. The Fc?R1?-109T > C polymorphism was significantly associated with IgE sensitization to cephalosporins in HCWs (P = 0.036, OR = 3.553; CI, 1.324-9.532). The in vitro functional assay demonstrated that the T allele of Fc?R1?-109T had greater promoter activity than did the C allele (P < 0.001). The Fc?R1?-109T > C polymorphism may be a potential genetic risk factor for increased IgE sensitization to cephalosporins. PMID:23166408

Nam, Young-Hee; Kim, Jeong-Eun; Kim, Seung-Hyun; Jin, Hyun Jung; Hwang, Eui-Kyung; Shin, Yoo-Seob; Ye, Young-Min

2012-01-01

174

An exploration of the communication preferences regarding genetic testing in individuals from families with identified breast\\/ovarian cancer mutations  

Microsoft Academic Search

The responsibility for informing at-risk relatives of the availability of genetic testing for breast\\/ovarian cancer gene (BRCA1\\u000a or BRCA2) mutations currently falls on the probands. This study explored the support needs of individuals from families with\\u000a identified BRCA1 or BRCA2 mutations when communicating about genetic risk and genetic testing with at-risk family members.\\u000a Thirty-nine semi-structured telephone interviews were conducted with

Paboda Ratnayake; Claire E. Wakefield; Bettina Meiser; Graeme Suthers; Melanie A. Price; Jessica Duffy; Kathy Tucker

2011-01-01

175

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

176

Identification of genetic elements that autonomously determine DNA methylation states.  

PubMed

Cytosine methylation is a repressive, epigenetically propagated DNA modification. Although patterns of DNA methylation seem tightly regulated in mammals, it is unclear how these are specified and to what extent this process entails genetic or epigenetic regulation. To dissect the role of the underlying DNA sequence, we sequentially inserted over 50 different DNA elements into the same genomic locus in mouse stem cells. Promoter sequences of approximately 1,000 bp autonomously recapitulated correct DNA methylation in pluripotent cells. Moreover, they supported proper de novo methylation during differentiation. Truncation analysis revealed that this regulatory potential is contained within small methylation-determining regions (MDRs). MDRs can mediate both hypomethylation and de novo methylation in cis, and their activity depends on developmental state, motifs for DNA-binding factors and a critical CpG density. These results demonstrate that proximal sequence elements are both necessary and sufficient for regulating DNA methylation and reveal basic constraints of this regulation. PMID:21964573

Lienert, Florian; Wirbelauer, Christiane; Som, Indrani; Dean, Ann; Mohn, Fabio; Schübeler, Dirk

2011-11-01

177

Determination of Timed Transitions in Identified Discrete-Event Models for Fault Detection  

E-print Network

Determination of Timed Transitions in Identified Discrete-Event Models for Fault Detection Stefan Schneider1, Lothar Litz1 and Jean-Jacques Lesage2 Abstract-- Model-based fault detection compares modeled. The method identifies a set of time guards leading to an advantageous trade-off between the fault detection

Boyer, Edmond

178

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

179

The genetic architecture of maize (Zea mays L.) kernel weight determination.  

PubMed

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

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

2014-09-01

180

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

181

Environmental and Climatic Determinants of Molecular Diversity and Genetic Population Structure in a Coenagrionid Damselfly  

Microsoft Academic Search

Identifying environmental factors that structure intraspecific genetic diversity is of interest for both habitat preservation and biodiversity conservation. Recent advances in statistical and geographical genetics make it possible to investigate how environmental factors affect geographic organisation and population structure of molecular genetic diversity within species. Here we present a study on a common and wide ranging insect, the blue tailed

Maren Wellenreuther; Rosa A. Sánchez-Guillén; Adolfo Cordero-Rivera; Erik I. Svensson; Bengt Hansson; Daniel Ortiz-Barrientos

2011-01-01

182

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

183

Genomic and Genetic Characterization of Cholangiocarcinoma Identifies Therapeutic Targets for Tyrosine Kinase Inhibitors  

PubMed Central

BACKGROUND & AIMS Cholangiocarcinoma is a heterogeneous disease with a poor outcome that accounts for 5%–10% of primary liver cancers. We characterized its genomic and genetic features and associated these with patient responses to therapy. METHODS We profiled the transcriptomes from 104 surgically resected cholangiocarcinoma samples collected from patients in Australia, Europe, and the United States; epithelial and stromal compartments from 23 tumors were laser capture microdissected. We analyzed mutations in KRAS, epidermal growth factor receptor (EGFR), and BRAF in samples from 69 tumors. Changes in gene expression were validated by immunoblotting and immunohistochemistry; integrative genomics combined data from the patients with data from 7 human cholangiocarcinoma cell lines, which were then exposed to trastuzumab and lapatinib. RESULTS Patients were classified into 2 subclasses, based on 5-year survival rate (72% vs 30%; ?2 = 11.61; P < .0007), time to recurrence (13.7 vs 22.7 months; P < .001), and the absence or presence of KRAS mutations (24.6%), respectively. Class comparison identified 4 survival subgroups (SGI–IV; ?2 = 8.34; P < .03); SGIII was characterized by genes associated with proteasomal activity and the worst prognosis. The tumor epithelium was defined by deregulation of the HER2 network and frequent overexpression of EGFR, the hepatocyte growth factor receptor (MET), pRPS6, and Ki67, whereas stroma was enriched in inflammatory cytokines. Lapatinib, an inhibitor of HER2 and EGFR, was more effective in inhibiting growth of cholangiocarcinoma cell lines than trastuzumab. CONCLUSIONS We provide insight into the pathogenesis of cholangiocarcinoma and identify previously unrecognized subclasses of patients, based on KRAS mutations and increased levels of EGFR and HER2 signaling, who might benefit from dual-target tyrosine kinase inhibitors. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes that regulate proteasome activity, indicating new therapeutic targets. PMID:22178589

Andersen, Jesper B.; Spee, Bart; Blechacz, Boris R.; Avital, Itzhak; Komuta, Mina; Barbour, Andrew; Conner, Elizabeth A.; Gillen, Matthew C.; Roskams, Tania; Roberts, Lewis R.; Factor, Valentina M.; Thorgeirsson, Snorri S.

2012-01-01

184

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

185

Association between GWAS-Identified Genetic Variations and Disease Prognosis for Patients with Colorectal Cancer  

PubMed Central

Genome-wide association studies (GWASs) have already identified at least 22 common susceptibility loci associated with an increased risk of colorectal cancer (CRC). This study examined the relationship between these single nucleotide polymorphisms (SNPs) and the clinical outcomes of patients with colorectal cancer. Seven hundred seventy-six patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. Twenty-two of the GWAS-identified SNPs were genotyped using a Sequenom MassARRAY. Among the 22 SNPs, two (rs1321311G>T in CDKN1A and rs10411210C>T in RHPN2) were significantly associated with the survival outcomes of CRC in a multivariate survival analysis. In a recessive model, the rs1321311 TT genotype (vs. GG + GT) and rs10411210 TT genotype (vs. CC + CT) were associated with a worse prognosis for disease-free survival (adjusted HR = 1.90; 95% confidence interval = 1.00-3.60; P = 0.050, adjusted HR = 1.94; 95% confidence interval = 1.05-3.57; P = 0.034, respectively) and overall survival (adjusted HR = 2.05; 95% confidence interval = 1.00-4.20; P = 0.049, adjusted HR = 2.06; 95% confidence interval = 1.05-4.05; P = 0.036, respectively). None of the other SNPs was significantly associated with any clinicopathologic features or survival. The present results suggest that the genetic variants of the CDKN1A (rs1321311) and RHPN2 (rs10411210) genes can be used as prognostic biomarkers for patients with surgically resected colorectal cancer. PMID:25799222

Chae, Yee Soo; Lee, Soo Jung; Park, Jae Yong; Choi, Jin Eun; Park, Jun Seok; Choi, Gyu Seog; Kim, Jong Gwang

2015-01-01

186

Genetic variants modulating CRIPTO serum levels identified by genome-wide association study in Cilento isolates.  

PubMed

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

187

The genetic architecture of skeletal convergence and sex determination in ninespine sticklebacks  

PubMed Central

SUMMARY The history of life offers plentiful examples of convergent evolution, the independent derivation of similar phenotypes in distinct lineages [1]. Convergent phenotypes among closely related lineages (frequently termed “parallel” evolution) are often assumed to result from changes in similar genes or developmental pathways [2], but the genetic origins of convergence remains poorly understood. Ninespine (Pungitius pungitius) and threespine (Gasterosteus aculeatus) stickleback fish provide many examples of convergent evolution of adaptive phenotypes, both within and between genera. The genetic architecture of several important traits is now known for threespine sticklebacks [3–10]; thus, ninespine sticklebacks thus provide a unique opportunity to critically test whether similar or different chromosome regions control similar phenotypes in these lineages. We have generated the first genome-wide linkage map for the ninespine stickleback and used quantitative trait locus (QTL) mapping to identify chromosome regions controlling several skeletal traits and sex determination. In ninespine sticklebacks, these traits mapped to chromosome regions not previously known to control the corresponding traits in threespine sticklebacks. Therefore, convergent morphological evolution in these related, but independent, vertebrate lineages may have different genetic origins. Comparative genetics in sticklebacks provides an exciting opportunity to study the mechanisms controlling similar phenotypic changes in different groups of animals. PMID:19500990

Shapiro, Michael D.; Summers, Brian R.; Balabhadra, Sarita; Aldenhoven, Jaclyn T.; Miller, Ashley L.; Cunningham, Christopher B.; Bell, Michael A.; Kingsley, David M.

2009-01-01

188

Genetic testing for sporadic hearing loss using targeted massively parallel sequencing identifies 10 novel mutations.  

PubMed

The genetic heterogeneity of non-syndromic hearing loss (NSHL) has hampered the identification of its pathogenic mutations. Several recent studies applied targeted genome enrichment (TGE) and massively parallel sequencing (MPS) to simultaneously screen a large set of known hearing loss (HL) genes. However, most of these studies were focused on familial cases. To evaluate the effectiveness of TGE and MPS on screening sporadic NSHL patients, we recruited 63 unrelated sporadic NSHL probands, who had various levels of HL and were excluded for mutations in GJB2, MT-RNR1, and SLC26A4 genes. TGE and MPS were performed on 131 known HL genes using the Human Deafness Panel oto-DA3 (Otogenetics Corporation., Norcross, GA). We identified 14 pathogenic variants in STRC, CATSPER2, USH2A, TRIOBP, MYO15A, GPR98, and TMPRSS3 genes in eight patients (diagnostic rate?=?12.7%). Among these variants, 10 were novel compound heterozygous mutations. The identification of pathogenic mutations could predict the progression of HL, and guide diagnosis and treatment of the disease. PMID:24853665

Gu, X; Guo, L; Ji, H; Sun, S; Chai, R; Wang, L; Li, H

2014-05-22

189

Common genetic variants associated with cognitive performance identified using the proxy-phenotype method  

PubMed Central

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. PMID:25201988

Rietveld, Cornelius A.; Esko, Tõnu; Davies, Gail; Pers, Tune H.; Turley, Patrick; Benyamin, Beben; Chabris, Christopher F.; Emilsson, Valur; Johnson, Andrew D.; Lee, James J.; de Leeuw, Christiaan; Marioni, Riccardo E.; Medland, Sarah E.; Miller, Michael B.; Rostapshova, Olga; van der Lee, Sven J.; Vinkhuyzen, Anna A. E.; Amin, Najaf; Conley, Dalton; Derringer, Jaime; van Duijn, Cornelia M.; Fehrmann, Rudolf; Franke, Lude; Glaeser, Edward L.; Hansell, Narelle K.; Hayward, Caroline; Iacono, William G.; Ibrahim-Verbaas, Carla; Jaddoe, Vincent; Karjalainen, Juha; Laibson, David; Lichtenstein, Paul; Liewald, David C.; Magnusson, Patrik K. E.; Martin, Nicholas G.; McGue, Matt; McMahon, George; Pedersen, Nancy L.; Pinker, Steven; Porteous, David J.; Posthuma, Danielle; Rivadeneira, Fernando; Smith, Blair H.; Starr, John M.; Tiemeier, Henning; Timpson, Nicholas J.; Trzaskowski, Maciej; Uitterlinden, André G.; Verhulst, Frank C.; Ward, Mary E.; Wright, Margaret J.; Davey Smith, George; Deary, Ian J.; Johannesson, Magnus; Plomin, Robert; Visscher, Peter M.; Benjamin, Daniel J.; Koellinger, Philipp D.

2014-01-01

190

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

191

Polynesian genetic affinities with southeast Asian populations as identified by mtDNA analysis  

SciTech Connect

Polynesian genetic affinities to populations of Asia were studied using mtDNA markers. A total of 1,037 individuals from 12 populations were screened for a 9-bp deletion in the intergenic region between the COII and tRNA{sup Lys}genes that approaches fixation in Polynesians. Sequence-specific oligonucleotide probes that identify specific mtDNA control region nucleotide substitutions were used to describe variation in individuals with the 9-bp deletion. The 9-bp deletion was not observed in northern Indians, Bangladeshis, or Pakistanis but was seen at low to moderate frequencies in the nine other Southeast Asian populations. Three substitutions in the control region at positions 16217, 16247 and 16261 have previously been observed at high frequency in Polynesian mtDNAs; this {open_quotes}Polynesian motif{close_quotes} was observed in 20% of east Indonesians with the 9-bp deletion but was observed in only one additional individual. mtDNA types related to the Polynesian motif are highest in frequency in the corridor from Taiwan south through the Philippines and east Indonesia, and the highest diversity for these types is in Taiwan. These results are consistent with linguistic evidence of a Taiwanese origin for the proto-Polynesian expansion, which spread throughout Oceania by way of Indonesia. 37 refs., 3 figs., 4 tabs.

Melton, T.; Redd, A.J.; Stoneking. M. [Pennsylvania State Univ., University Park, PA (United States)] [and others

1995-08-01

192

Common genetic variants associated with cognitive performance identified using the proxy-phenotype method.  

PubMed

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. PMID:25201988

Rietveld, Cornelius A; Esko, Tõnu; Davies, Gail; Pers, Tune H; Turley, Patrick; Benyamin, Beben; Chabris, Christopher F; Emilsson, Valur; Johnson, Andrew D; Lee, James J; de Leeuw, Christiaan; Marioni, Riccardo E; Medland, Sarah E; Miller, Michael B; Rostapshova, Olga; van der Lee, Sven J; Vinkhuyzen, Anna A E; Amin, Najaf; Conley, Dalton; Derringer, Jaime; van Duijn, Cornelia M; Fehrmann, Rudolf; Franke, Lude; Glaeser, Edward L; Hansell, Narelle K; Hayward, Caroline; Iacono, William G; Ibrahim-Verbaas, Carla; Jaddoe, Vincent; Karjalainen, Juha; Laibson, David; Lichtenstein, Paul; Liewald, David C; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McMahon, George; Pedersen, Nancy L; Pinker, Steven; Porteous, David J; Posthuma, Danielle; Rivadeneira, Fernando; Smith, Blair H; Starr, John M; Tiemeier, Henning; Timpson, Nicholas J; Trzaskowski, Maciej; Uitterlinden, André G; Verhulst, Frank C; Ward, Mary E; Wright, Margaret J; Davey Smith, George; Deary, Ian J; Johannesson, Magnus; Plomin, Robert; Visscher, Peter M; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D

2014-09-23

193

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

194

New de novo Genetic Mutations in Schizophrenia Identified http://scicasts.com/bio/2039-disease-processes/4882-new-de-novo-genetic-mutations-in-schizophrenia-identified[11/12/2012 12:43:09 PM  

E-print Network

New de novo Genetic Mutations in Schizophrenia Identified http://scicasts.com/bio/2039-disease Subscribe Advertise Partner Contact Us Genomics Proteomics Bioresearch Bio-IT Scientific Computing from Down syndrome Cell Line Lab Technology Researchers Model Human Disease in an Organ-on-a- Chip

195

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

196

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

197

Candidate gene approach to identifying rare genetic variants associated with lone atrial fibrillation  

PubMed Central

BACKGROUND Rare variants in candidate atrial fibrillation (AF) genes have been associated with AF in small kindreds. The extent to which such polymorphisms contribute to AF is unknown. OBJECTIVE The purpose of this study was to determine the spectrum and prevalence of rare amino acid coding (AAC) variants in candidate AF genes in a large cohort of unrelated lone AF probands. METHODS We resequenced 45 candidate genes in 303 European American (EA) lone AF probands (186 lone AF probands screened for each gene on average [range 89–303], 63 screened for all) identified in the Vanderbilt AF Registry (2002–2012). Variants detected were screened against 4300 EAs from the Exome Sequencing Project (ESP) to identify very rare (minor allele frequency ? 0.04%) AAC variants and these were tested for AF co-segregation in affected family members where possible. RESULTS Median age at AF onset was 46.0 years [interquartile range 33.0–54.0], and 35.6% had a family history of AF. Overall, 63 very rare AAC variants were identified in 60 of 303 lone AF probands, and 10 of 19 (52.6%) had evidence of co-segregation with AF. Among the 63 lone AF probands who had 45 genes screened, the very rare variant burden was 22%. Compared with the 4300 EA ESP, the proportion of lone AF probands with a very rare AAC variant in CASQ2 and NKX2-5 was increased 3–5-fold (P < .05). CONCLUSION No very rare AAC variants were identified in ~80% of lone AF probands. Potential reasons for the lack of very rare AAC variants include a complex pattern of inheritance, variants in as yet unidentified AF genes or in noncoding regions, and environmental factors. PMID:24120998

Weeke, Peter; Parvez, Babar; Blair, Marcia; Short, Laura; Ingram, Christie; Kucera, Gayle; Stubblefield, Tanya; Roden, Dan M.

2013-01-01

198

Bayesian analysis of genetic associations of skin lesions and behavioural traits to identify genetic components of individual aggressiveness in pigs.  

PubMed

There is increasing interest in genetic selection against behavioural traits that impact negatively on welfare and productivity in commercial livestock production. Post-mixing aggressiveness in pigs shows wide phenotypic variation, affects health, welfare and growth performance and is a routine feature of production. A Bayesian approach was used to estimate the heritability of three traits associated with aggressiveness in pigs during the 24 h post-mixing; duration in reciprocal aggression, and in receipt of, or delivery of non-reciprocal aggression (NRA). For the purposes of genetic selection, recording aggressive behaviour is excessively labour intensive. The genetic correlations were quantified between the behavioural traits and an easily measurable indicator trait; the number of skin lesions following mixing (lesion score, LS). The heritabilities for the three behavioural traits ranged from 0.17 to 0.46 (receipt of NRA and reciprocal aggression respectively). The duration in reciprocal aggression and in delivery of NRA showed a strong genetic correlation (r g = 0.79 with 95% Bayesian credibility interval of 0.62-0.94). The genetic correlation between LS and these two behaviours indicated that selection on breeding values of LS could be used to reduce aggressiveness. The duration in receipt of NRA appeared to be regulated by different genes or genomic effects compared with the other behavioural traits and LS. Although duration in receipt of NRA was not genetically associated with LS, it was lowly but significantly environmentally associated with the residuals of central and caudal LS (r e = 0.28-0.32), indicating that pigs that received NRA also received bites on the central and caudal third of the body. The pen that the animals were mixed into was found to be a very important factor for the analysed traits, in particular those representing behavioural characteristics. Based on the estimated genetic parameters, it is concluded that selection on breeding values for reduced LS (especially central LS) is expected to reduce reciprocal aggression and the delivery of NRA but will not change the receipt of NRA directly. PMID:17987375

Turner, S P; Roehe, R; Mekkawy, W; Farnworth, M J; Knap, P W; Lawrence, A B

2008-01-01

199

Identifying Shared Genetic Structure Patterns among Pacific Northwest Forest Taxa: Insights from Use of Visualization Tools and Computer Simulations  

Microsoft Academic Search

BackgroundIdentifying causal relationships in phylogeographic and landscape genetic investigations is notoriously difficult, but can be facilitated by use of multispecies comparisons.Methodology\\/Principal FindingsWe used data visualizations to identify common spatial patterns within single lineages of four taxa inhabiting Pacific Northwest forests (northern spotted owl: Strix occidentalis caurina; red tree vole: Arborimus longicaudus; southern torrent salamander: Rhyacotriton variegatus; and western white pine:

Mark P. Miller; Susan M. Haig

2010-01-01

200

Determinants of Public Attitudes to Genetically Modified Salmon  

PubMed Central

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

201

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

202

Identifying QTLs for fire-blight resistance via a European pear ( Pyrus communis L.) genetic linkage map  

Microsoft Academic Search

The existence of different levels of susceptibility to fire blight (Erwinia amylovora) in European pear (Pyrus communis L.) cultivars suggests that it is possible to identify QTLs related to resistance in pear germplasm. Given the polygenic nature of this trait, we designed two genetic maps of the parental lines 'Passe Crassane' (susceptible) and 'Harrow Sweet' (resistant) using SSRs, MFLPs, AFLPs,

L. Dondini; L. Pierantoni; F. Gaiotti; R. Chiodini; S. Tartarini; C. Bazzi; S. Sansavini

2005-01-01

203

Am. J. Hum. Genet. 76:349357, 2005 Fine Mapping and Positional Candidate Studies Identify HLA-G  

E-print Network

Am. J. Hum. Genet. 76:349­357, 2005 349 Report Fine Mapping and Positional Candidate Studies Identify HLA-G as an Asthma Susceptibility Gene on Chromosome 6p21 Dan Nicolae,1 Nancy J. Cox,2,3 Lucille A Kogut,3 Nina M. Patel,3 Jeffrey Goodenbour,2 Timothy Howard,7,8 Raoul Wolf,4 Gerard H. Koppelman,11

Das, Soma

204

Mitochondrial genetic variants identified to be associated with posttraumatic stress disorder  

PubMed Central

Despite the fact that mitochondrial dysfunctions are increasingly recognized as key components in stress-related mental disorders, very little is known about the association between posttraumatic stress disorder (PTSD) and mitochondrial variants. To identify susceptibility mitochondrial genes for PTSD, we analyzed a total number of 978 mitochondrial single-nucleotide polymorphisms (mtSNPs) in a sample of 1238 individuals participating in the KORA (Cooperative Health Research in the Region of Augsburg) study. Participants were classified with ‘no PTSD', ‘partial PTSD' or ‘full PTSD' by applying the Posttraumatic Diagnostic Scale and the Impact of Event Scale. To assess PTSD–mtSNP association while taking heteroplasmy into account, we used the raw signal intensity values measured on the microarray and applied linear regression. Significant associations were obtained between full versus no PTSD and two mtSNPs; mt8414C?T (?=?0.954±0.06, Padjusted=0.037) located in adenosine triphosphate (ATP) synthase subunit 8 (MT-ATP8) and mt12501G?A (?=?1.782±0.40, Padjusted=0.015) located in the NADH dehydrogenase subunits 5 (MT-ND5). Heteroplasmy for the two variants towards a larger number of the respective minor alleles increases the risk of having PTSD. NADH dehydrogenase and ATP synthase are both linked to the regulation of reactive oxygen species. Our results highlight the important role of the mitochondrial genome among the factors that contribute to the risk of PTSD. Mitochondrial genetic variants may be more important than has previously been assumed, leading to further insights regarding effects of existing medications, or even to the development of innovative treatments. As this is the first mitochondrial genome-wide association study for PTSDs, further analyses are needed to follow up on the present findings. PMID:25756807

Flaquer, A; Baumbach, C; Ladwig, K-H; Kriebel, J; Waldenberger, M; Grallert, H; Baumert, J; Meitinger, T; Kruse, J; Peters, A; Emeny, R; Strauch, K

2015-01-01

205

Mitochondrial genetic variants identified to be associated with posttraumatic stress disorder.  

PubMed

Despite the fact that mitochondrial dysfunctions are increasingly recognized as key components in stress-related mental disorders, very little is known about the association between posttraumatic stress disorder (PTSD) and mitochondrial variants. To identify susceptibility mitochondrial genes for PTSD, we analyzed a total number of 978 mitochondrial single-nucleotide polymorphisms (mtSNPs) in a sample of 1238 individuals participating in the KORA (Cooperative Health Research in the Region of Augsburg) study. Participants were classified with 'no PTSD', 'partial PTSD' or 'full PTSD' by applying the Posttraumatic Diagnostic Scale and the Impact of Event Scale. To assess PTSD-mtSNP association while taking heteroplasmy into account, we used the raw signal intensity values measured on the microarray and applied linear regression. Significant associations were obtained between full versus no PTSD and two mtSNPs; mt8414C?T (?=-0.954±0.06, Padjusted=0.037) located in adenosine triphosphate (ATP) synthase subunit 8 (MT-ATP8) and mt12501G?A (?=-1.782±0.40, Padjusted=0.015) located in the NADH dehydrogenase subunits 5 (MT-ND5). Heteroplasmy for the two variants towards a larger number of the respective minor alleles increases the risk of having PTSD. NADH dehydrogenase and ATP synthase are both linked to the regulation of reactive oxygen species. Our results highlight the important role of the mitochondrial genome among the factors that contribute to the risk of PTSD. Mitochondrial genetic variants may be more important than has previously been assumed, leading to further insights regarding effects of existing medications, or even to the development of innovative treatments. As this is the first mitochondrial genome-wide association study for PTSDs, further analyses are needed to follow up on the present findings. PMID:25756807

Flaquer, A; Baumbach, C; Ladwig, K-H; Kriebel, J; Waldenberger, M; Grallert, H; Baumert, J; Meitinger, T; Kruse, J; Peters, A; Emeny, R; Strauch, K

2015-01-01

206

Common Genetic Determinants of Uveitis Shared with Other Autoimmune Disorders1  

PubMed Central

Uveitis is a complex multifactorial autoimmune disease of the eye characterized by inflammation of the uvea and retina, degeneration of the retina, and blindness in genetically predisposed patients. Using the rat model of experimental autoimmune uveitis (EAU), we previously identified three quantitative trait loci (QTL) associated with EAU on rat chromosomes 4, 12, and 10 (Eau1, Eau2, and Eau3). The primary goal of the current study is to delineate additional non-MHC chromosomal regions that control susceptibility to EAU, and to identify any QTLs that overlap with the QTLs of other autoimmune diseases. Using a set of informative microsatellite markers and F2 generations of resistant and susceptible MHC class II-matched rat strains (F344 and LEW), we have identified several new significant or suggestive QTLs on rat chromosomes 2, 3, 7, 10, and 19 that control susceptibility to EAU. A protective allele was identified in the susceptible LEW strain in the Eau5 locus at D7Wox18, and epistatic interactions between QTLs were found to influence the severity of disease. The newly identified regions (Eau4 through Eau9) colocalize with the genetic determinants of other autoimmune disease models, and to disease-regulating syntenic regions identified in autoimmune patients on human chromosomes 4q21-31, 5q31-33, 16q22-24, 17p11-q12, 20q11-13, and 22q12-13. Our results suggest that uveitis shares some of the pathogenic mechanisms associated with other autoimmune diseases, and lends support to the “common gene, common pathway” hypothesis for autoimmune disorders. PMID:18453595

Mattapallil, Mary J.; Sahin, Azize; Silver, Phyllis B.; Sun, Shu-Hui; Chan, Chi-Chao; Remmers, Elaine F.; Hejtmancik, J. Fielding; Caspi, Rachel R.

2008-01-01

207

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

208

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

209

Functional Genetic Screen Identifies Increased Sensitivity to WEE1 Inhibition in Cells with Defects in Fanconi Anemia and HR Pathways.  

PubMed

WEE1 kinase regulates CDK1 and CDK2 activity to facilitate DNA replication during S-phase and to prevent unscheduled entry into mitosis. WEE1 inhibitors synergize with DNA-damaging agents that arrest cells in S-phase by triggering direct mitotic entry without completing DNA synthesis, resulting in catastrophic chromosome fragmentation and apoptosis. Here, we investigated how WEE1 inhibition could be best exploited for cancer therapy by performing a functional genetic screen to identify novel determinants of sensitivity to WEE1 inhibition. Inhibition of kinases that regulate CDK activity, CHK1 and MYT1, synergized with WEE1 inhibition through both increased replication stress and forced mitotic entry of S-phase cells. Loss of multiple components of the Fanconi anemia (FA) and homologous recombination (HR) pathways, in particular DNA helicases, sensitized to WEE1 inhibition. Silencing of FA/HR genes resulted in excessive replication stress and nucleotide depletion following WEE1 inhibition, which ultimately led to increased unscheduled mitotic entry. Our results suggest that cancers with defects in FA and HR pathways may be targeted by WEE1 inhibition, providing a basis for a novel synthetic lethal strategy for cancers harboring FA/HR defects. Mol Cancer Ther; 14(4); 865-76. ©2015 AACR. PMID:25673822

Aarts, Marieke; Bajrami, Ilirjana; Herrera-Abreu, Maria T; Elliott, Richard; Brough, Rachel; Ashworth, Alan; Lord, Christopher J; Turner, Nicholas C

2015-04-01

210

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.; Castañeda, Santos; Ramentol, Marc; Rodriguez-Rodriguez, Luis; Narváez, Javier; Blanco, Ricardo; Ortego-Centeno, Norberto; Palm, Øyvind; 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

211

Cinematic Genetics: GATTACA, Essentially Yours, and the Rhetoric of Genetic Determinism  

Microsoft Academic Search

This essay investigates the Australian Law Reform Commission's (ALRC) use of the fictional film GATTACA in the policy brief, “Essentially Yours,” as a rhetorical commonplace to frame various ethical, legal, and scientific issues related to genetic technologies. Because emerging genetic therapy technologies invite both fear and fascination, the ALRC faces the rhetorical challenge of maintaining a distinction between genetic science

Ron Von Burg

2010-01-01

212

Characterization of a circadian rhythm mutant identified in a genetic screen in Neurospora crassa  

E-print Network

the fungus is easy to manipulate, both genetically and biochemically, and the conidiation rhythm is easily monitored using specialized growth tubes called race tubes. One property of the circadian clock is that it can be reset by an environmental stimulus...

Keasler, Victor Vasco

2013-02-22

213

Genetic Essentialism: On the Deceptive Determinism of DNA  

ERIC Educational Resources Information Center

This article introduces the notion of genetic essentialist biases: cognitive biases associated with essentialist thinking that are elicited when people encounter arguments that genes are relevant for a behavior, condition, or social group. Learning about genetic attributions for various human conditions leads to a particular set of thoughts…

Dar-Nimrod, Ilan; Heine, Steven J.

2011-01-01

214

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

215

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

216

The role of nutrition and genetics as key determinants of the positive height trend.  

PubMed

The aim of this study was to identify the most important variables determining current differences in physical stature in Europe and some of its overseas offshoots such as Australia, New Zealand and USA. We collected data on the height of young men from 45 countries and compared them with long-term averages of food consumption from the FAOSTAT database, various development indicators compiled by the World Bank and the CIA World Factbook, and frequencies of several genetic markers. Our analysis demonstrates that the most important factor explaining current differences in stature among nations of European origin is the level of nutrition, especially the ratio between the intake of high-quality proteins from milk products, pork meat and fish, and low-quality proteins from wheat. Possible genetic factors such as the distribution of Y haplogroup I-M170, combined frequencies of Y haplogroups I-M170 and R1b-U106, or the phenotypic distribution of lactose tolerance emerge as comparably important, but the available data are more limited. Moderately significant positive correlations were also found with GDP per capita, health expenditure and partly with the level of urbanization that influences male stature in Western Europe. In contrast, male height correlated inversely with children's mortality and social inequality (Gini index). These results could inspire social and nutritional guidelines that would lead to the optimization of physical growth in children and maximization of the genetic potential, both at the individual and national level. PMID:25190282

Grasgruber, P; Cacek, J; Kalina, T; Sebera, M

2014-12-01

217

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, Michèle; Tikly, Mohammed

2014-01-01

218

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, Michèle; Tikly, Mohammed

2014-01-01

219

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

Federal Register 2010, 2011, 2012, 2013, 2014

...determination on the status of the Monsanto Company and Forage Genetics International alfalfa lines designated as events J101 and J163...determination on the status of the Monsanto Company and Forage Genetics International alfalfa lines designated as events J101 and...

2010-02-24

220

75 FR 1585 - Draft Environmental Impact Statement; Determination of Regulated Status of Alfalfa Genetically...  

Federal Register 2010, 2011, 2012, 2013, 2014

...determination on the status of the Monsanto Company and Forage Genetics International alfalfa lines designated as events J101 and J163...determination, effective June 14, 2005, that the Monsanto/Forage Genetics International (FGI) alfalfa events J101 and J163 were...

2010-01-12

221

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...

222

Identifying Determinants of Academic Selfconfidence among Science, Math, Engineering, and Technology Students  

Microsoft Academic Search

This study attempts to identify determinants of the gender gap in science, math, engineering, and technology (SMET) students' levels of self-confidence in math, science, and overall academic ability. Results from multivariate regression analyses of 336 undergraduate engineering majors at the University of Washington (UW) who completed the Engineering Student Experience Survey point to perceived respect from professors as the strongest

Penelope M. Huang; Suzanne G. Brainard

2001-01-01

223

Genetic and Environmental Determinants of Bitter Perception and Sweet Preferences  

PubMed Central

Objective Flavor is the primary dimension by which young children determine food acceptance. 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 variations in the newly discovered TAS2R38 taste gene as well as cultural differences are associated with differences in sensitivity to the bitter taste of propylthiouracil (PROP) and preferences for sucrose and sweet-tasting foods and beverages in children and adults. Design Genomic DNA was extracted from cheek cells of a racially and ethnically diverse sample of 143 children and their mothers. Alleles of the gene TAS2R38 were genotyped. Participants were grouped by the first variant site, denoted A49P, because the allele predicts a change from the amino acid alanine (A) to proline (P) at position 49. Henceforth, individuals who were homozygous for the bitter-insensitive allele are referred to as AA, those who were heterozygous for the bitter-insensitive allele are referred to as AP, and those who were homozygous for the bitter-sensitive allele are referred to as PP. Using identical procedures for children and mothers, PROP sensitivity and sucrose preferences were assessed by using forced-choice procedures that were embedded in the context of games that minimized the impact of language development and were sensitive to the cognitive limitations of pediatric populations. Participants were also asked about their preferences in cereals and beverages, and mothers completed a standardized questionnaire that measured various dimensions of their children’s temperament. Results Genetic variation of the A49P allele influenced bitter perception in children and adults. However, the phenotype-genotype relationship was modified by age such that 64% of heterozygous children, but only 43% of the heterozygous mothers, were sensitive to the lowest concentration (56 micromoles/liter) of PROP. Genotypes at the TAS2R38 locus were significantly related to preferences for sucrose and for sweet-tasting beverages and foods such as cereals in children. AP and PP children preferred significantly higher concentrations of sucrose solutions than did AA children. They were also significantly less likely to include milk or water as 1 of their 2 favorite beverages (18.6% vs 40%) and were more likely to include carbonated beverages as 1 of their most preferred beverages (46.4% vs 28.9%). PP children liked cereals and beverages with a significantly higher sugar content. There were also significant main effects of race/ ethnicity on preferences and food habits. As a group, black children liked cereals with a significantly higher sugar content than did white children, and they were also significantly more likely to report that they added sugar to their cereals. Unlike children, there was no correspondence between TAS2R38 genotypes and sweet preference in adults. Here, the effects of race/ethnicity were the strongest determinants, thus suggesting that cultural forces and experience may override this genotype effect on sweet preferences. Differences in taste experiences also affected mother–child interaction, especially when the 2 resided in different sensory worlds. That is, children who had 1 or 2 bitter-sensitive alleles, but whose mothers had none, were perceived by their mothers as being more emotional than children who had no bitter-sensitive alleles. Conclusion Variations in a taste receptor gene accounted for a major portion of individual differences in PROP bitterness perception in both children and adults, as well as a portion of individual differences in preferences for sweet flavors in children but not in adults. These findings underscore the advantages of studying genotype effects on behavioral outcomes in children, especially as they relate to taste preferences because cultural forces may sometimes override the A49P

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

2006-01-01

224

A Systems Genetic Approach to Identify Low Dose Radiation-Induced Lymphoma Susceptibility/DOE2013FinalReport  

SciTech Connect

The ultimate goal of this project is to identify the combinations of genetic variants that confer an individual's susceptibility to the effects of low dose (0.1 Gy) gamma-radiation, in particular with regard to tumor development. In contrast to the known effects of high dose radiation in cancer induction, the responses to low dose radiation (defined as 0.1 Gy or less) are much less well understood, and have been proposed to involve a protective anti-tumor effect in some in vivo scientific models. These conflicting results confound attempts to develop predictive models of the risk of exposure to low dose radiation, particularly when combined with the strong effects of inherited genetic variants on both radiation effects and cancer susceptibility. We have used a Â?Â?Systems Genetics approach in mice that combines genetic background analysis with responses to low and high dose radiation, in order to develop insights that will allow us to reconcile these disparate observations. Using this comprehensive approach we have analyzed normal tissue gene expression (in this case the skin and thymus), together with the changes that take place in this gene expression architecture a) in response to low or high- dose radiation and b) during tumor development. Additionally, we have demonstrated that using our expression analysis approach in our genetically heterogeneous/defined radiation-induced tumor mouse models can uniquely identify genes and pathways relevant to human T-ALL, and uncover interactions between common genetic variants of genes which may lead to tumor susceptibility.

Balmain, Allan [University of California, San Francisco; Song, Ihn Young [University of California, San Francisco

2013-05-15

225

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

226

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

PubMed Central

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

227

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 São 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

228

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.

229

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...

230

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

Microsoft Academic Search

Genome-wide association studies are providing new insights into the genetic basis of metabolic and cardi- ovascular traits. In the past 3 years, common variants in 50 loci have been strongly associated with meta- bolic and cardiovascular traits. Several of these loci have implicated genes without a previously known connection with metabolism. Further studies will be required to characterize the full

Karen L. Mohlke; Michael Boehnke; Goncalo R. Abecasis

2008-01-01

231

Identifying future models for delivering genetic services: a nominal group study in primary care  

Microsoft Academic Search

: BACKGROUND: To enable primary care medical practitioners to generate a range of possible service delivery models for genetic counselling services and critically assess their suitability. METHODS: Modified nominal group technique using in primary care professional development workshops. RESULTS: 37 general practitioners in Wales, United Kingdom too part in the nominal group process. The practitioners who attended did not believe

Glyn Elwyn; Adrian Edwards; Rachel Iredale; Peter Davies; Jonathon Gray

2005-01-01

232

Diverse Genetic Markers Concordantly Identify Bovine Origin Escherichia coli O157 Genotypes Underrepresented in Human Disease  

Technology Transfer Automated Retrieval System (TEKTRAN)

Genetic markers previously reported to occur at significantly different frequencies in isolates of Escherichia coli O157:H7 obtained from cattle and from clinically affected humans are congruent and delineate at least five groups. Isolates in three of these groups consistently carry one or more mark...

233

Using the GRIN-Global System to Identify Useful Plant Genetic Resources & Information  

Technology Transfer Automated Retrieval System (TEKTRAN)

The GRIN-Global (GG) System has been developed to provide the world's crop genebanks and plant genetic resource (PGR) users with a powerful, flexible, easy-to-use PGR information management system. Developed jointly by the USDA Agricultural Research Service, Bioversity International and the Global C...

234

Genetic analysis of the two zebrafish patched homologues identifies novel roles for the hedgehog signaling pathway  

Microsoft Academic Search

BACKGROUND: Aberrant activation of the Hedgehog (Hh) signaling pathway in different organisms has shown the importance of this family of morphogens during development. Genetic screens in zebrafish have assigned specific roles for Hh in proliferation, differentiation and patterning, but mainly as a result of a loss of its activity. We attempted to fully activate the Hh pathway by removing both

Marco J Koudijs; Marjo J den Broeder; Evelyn Groot; Fredericus JM van Eeden

2008-01-01

235

Genetically Modified Organisms and Trade Rules: Identifying Important Challenges for the WTO  

Microsoft Academic Search

Controversial debates associated with the establishment of international market access rules for genetically modified organisms (GMOs) illustrate a more general challenge facing the World Trade Organisation (WTO); to acceptably accommodate growing consumer concerns regarding a product's production and processing methods (PPM). This paper aims to clarify the debates by examining the foundations of and the procedures for the WTO's decision–making

Grant E. Isaac; William A. Kerr

2003-01-01

236

Social-Cognition and the Broad Autism Phenotype: Identifying Genetically Meaningful Phenotypes  

ERIC Educational Resources Information Center

Background: Strong evidence from twin and family studies suggests that the genetic liability to autism may be expressed through personality and language characteristics qualitatively similar, but more subtly expressed than those defining the full syndrome. This study examined behavioral features of this "broad autism phenotype" (BAP) in relation…

Losh, Molly; Piven, Joseph

2007-01-01

237

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

238

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

239

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.  

PubMed

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants. PMID:25616667

Goris, An; Pauwels, Ine; Gustavsen, Marte W; van Son, Brechtje; Hilven, Kelly; Bos, Steffan D; Celius, Elisabeth Gulowsen; Berg-Hansen, Pål; Aarseth, Jan; Myhr, Kjell-Morten; D'Alfonso, Sandra; Barizzone, Nadia; Leone, Maurizio A; Martinelli Boneschi, Filippo; Sorosina, Melissa; Liberatore, Giuseppe; Kockum, Ingrid; Olsson, Tomas; Hillert, Jan; Alfredsson, Lars; Bedri, Sahl Khalid; Hemmer, Bernhard; Buck, Dorothea; Berthele, Achim; Knier, Benjamin; Biberacher, Viola; van Pesch, Vincent; Sindic, Christian; Bang Oturai, Annette; Søndergaard, Helle Bach; Sellebjerg, Finn; Jensen, Poul Erik H; Comabella, Manuel; Montalban, Xavier; Pérez-Boza, Jennifer; Malhotra, Sunny; Lechner-Scott, Jeannette; Broadley, Simon; Slee, Mark; Taylor, Bruce; Kermode, Allan G; Gourraud, Pierre-Antoine; Sawcer, Stephen J; Andreassen, Bettina Kullle; Dubois, Bénédicte; Harbo, Hanne F

2015-03-01

240

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

241

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

242

[Asthma: a complex disease determined by genetic and environmental factors].  

PubMed

Asthma is a complex disease highly dependent of environmental exposure and genetic background. Through linkage analysis, positional cloning and genome wide association studies, novel asthma genes have come out such as ADAM-33 or ORMLD3. Important environmental factors include allergenic exposure, pollutants and especially particulate matters, tobacco, aerosol exposure, viral infections and level of exposure to endotoxin. The effects of environmental factors are modulated by the genetic sequence and numerous single nucleotide polymorphisms (SNPs). Recently, it has also become clear that environmental factors may alter gene expression by DNA methylation or histone methylation/acetylation without changing the gene sequence and thereby changing asthmatic phenotype. PMID:22891480

Louis, R; Schleich, F; Corhay, J-L; Louis, E

2012-01-01

243

Newly identified genetic risk variants for celiac disease related to the immune response  

Microsoft Academic Search

Our genome-wide association study of celiac disease previously identified risk variants in the IL2–IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P <

Karen A Hunt; Alexandra Zhernakova; Graham Turner; Graham A R Heap; Lude Franke; Marcel Bruinenberg; Jihane Romanos; Lotte C Dinesen; Anthony W Ryan; Davinder Panesar; Rhian Gwilliam; Fumihiko Takeuchi; William M McLaren; Geoffrey K T Holmes; Peter D Howdle; Julian R F Walters; David S Sanders; Raymond J Playford; Gosia Trynka; Chris J J Mulder; M Luisa Mearin; Wieke H M Verbeek; Valerie Trimble; Fiona M Stevens; Colm O'Morain; Nicholas P Kennedy; Dermot Kelleher; Daniel J Pennington; David P Strachan; Wendy L McArdle; Charles A Mein; Martin C Wapenaar; Panos Deloukas; Ralph McGinnis; Ross McManus; Cisca Wijmenga; David A van Heel

2008-01-01

244

Identifying indicator species for post-release monitoring of genetically modified, herbicide resistant crops  

Microsoft Academic Search

In Europe, regulations for release and placing-on-the-market of genetically modified (GM) crops require post-release monitoring\\u000a of their impact on the environment. Monitoring potential adverse effects of GM crops includes direct effects as well as indirect\\u000a effects, e.g. GM crop specific changes in land and pest management. Currently, there is a gap in the pre-release risk assessments\\u000a conducted for regulatory approval

Angelika Hilbeck; Matthias Meier; Armin Benzler

2008-01-01

245

Genome-wide Association Study Identifies Four Genetic Loci Associated with Thyroid Volume and Goiter Risk  

PubMed Central

Thyroid disorders such as goiters represent important diseases, especially in iodine-deficient areas. Sibling studies have demonstrated that genetic factors substantially contribute to the interindividual variation of thyroid volume. We performed a genome-wide association study of this phenotype by analyzing a discovery cohort consisting of 3620 participants of the Study of Health in Pomerania (SHIP). Four genetic loci were associated with thyroid volume on a genome-wide level of significance. Of these, two independent loci are located upstream of and within CAPZB, which encodes the ? subunit of the barbed-end F-actin binding protein that modulates actin polymerization, a process crucial in the colloid engulfment during thyroglobulin mobilization in the thyroid. The third locus marks FGF7, which encodes fibroblast growth factor 7. Members of this protein family have been discussed as putative signal molecules involved in the regulation of thyroid development. The fourth locus represents a “gene desert” on chromosome 16q23, located directly downstream of the predicted coding sequence LOC440389, which, however, had already been removed from the NCBI database as a result of the standard genome annotation processing at the time that this study was initiated. Experimental proof of the formerly predicted mature mRNA, however, demonstrates that LOC440389 indeed represents a real gene. All four associations were replicated in an independent sample of 1290 participants of the KORA study. These results increase the knowledge about genetic factors and physiological mechanisms influencing thyroid volume. PMID:21565293

Teumer, Alexander; Rawal, Rajesh; Homuth, Georg; Ernst, Florian; Heier, Margit; Evert, Matthias; Dombrowski, Frank; Völker, Uwe; Nauck, Matthias; Radke, Dörte; Ittermann, Till; Biffar, Reiner; Döring, Angela; Gieger, Christian; Klopp, Norman; Wichmann, H.-Erich; Wallaschofski, Henri; Meisinger, Christa; Völzke, Henry

2011-01-01

246

Genome wide DNA copy number analysis of serous type ovarian carcinomas identifies genetic markers predictive of clinical outcome.  

PubMed

Ovarian cancer is the fifth leading cause of cancer death in women. Ovarian cancers display a high degree of complex genetic alterations involving many oncogenes and tumor suppressor genes. Analysis of the association between genetic alterations and clinical endpoints such as survival will lead to improved patient management via genetic stratification of patients into clinically relevant subgroups. In this study, we aim to define subgroups of high-grade serous ovarian carcinomas that differ with respect to prognosis and overall survival. Genome-wide DNA copy number alterations (CNAs) were measured in 72 clinically annotated, high-grade serous tumors using high-resolution oligonucleotide arrays. Two clinically annotated, independent cohorts were used for validation. Unsupervised hierarchical clustering of copy number data derived from the 72 patient cohort resulted in two clusters with significant difference in progression free survival (PFS) and a marginal difference in overall survival (OS). GISTIC analysis of the two clusters identified altered regions unique to each cluster. Supervised clustering of two independent large cohorts of high-grade serous tumors using the classification scheme derived from the two initial clusters validated our results and identified 8 genomic regions that are distinctly different among the subgroups. These 8 regions map to 8p21.3, 8p23.2, 12p12.1, 17p11.2, 17p12, 19q12, 20q11.21 and 20q13.12; and harbor potential oncogenes and tumor suppressor genes that are likely to be involved in the pathogenesis of ovarian carcinoma. We have identified a set of genetic alterations that could be used for stratification of high-grade serous tumors into clinically relevant treatment subgroups. PMID:22355333

Engler, David A; Gupta, Sumeet; Growdon, Whitfield B; Drapkin, Ronny I; Nitta, Mai; Sergent, Petra A; Allred, Serena F; Gross, Jenny; Deavers, Michael T; Kuo, Wen-Lin; Karlan, Beth Y; Rueda, Bo R; Orsulic, Sandra; Gershenson, David M; Birrer, Michael J; Gray, Joe W; Mohapatra, Gayatry

2012-01-01

247

Diversity Outbred Mice Identify Population-Based Exposure Thresholds and Genetic Factors that Influence Benzene-Induced Genotoxicity  

PubMed Central

Background Inhalation of benzene at levels below the current exposure limit values leads to hematotoxicity in occupationally exposed workers. Objective We sought to evaluate Diversity Outbred (DO) mice as a tool for exposure threshold assessment and to identify genetic factors that influence benzene-induced genotoxicity. Methods We exposed male DO mice to benzene (0, 1, 10, or 100 ppm; 75 mice/exposure group) via inhalation for 28 days (6 hr/day for 5 days/week). The study was repeated using two independent cohorts of 300 animals each. We measured micronuclei frequency in reticulocytes from peripheral blood and bone marrow and applied benchmark concentration modeling to estimate exposure thresholds. We genotyped the mice and performed linkage analysis. Results We observed a dose-dependent increase in benzene-induced chromosomal damage and estimated a benchmark concentration limit of 0.205 ppm benzene using DO mice. This estimate is an order of magnitude below the value estimated using B6C3F1 mice. We identified a locus on Chr 10 (31.87 Mb) that contained a pair of overexpressed sulfotransferases that were inversely correlated with genotoxicity. Conclusions The genetically diverse DO mice provided a reproducible response to benzene exposure. The DO mice display interindividual variation in toxicity response and, as such, may more accurately reflect the range of response that is observed in human populations. Studies using DO mice can localize genetic associations with high precision. The identification of sulfotransferases as candidate genes suggests that DO mice may provide additional insight into benzene-induced genotoxicity. Citation French JE, Gatti DM, Morgan DL, Kissling GE, Shockley KR, Knudsen GA, Shepard KG, Price HC, King D, Witt KL, Pedersen LC, Munger SC, Svenson KL, Churchill GA. 2015. Diversity Outbred mice identify population-based exposure thresholds and genetic factors that influence benzene-induced genotoxicity. Environ Health Perspect 123:237–245;?http://dx.doi.org/10.1289/ehp.1408202 PMID:25376053

Gatti, Daniel M.; Morgan, Daniel L.; Kissling, Grace E.; Shockley, Keith R.; Knudsen, Gabriel A.; Shepard, Kim G.; Price, Herman C.; King, Deborah; Witt, Kristine L.; Pedersen, Lars C.; Munger, Steven C.; Svenson, Karen L.; Churchill, Gary A.

2014-01-01

248

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

249

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

250

Genetic Endowment and Environment in the Determination of Behavior.  

ERIC Educational Resources Information Center

A research workshop was organized to bring together geneticists, psychologists, and other behavioral scientists. The intent was to bring about an interaction of ideas concerned with the genetics of behavior and learning. The emphasis was upon interdisciplinary study among scientists from several fields. Specific issues were isolated in those areas…

Ehrman, Lee; And Others

251

Determination of thermal compact model via evolutionary genetic optimization method  

Microsoft Academic Search

Genetic Algorithms (GA) are adaptive search algorithms based on the theory of natural selection and survival of the fittest. In this study, GA was used to derive a thermal compact model of a micro lead frame package. The GA derived model was then used to compute the junction temperature (Tj) of the package for various boundary conditions. The results obtained

Parthiban Arunasalam; Kankanhally N. Seetharamu; Ishak Abdul Azid

2005-01-01

252

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

253

Genetic determinism of the cellular immune reaction in Drosophila melanogaster  

Microsoft Academic Search

Larvae of Drosophila melanogaster produce a haemocytic reaction against eggs of the parasitoid Leptopilina boulardi, which leads to the formation of a multicellular capsule surrounding the foreign object. Melanization resulting from the conversion of phenol to o-quinones frequently accompanies the cellular reaction. Although various cytological and biochemical aspects of this reaction have been investigated, very little is known about genetic

Y Carton; F Frey; A Nappi

1992-01-01

254

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

255

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

256

A Novel Approach to Identify Candidate Prognostic Factors for Hepatitis C Treatment Response Integrating Clinical and Viral Genetic Data  

PubMed Central

The combined therapy of pegylated interferon (IFN) plus ribavirin (RBV) has been for a long time the standard treatment for patients infected with hepatitis C virus (HCV). In the case of genotype 1, only 38%–48% of patients have a positive response to the combined treatment. In previous studies, viral genetic information has been occasionally included as a predictor. Here, we consider viral genetic variation in addition to 11 clinical and 19 viral populations and evolutionary parameters to identify candidate baseline prognostic factors that could be involved in the treatment outcome. We obtained potential prognostic models for HCV subtypes la and lb in combination as well as separately. We also found that viral genetic information is relevant for the combined treatment assessment of patients, as the potential prognostic model of joint subtypes includes 9 viral-related variables out of 11. Our proposed methodology fully characterizes viral genetic information and finds a combination of positions that modulate inter-patient variability. PMID:25780333

Amadoz, Alicia; González-Candelas, Fernando

2015-01-01

257

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

258

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 has a unique solution. In this study, we used the Genetic Algorithm to investigate whether

Fibich, Gadi

259

Determining the community structure of the coral Seriatopora hystrix from hydrodynamic and genetic networks  

Microsoft Academic Search

The exchange of genetic information between coral reefs through the transport of larvae can be described in terms of networks that capture the linkages between distant populations. A key question arising from these networks is the determination of the highly connected modules (communities). Communities can be defined using genetic similarity or distance statistics between multiple samples but due to limited

Stuart Kininmonth; Madeleine J. H. van Oppen; Hugh P. Possingham

2010-01-01

260

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

261

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; Cadiñanos, 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

262

Identifying genetic loci associated with antidepressant drug response with drug-gene interaction models in a population-based study.  

PubMed

It has been difficult to identify genes affecting drug response to Selective Serotonin Reuptake Inhibitors (SSRIs). We used multiple cross-sectional assessments of depressive symptoms in a population-based study to identify potential genetic interactions with SSRIs as a model to study genetic variants associated with SSRI response. This study, embedded in the prospective Rotterdam Study, included all successfully genotyped participants with data on depressive symptoms (CES-D scores). We used repeated measurement models to test multiplicative interaction between genetic variants and use of SSRIs on repeated CESD scores. Besides a genome-wide analysis, we also performed an analysis which was restricted to genes related to the serotonergic signaling pathway. A total of 273 out of 14 937 assessments of depressive symptoms in 6443 participants, use of an SSRI was recorded. After correction for multiple testing, no plausible loci were identified in the genome-wide analysis. However, among the top 10 independent loci with the lowest p-values, findings within two genes (FSHR and HMGB4) might be of interest. Among 26 genes related to the serotonergic signaling pathway, the rs6108160 polymorphism in the PLCB1 gene reached statistical significance after Bonferroni correction (p-value = 8.1e-5). Also, the widely replicated 102C > T polymorphism in the HTR2A gene showed a statistically significant drug-gene interaction with SSRI use. Therefore, the present study suggests that drug-gene interaction models on (repeated) cross-sectional assessments of depressive symptoms in a population-based study can identify potential loci that may influence SSRI response. PMID:25649181

Noordam, Raymond; Direk, Nese; Sitlani, Colleen M; Aarts, Nikkie; Tiemeier, Henning; Hofman, Albert; Uitterlinden, André G; Psaty, Bruce M; Stricker, Bruno H; Visser, Loes E

2015-03-01

263

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

264

A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses   

E-print Network

New strategies are required to identify the most important targets of protective immunity in complex eukaryotic pathogens. Natural selection maintains allelic variation in some antigens of the malaria parasite Plasmodium ...

Conway, David J; Cavanagh, David R; Tanabe, K; Roper, C; Mikes, Z S; Sakihama, N; Bojang, K A; Oduola, A M J; Kremsner, P G; Arnot, D E; Greenwood, B M; McBride, J S

265

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

266

The geographical and environmental determinants of genetic diversity for four alpine conifers of the European Alps.  

PubMed

Climate is one of the most important drivers of local adaptation in forest tree species. Standing levels of genetic diversity and structure within and among natural populations of forest trees are determined by the interplay between climatic heterogeneity and the balance between selection and gene flow. To investigate this interplay, single nucleotide polymorphisms (SNPs) were genotyped in 24 to 37 populations from four subalpine conifers, Abies alba Mill., Larix decidua Mill., Pinus cembra L. and Pinus mugo Turra, across their natural ranges in the Italian Alps and Apennines. Patterns of population structure were apparent using a Bayesian clustering program, STRUCTURE, which identified three to five genetic groups per species. Geographical correlates with these patterns, however, were only apparent for P. cembra. Multivariate environmental variables [i.e. principal components (PCs)] were subsequently tested for association with SNPs using a Bayesian generalized linear mixed model. The majority of the SNPs, ranging from six in L. decidua to 18 in P. mugo, were associated with PC1, corresponding to winter precipitation and seasonal minimum temperature. In A. alba, four SNPs were associated with PC2, corresponding to the seasonal minimum temperature. Functional annotation of those genes with the orthologs in Arabidopsis revealed several genes involved in abiotic stress response. This study provides a detailed assessment of population structure and its association with environment and geography in four coniferous species in the Italian mountains. PMID:23058000

Mosca, E; Eckert, A J; Di Pierro, E A; Rocchini, D; La Porta, Nicola; Belletti, P; Neale, D B

2012-11-01

267

Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.  

PubMed

The autism spectrum disorders are a collective of conditions that have in common impaired socialization and communication in association with stereotypic behaviors. The reported incidence of autism spectrum disorders has increased dramatically over the past two decades. In addition, increased attention has been paid to these conditions by both lay and professional groups. These trends have resulted in an increase in the number of referrals to clinical geneticist for the evaluation of persons with autism spectrum disorders. The primary roles of the geneticist in this process are to define etiology when possible, to provide genetic counseling, and to contribute to case management. In deciding on the appropriate evaluation for a particular patient, the geneticist will consider a host of factors: (i) ensuring an accurate diagnosis of autism before proceeding with any investigation; (ii) discussing testing options, diagnostic yields, and family investment before proceeding with an evaluation; (iii) communicating and coordinating with the patient-centered medical home (PCMH); (iv) assessing the continuously expanding and evolving list of available laboratory-testing modalities in light of the published literature; (v) recognizing the expanded phenotypes of well-described syndromic and metabolic conditions that overlap with autism spectrum disorders; and (vi) defining an individualized evaluation plan based on the unique history and clinical features of a given patient. The guidelines in this paper have been developed to assist the clinician in the consideration of these factors. It updates the original publication from 2008.Genet Med 2013:15(5):399-407. PMID:23519317

Schaefer, G Bradley; Mendelsohn, Nancy J

2013-05-01

268

Mapping eQTLs in the Norfolk Island Genetic Isolate Identifies Candidate Genes for CVD Risk Traits  

PubMed Central

Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10?7) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations. PMID:24314549

Benton, Miles C.; Lea, Rod A.; Macartney-Coxson, Donia; Carless, Melanie A.; Göring, Harald H.; Bellis, Claire; Hanna, Michelle; Eccles, David; Chambers, Geoffrey K.; Curran, Joanne E.; Harper, Jacquie L.; Blangero, John; Griffiths, Lyn R.

2013-01-01

269

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

270

Genetic diversity of Brucella abortus isolates as determined by amplified fragment length polymorphism (AFLP) analysis  

E-print Network

with the powerful Bionumerics software package to determine the genetic relationships between B. abortus field isolates, collected from infections in wild herds of elk and bison to achieve a better understanding of the molecular diversity and evolution of B. abortus...

Bliss, Katherine Ann

2013-02-22

271

76 FR 63279 - Monsanto Co.; Determination of Nonregulated Status for Soybean Genetically Engineered for Insect...  

Federal Register 2010, 2011, 2012, 2013, 2014

...from the Monsanto Company (Monsanto) of St. Louis, MO, seeking a determination of nonregulated status for soybean (Glycine max) designated as event MON 87701, which has been genetically engineered for insect resistance, stating that this...

2011-10-12

272

Application of Genetic Algorithms and Thermogravimetry to Determine the Kinetics of Polyurethane Foam in Smoldering Combustion   

E-print Network

In this work, the kinetic parameters governing the thermal and oxidative degradation of flexible polyurethane foam are determined using thermogravimetric data and a genetic algorithm. These kinetic parameters are needed ...

Rein, Guillermo; Lautenberger, Chris; Fernandez-Pello, Carlos; Torero, Jose L; Urban, David

273

Expression-based Genetic/Physical Maps of Single-Nucleotide Polymorphisms Identified by the Cancer Genome Anatomy Project  

PubMed Central

SNPs (Single-Nucleotide Polymorphisms), the most common DNA variant in humans, represent a valuable resource for the genetic analysis of cancer and other illnesses. These markers may be used in a variety of ways to investigate the genetic underpinnings of disease. In gene-based studies, the correlations between allelic variants of genes of interest and particular disease states are assessed. An extensive collection of SNP markers may enable entire molecular pathways regulating cell metabolism, growth, or differentiation to be analyzed by this approach. In addition, high-resolution genetic maps based on SNPs will greatly facilitate linkage analysis and positional cloning. The National Cancer Institute's CGAP-GAI (Cancer Genome Anatomy Project Genetic Annotation Initiative) group has identified 10,243 SNPs by examining publicly available EST (Expressed Sequence Tag) chromatograms. More than 6800 of these polymorphisms have been placed on expression-based integrated genetic/physical maps. In addition to a set of comprehensive SNP maps, we have produced maps containing single nucleotide polymorphisms in genes expressed in breast, colon, kidney, liver, lung, or prostate tissue. The integrated maps, a SNP search engine, and a Java-based tool for viewing candidate SNPs in the context of EST assemblies can be accessed via the CGAP-GAI web site (http://cgap.nci.nih.gov/GAI/). Our SNP detection tools are available to the public for noncommercial use. [The sequence data described in this paper have been submitted to the db SNP data library under accession nos. SS8196–SS18418.] PMID:10958644

Clifford, Robert; Edmonson, Michael; Hu, Ying; Nguyen, Cu; Scherpbier, Titia; Buetow, Kenneth H.

2000-01-01

274

Researchers identify dozens of new de novo genetic mutations in schizophrenia http://www.psypost.org/...earchers-identify-dozens-of-new-de-novo-genetic-mutations-in-schizophrenia-14228?utm_source=twitterfeed&utm_medium=twitter[10/10/2012 4:38:00 PM  

E-print Network

Researchers identify dozens of new de novo genetic mutations in schizophrenia http://www.psypost.org/...earchers-identify-dozens-of-new-de-novo-genetic-mutations-in-schizophrenia-14228?utm_source=twitterfeed&utm_medium=twitter[10/10/2012 4:38:00 PM] HOME » MENTAL HEALTH » SCHIZOPHRENIA & PSYCHOSIS » Researchers identify dozens

275

Identifiers Identifiers  

E-print Network

, July 1998. . Tim Berners­Lee: Cool URIs don't change. [http://www.w3.org/Provider/Style/URI] Stefan://archive.ncsa.uiuc.edu/demoweb/url­primer.html] . T. Berners­Lee, R. Fielding, L. Masinter: Uniform Resource Identifiers (URI): Generic Syntax. RFC Names. RFC 1737, December 1994, 7 pages. . T. Berners­Lee, L. Masinter, M. McCahill: Uniform Resource

Brass, Stefan

276

Identifiers Identifiers  

E-print Network

, July 1998. . Tim Berners­Lee: Cool URIs don't change. [http://www.w3.org/Provider/Style/URI] . Uniform://archive.ncsa.uiuc.edu/demoweb/url­primer.html] . T. Berners­Lee, R. Fielding, L. Masinter: Uniform Resource Identifiers (URI): Generic Syntax. RFC Names. RFC 1737, December 1994, 7 pages. . T. Berners­Lee, L. Masinter, M. McCahill: Uniform Resource

Brass, Stefan

277

Genetic Determinants of On-Aspirin Platelet Reactivity: Focus on the Influence of PEAR1  

PubMed Central

Background Platelet aggregation during aspirin treatment displays considerable inter-individual variability. A genetic etiology likely exists, but it remains unclear to what extent genetic polymorphisms determine platelet aggregation in aspirin-treated individuals. Aim To identify platelet-related single nucleotide polymorphisms (SNPs) influencing platelet aggregation during aspirin treatment. Furthermore, we explored to what extent changes in cyclooxygenase-1 activity and platelet activation may explain such influence. Methods We included 985 Danish patients with stable coronary artery disease treated with aspirin 75 mg/day mono antiplatelet therapy. Patients were genotyped for 16 common SNPs in platelet-related genes using standard PCR-based methods (TaqMan). Platelet aggregation was evaluated by whole blood platelet aggregometry employing Multiplate Analyzer (agonists: arachidonic acid and collagen) and VerifyNow Aspirin. Serum thromboxane B2 was measured to confirm aspirin adherence and was used as a marker of cyclooxygenase-1 activity. Soluble P-selectin was used as marker of platelet activation. Platelet aggregation, cyclooxygenase-1 activity, and platelet activation were compared across genotypes in adjusted analyses. Results The A-allele of the rs12041331 SNP in the platelet endothelial aggregation receptor-1 (PEAR1) gene was associated with reduced platelet aggregation and increased platelet activation, but not with cyclooxygenase-1 activity. Platelet aggregation was unaffected by the other SNPs analyzed. Conclusion A common genetic variant in PEAR1 (rs12041331) reproducibly influenced platelet aggregation in aspirin-treated patients with coronary artery disease. The exact biological mechanism remains elusive, but the effect of this polymorphism may be related to changes in platelet activation. Furthermore, 14 SNPs previously suggested to influence aspirin efficacy were not associated with on-aspirin platelet aggregation. Clinical Trial Registration ClinicalTrials.gov NCT01383304 PMID:25360888

Würtz, Morten; Nissen, Peter H.; Grove, Erik Lerkevang; Kristensen, Steen Dalby; Hvas, Anne-Mette

2014-01-01

278

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

279

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, Tõnu; 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, Håkon 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

280

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

281

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

282

Characterization of Pellicle Inhibition in Gluconacetobacter xylinus 53582 by a Small Molecule, Pellicin, Identified by a Chemical Genetics Screen  

Microsoft Academic Search

Pellicin ([2E]-3-phenyl-1-[2,3,4,5-tetrahydro-1,6-benzodioxocin-8-yl]prop-2-en-1-one) was identified in a chemical genetics screen of 10,000 small molecules for its ability to completely abolish pellicle production in Gluconacetobacter xylinus. Cells grown in the presence of pellicin grew 1.5 times faster than untreated cells. Interestingly, growth in pellicin also caused G. xylinus cells to elongate. Measurement of cellulose synthesis in vitro showed that cellulose synthase activity

Janice L. Strap; Andrew Latos; Isaac Shim; Dario T. Bonetta

2011-01-01

283

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...

284

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...

285

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...

286

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

287

Population size and time since island isolation determine genetic diversity loss in insular frog populations.  

PubMed

Understanding the factors that contribute to loss of genetic diversity in fragmented populations is crucial for conservation measurements. Land-bridge archipelagoes offer ideal model systems for identifying the long-term effects of these factors on genetic variations in wild populations. In this study, we used nine microsatellite markers to quantify genetic diversity and differentiation of 810 pond frogs (Pelophylax nigromaculatus) from 24 islands of the Zhoushan Archipelago and three sites on nearby mainland China and estimated the effects of the island area, population size, time since island isolation, distance to the mainland and distance to the nearest larger island on reduced genetic diversity of insular populations. The mainland populations displayed higher genetic diversity than insular populations. Genetic differentiations and no obvious gene flow were detected among the frog populations on the islands. Hierarchical partitioning analysis showed that only time since island isolation (square-root-transformed) and population size (log-transformed) significantly contributed to insular genetic diversity. These results suggest that decreased genetic diversity and genetic differentiations among insular populations may have been caused by random genetic drift following isolation by rising sea levels during the Holocene. The results provide strong evidence for a relationship between retained genetic diversity and population size and time since island isolation for pond frogs on the islands, consistent with the prediction of the neutral theory for finite populations. Our study highlights the importance of the size and estimated isolation time of populations in understanding the mechanisms of genetic diversity loss and differentiation in fragmented wild populations. PMID:24351057

Wang, Supen; Zhu, Wei; Gao, Xu; Li, Xianping; Yan, Shaofei; Liu, Xuan; Yang, Ji; Gao, Zengxiang; Li, Yiming

2014-02-01

288

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

289

Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia  

PubMed Central

Stroke is a devastating complication of sickle cell anemia (SCA), occurring in 11% of patients before age 20 years. Previous studies of sibling pairs have demonstrated a genetic component to the development of cerebrovascular disease in SCA, but few candidate genetic modifiers have been validated as having a substantial effect on stroke risk. We performed an unbiased whole-genome search for genetic modifiers of stroke risk in SCA. Genome-wide association studies were performed using genotype data from single-nucleotide polymorphism arrays, whereas a pooled DNA approach was used to perform whole-exome sequencing. In combination, 22 nonsynonymous variants were identified and represent key candidates for further in-depth study. To validate the association of these mutations with the risk for stroke, the 22 candidate variants were genotyped in an independent cohort of control patients (n = 231) and patients with stroke (n = 57) with SCA. One mutation in GOLGB1 (Y1212C) and another mutation in ENPP1 (K173Q) were confirmed as having significant associations with a decreased risk for stroke. These mutations were discovered and validated by an unbiased whole-genome approach, and future studies will focus on how these functional mutations may lead to protection from stroke in the context of SCA. PMID:23422753

Sheehan, Vivien; Linder, Heidi; Howard, Thad A.; Wang, Yong-Dong; Hoppe, Carolyn C.; Aygun, Banu; Adams, Robert J.; Neale, Geoffrey A.; Ware, Russell E.

2013-01-01

290

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

291

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

PubMed

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

Ben, Cécile; Toueni, Maoulida; Montanari, Sara; Tardin, Marie-Claire; Fervel, Magalie; Negahi, Azam; Saint-Pierre, Laure; Mathieu, Guillaume; Gras, Marie-Christine; Noël, Dominique; Prospéri, Jean-Marie; Pilet-Nayel, Marie-Laure; Baranger, Alain; Huguet, Thierry; Julier, Bernadette; Rickauer, Martina; Gentzbittel, Laurent

2013-01-01

292

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; Piñero, Daniel

2013-01-01

293

Comparison of RAPD and RFLP genetic markers in determining genetic similarity among Brassica oleracea L. genotypes  

Microsoft Academic Search

Genetic similarity among 45 Brassica Oleracea genotypes was compared using two molecular markers, random amplified polymorphic DNA (RAPD) and restriction fragment length polymorphisms (RFLPs). The genotypes included 37 broccolis (var. italica), five cauliflowers (var. botrytis) and three cabbages (var. capitata) which represented a wide range of commercially-available germplasm, and included open-pollinated cultivars, commercial hybrids, and inbred parents of hybrid cultivars.

J. B. dos Santos; J. Nienhuis; P. Skroch; J. Tivang; M. K. Slocum

1994-01-01

294

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

295

Genetic structure of Aedes aegypti populations determined using pairwise comparisons.  

PubMed

The biological characteristics of Aedes aegypti (Diptera, Culicidae), which is a vector of dengue and yellow fever, make this organism a good model for studying population structure and the events that may influence it under the effect of human activity. We assessed the genetic variability of five A. aegypti populations using RAPD-PCR technique and six primers. Four populations were from Brazil and one was from the USA. A total of 165 polymorphic DNA loci were generated. Considering the six primers and the five populations, the mean value of inter-population genetic diversity (Gst) was 0.277, which is considered high according to the Wright classification. However, pairwise comparisons of the populations gave variable Gst values ranging from 0.044 to 0.289. This variation followed the population's geographic distance to some extent but was also influenced by human activity. The lowest Gst values were obtained in the comparison of populations from cities with intensive commercial and medical contacts. These mosquito populations were previously classified as insecticide resistant, susceptible, or with decreased susceptibility; this parameter apparently had an effect on the Gst values obtained in the pairwise comparisons. PMID:24085439

Patarro, T de F; Guirado, M M; Ravazzi, L M; Bicudo, H E M de C

2013-01-01

296

Integrative Approach to Pain Genetics Identifies Pain Sensitivity Loci across Diseases  

Microsoft Academic Search

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

David Ruau; Joel T. Dudley; Rong Chen; Nicholas G. Phillips; Gary E. Swan; Laura C. Lazzeroni; J. David Clark; Atul J. Butte; Martin S. Angst

2012-01-01

297

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

298

Molecular modeling, organ culture and reverse genetics for a newly identified human rhinovirus C  

PubMed Central

A recently recognized human rhinovirus species C (HRV-C) is associated with up to half of HRV infections in young children. We for the first time propagated two HRV-C isolates ex vivo in organ culture of nasal epithelial cells, sequenced a new C15 isolate, and developed the first reverse genetics system for HRV-C. Using contact points for the known HRV receptors, intercellular adhesion molecule 1 (ICAM-1) and low density lipoprotein receptor (LDLR), inter- and intraspecies footprint analysis predicted a unique cell attachment site for HRV-Cs. Antibodies directed to binding sites for HRV-A and -B failed to inhibit HRV-C attachment, consistent with the alternative receptor footprint. HRV-A and -B infected HeLa and WisL cells, but HRV-C did not. However, HRV-C RNA synthesized in vitro and transfected into both cell types resulted in cytopathic effect and recovery of functional virus, indicating that the viral attachment mechanism is a primary distinguishing feature of HRV-C. PMID:21483405

Bochkov, Yury A; Palmenberg, Ann C; Lee, Wai-Ming; Rathe, Jennifer A; Amineva, Svetlana P; Sun, Xin; Pasic, Thomas R; Jarjour, Nizar N; Liggett, Stephen B; Gern, James E

2010-01-01

299

Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease  

PubMed Central

SUMMARY The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer’s disease (LOAD), we constructed gene regulatory networks in 1647 post-mortem brain tissues from LOAD patients and non-demented subjects, and demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune and microglia-specific module dominated by genes involved in pathogen phagocytosis, containing TYROBP as a key regulator and up-regulated in LOAD. Mouse microglia cells over-expressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a novel framework to test models of disease mechanisms underlying LOAD. PMID:23622250

Zhang, Bin; Gaiteri, Chris; Bodea, Liviu-Gabriel; Wang, Zhi; McElwee, Joshua; Podtelezhnikov, Alexei A.; Zhang, Chunsheng; Xie, Tao; Tran, Linh; Dobrin, Radu; Fluder, Eugene; Clurman, Bruce; Melquist, Stacey; Narayanan, Manikandan; Suver, Christine; Shah, Hardik; Mahajan, Milind; Gillis, Tammy; Mysore, Jayalakshmi; MacDonald, Marcy E.; Lamb, John R.; Bennett, David A; Molony, Cliona; Stone, David J.; Gudnason, Vilmundur; Myers, Amanda J.; Schadt, Eric E.; Neumann, Harald; Zhu, Jun; Emilsson, Valur

2013-01-01

300

Genetic characteristics of cellulose-forming acetic acid bacteria identified phenotypically as Gluconacetobacter xylinus.  

PubMed

Gluconacetobacter xylinus (=Acetobacter xylinum) shows variety in acid formation from sugars and sugar-alcohols. Toyosaki et al. proposed new subspecies of G. xylinus (=Acetobacter xylinum) subsp. sucrofermentans in point of acid formation from sucrose and a homology index of 58.2% with the type strain of G. xylinus subsp. xylinus in DNA-DNA hybridization experiments. We tried DNA-DNA hybridization to clarify relationship between acid formation from sugars and classification of G. xylinus. The G + C contents of G. xylinus showed 60.1-62.4 mol% with a range of 2.3 mol%. When type strains of G. xylinus subsp. xylinus, G. xylinus subsp. sucrofermentans, and IFO 3288 forming acid from sucrose, were used as probes, the DNAs from three strains showed 67-100%, 64-89%, and 60-100% similarity to those from sixteen strains including bacteria that form acid from sucrose or not. These results show that homology indexes do not reflect differences of acid formation from sucrose. As a results, the species G. xylinus was proved to be genetically homogeneous. PMID:10830489

Tanaka, M; Murakami, S; Shinke, R; Aoki, K

2000-04-01

301

Genetically identified complete hydatidiform mole coexisting with a live twin fetus: comparison with conventional diagnosis.  

PubMed

Twin pregnancy consisting of a complete hydatidiform mole (CHM) along with a live co-existing fetus is a rare entity and difficult to diagnose. A 37-year-old Japanese woman demonstrated a living fetus, a placenta and a multicystic mass within one gestational sac on ultrasound at 10 weeks. Termination of the pregnancy was performed, and the specimen was classified as partial mole by macro- and microscopic findings. The karyotype of the molar tissue was 46XX. DNA polymorphism analysis demonstrated that fetal DNA showed bi-parental origin while molar DNA showed paternal origin only. Thus, this case was erroneously classified by ultrasonography, macroscopic and pathologic findings, then correctly diagnosed as a twin pregnancy with a CHM and co-existing normal twin fetus by DNA polymorphism analysis. Immunohistochemistry of p57(KIP2), the paternally imprinted and maternally expressed gene, supported the genetic diagnosis. This case suggested that conventional diagnostic methods were inadequate for accurate diagnosis of CHM with a co-existing fetus. DNA polymorphism analysis should be requested for the diagnosis of hydatidiform mole, especially in cases where it is difficult to discriminate between partial hydatidiform mole and CHM with a co-existing fetus. PMID:17664887

Sumigama, Seiji; Itakura, Atsuo; Yamamoto, Toshimichi; Nagasaka, Tetsuro; Yamamoto, Eiko; Ino, Kazuhiko; Kikkawa, Fumitaka

2007-01-01

302

An In vivo Chemical Genetic Screen Identifies Phosphodiesterase 4 as a Pharmacological Target for Hedgehog signaling Inhibition  

PubMed Central

SUMMARY Hedgehog (Hh) signaling plays an integral role in vertebrate development, and its dysregulation has been widely accepted as a driver of numerous malignancies. While a variety of small molecules target Smoothened (Smo) as a strategy for Hh inhibition, Smo gain of function mutations have limited their clinical implementation. Modulation of targets downstream of Smo could define a paradigm for treatment of Hh-dependent cancers. Here, we describe eggmanone, a small molecule identified from a chemical genetic zebrafish screen which induced a Hh-null phenotype. Eggmanone exerts its Hh-inhibitory effects through selective antagonism of phosphodiesterase (PDE) 4, leading to protein kinase A activation and subsequent Hh blockade. Our study implicates PDE4 as a target for Hh inhibition, suggests an improved strategy for Hh-dependent cancer therapy and identifies a unique probe of downstream-of-Smo Hh modulation. PMID:25818300

Williams, Charles H.; Hempel, Jonathan E.; Hao, Jijun; Frist, Audrey Y.; Williams, Michelle M.; Fleming, Jonathan T.; Sulikowski, Gary A.; Cooper, Michael K.; Chiang, Chin; Hong, Charles C.

2015-01-01

303

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

PubMed

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological 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, Tõnu; 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, Åsa; 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 O; de Faire, Ulf; de Vegt, Femmie; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M; Farrall, Martin; Ferrario, Marco M; Ferrières, 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; Kivimäki, 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; Keinanen-Kiukaanniemi, Sirkka M; Kiemeney, Lambertus A; Kuh, Diana; Laakso, Markku; Lehtimäki, Terho; Levinson, Douglas F; Martin, Nicholas G; Metspalu, Andres; Morris, Andrew D; Nieminen, Markku S

2013-05-01

304

A high-resolution genetic map of yellow monkeyflower identifies chemical defense QTLs and recombination rate variation.  

PubMed

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

2014-05-01

305

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

306

Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients.  

PubMed

Fetal hemoglobin (HbF) level has emerged as an important prognostic factor in sickle-cell disease (SCD) and can be measured by the proportion of HbF-containing erythrocytes (F-cells). Recently, BCL11A (zinc-finger protein) was identified as a regulator of HbF, and the strongest association signals were observed either directly for rs766432 or for correlated single-nucleotide polymorphisms (SNPs). To identify additional independently associated genetic variants, we performed a genome-wide association study (GWAS) on the proportion of F-cells in individuals of African ancestry with SCD from the Silent Infarct Transfusion (SIT) Trial cohort. Our study not only confirms the association of rs766432 (P-value <3.32 × 10(-13)), but also identifies an independent novel intronic SNP, rs7606173, associated with F-cells (P-value <1.81 × 10(-15)). The F-cell variances explained independently by these two SNPs are ?13% (rs7606173) and ?11% (rs766432), whereas, together they explain ?16%. Additionally, in men, we identify a novel locus on chromosome 17, glucagon-like peptide-2 receptor (GLP2R), associated with F-cell regulation (rs12103880; P-value <3.41 × 10(-8)). GLP2R encodes a G protein-coupled receptor and involved in proliferative and anti-apoptotic cellular responses. These findings highlight the importance of denser genetic screens and suggest further exploration of the BCL11A and GLP2R loci to gain additional insight into HbF/F-cell regulation. PMID:21326311

Bhatnagar, Pallav; Purvis, Shirley; Barron-Casella, Emily; DeBaun, Michael R; Casella, James F; Arking, Dan E; Keefer, Jeffrey R

2011-04-01

307

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...

308

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

309

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome.  

PubMed

NOTCH1 has been found recurrently mutated in a subset of patients with chronic lymphocytic leukemia (CLL). To analyze biological features and clinical impact of NOTCH1 mutations in CLL, we sequenced this gene in 565 patients. NOTCH1 mutations, found in 63 patients (11%), were associated with unmutated IGHV, high expression of CD38 and ZAP-70, trisomy 12, advanced stage and elevated lactate dehydrogenase. Sequential analysis in 200 patients demonstrated acquisition of mutation in one case (0.5%) and disappearance after treatment in two. Binet A and B patients with NOTCH1-mutated had a shorter time to treatment. NOTCH1-mutated patients were more frequently refractory to therapy and showed shorter progression-free and overall survival after complete remission. Overall survival was shorter in NOTCH1-mutated patients, although not independently from IGHV. NOTCH1 mutation increased the risk of transformation to diffuse large B-cell lymphoma independently from IGHV, with this being validated in resampling tests of replicability. In summary, NOTCH1 mutational status, that was rarely acquired during the course of the disease, identify a genetic subgroup with high risk of transformation and poor outcome. This recently identified genetic subgroup of CLL patients deserves prospective studies to define their best management. PMID:23295735

Villamor, N; Conde, L; Martínez-Trillos, A; Cazorla, M; Navarro, A; Beà, S; López, C; Colomer, D; Pinyol, M; Aymerich, M; Rozman, M; Abrisqueta, P; Baumann, T; Delgado, J; Giné, E; González-Díaz, M; Hernández, J M; Colado, E; Payer, A R; Rayon, C; Navarro, B; José Terol, M; Bosch, F; Quesada, V; Puente, X S; López-Otín, C; Jares, P; Pereira, A; Campo, E; López-Guillermo, A

2013-04-01

310

Genetic screening test for psoriatic arthritis and UVB irradiation potential responders: A new tool to identify psoriasis subpopulation patients?  

PubMed Central

Psoriatic arthritis (PsA) is a psoriasis-associated inflammatory disease of the joints and enthuses. The occurrence of PsA is linked to the complex interplay of gene environment, and immune system. Genetic factors have long been recognized to play an important role in PsA. Genes within the major histocompatibility complex (MHC) region have been shown to be associated with PsA. These include genes coded in the HLA region, (especially Class I antigens) and non-HLA genes (i.e., MHC class I chain-related antigen A, MICA, and TNF-? genes). Association studies in PsA have also identified a number of genes outside MHC region, including interleukin-1 (IL-1) gene cluster, killer-cell immunoglobulin-like receptors (KIRs), and IL-23R genes. Established systemic treatments for moderate-severe psoriasis and PsA may be potentially dangerous and usually time consuming for the patient and often expensive for the National Health Systems. Tests which could predict which subset of psoriatic patients could develop the most severe forms of the disease (i.e., PsA) or will respond to well-established (UVB irradiation) or other systemic treatments are now required. The goal of genetic test screening is to rapidly and safely identify subjects for preventive or early treatment or extended surveillance prior to the onset of signs and symptoms. Genetic tests today represent a reliable investigation procedure which could rapidly and consistently improve the diagnostic ability of the dermatologist and contribute to the early and correct treatment of the different subsets of PsA. PMID:23130225

Lotti, Torello; Tognetti, Linda; Galeone, Massimiliano; Bruscino, Nicola; Moretti, Silvia; Giorgini, Simonetta

2011-01-01

311

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

312

High density array screening to identify the genetic requirements for transition metal tolerance in Saccharomyces cerevisiae.  

PubMed

Biological systems have developed with a strong dependence on transition metals for accomplishing a number of biochemical reactions. Iron, copper, manganese and zinc are essential for virtually all forms of life with their unique chemistries contributing to a variety of physiological processes including oxygen transport, generation of cellular energy and protein structure and function. Properties of these metals (and to a lesser extent nickel and cobalt) that make them so essential to life also make them extremely cytotoxic in many cases through the formation of damaging oxygen radicals via Fenton chemistry. While life has evolved to exploit the chemistries of transition metals to drive physiological reactions, systems have concomitantly evolved to protect against the damaging effects of these same metals. Saccharomyces cerevisiae is a valuable tool for studying metal homeostasis with many of the genes identified thus far having homologs in higher eukaryotes including humans. Using high density arrays, we have screened a haploid S. cerevisiae deletion set containing 4786 non-essential gene deletions for strains sensitive to each of Fe, Cu, Mn, Ni, Zn and Co and then integrated the six screens using cluster analysis to identify pathways that are unique to individual metals and others with function shared between metals. Genes with no previous implication in metal homeostasis were found to contribute to sensitivity to each metal. Significant overlap was observed between the strains that were sensitive to Mn, Ni, Zn and Co with many of these strains lacking genes for the high affinity Fe transport pathway and genes involved in vacuolar transport and acidification. The results from six genome-wide metal tolerance screens show that there is some commonality between the cellular defenses against the toxicity of Mn, Ni, Zn and Co with Fe and Cu requiring different systems. Additionally, potential new factors been identified that function in tolerance to each of the six metals. PMID:21212869

Bleackley, Mark R; Young, Barry P; Loewen, Christopher J R; MacGillivray, Ross T A

2011-02-01

313

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

USGS Publications Warehouse

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.

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

2013-01-01

314

DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features.  

PubMed

Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvival lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation. PMID:25612624

Arribas, Alberto J; Rinaldi, Andrea; Mensah, Afua A; Kwee, Ivo; Cascione, Luciano; Robles, Eloy F; Martinez-Climent, Jose A; Oscier, David; Arcaini, Luca; Baldini, Luca; Marasca, Roberto; Thieblemont, Catherine; Briere, Josette; Forconi, Francesco; Zamò, Alberto; Bonifacio, Massimiliano; Mollejo, Manuela; Facchetti, Fabio; Dirnhofer, Stephan; Ponzoni, Maurilio; Bhagat, Govind; Piris, Miguel A; Gaidano, Gianluca; Zucca, Emanuele; Rossi, Davide; Bertoni, Francesco

2015-03-19

315

High density genetic mapping identifies new susceptibility loci for rheumatoid arthritis  

PubMed Central

Summary Using the Immunochip custom single nucleotide polymorphism (SNP) array, designed for dense genotyping of 186 genome wide association study (GWAS) confirmed loci we analysed 11,475 rheumatoid arthritis cases of European ancestry and 15,870 controls for 129,464 markers. The data were combined in meta-analysis with GWAS data from additional independent cases (n=2,363) and controls (n=17,872). We identified fourteen novel loci; nine were associated with rheumatoid arthritis overall and 5 specifically in anti-citrillunated peptide antibody positive disease, bringing the number of confirmed European ancestry rheumatoid arthritis loci to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at six loci and association to low frequency variants (minor allele frequency <0.05) at 4 loci. Bioinformatic analysis of the data 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; Raychaudhuri, Soumya; Klareskog, Lars; Gregersen, Peter K; Worthington, Jane

2012-01-01

316

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

317

Genetic Determinants of 21-Hydroxylase Autoantibodies Amongst Patients of the Type 1 Diabetes Genetics Consortium  

PubMed Central

Background: Autoantibodies to 21-hydroxylase (21OH-AA) precede the onset of autoimmune Addison's disease (AD) and are found in 1.5% of individuals with type 1 diabetes mellitus (T1DM). The greatest genetic risk for both disorders is found in the major histocompatibility complex (MHC), suggesting a common pathophysiology between AD and T1DM. Screening for 21OH-AA in newly diagnosed T1DM patients is a valuable prognostic tool, made stronger when MHC genotype is considered. Methods: The Type 1 Diabetes Genetics Consortium has collected genotype data in T1DM subjects with tissue-specific autoantibody typing. Genotype and phenotype data in individuals positive and negative for 21OH-AA are compared. Results: Major genetic risk for 21OH-AA is in the MHC haplotypes DRB1*04-DQB1*0302 (primarily DRB1*0404) and DRB1*0301-DQB1*0201. Protective effects in class II MHC haplotypes DRB1*0101-DQB1*0501 and DRB1*0701-DQB1*0202 also were detected. There is no difference in the presence of HLA-B15 and little difference in the presence of HLA-B8 (after class II effects are accounted for) in T1DM patients with 21OH-AA compared with known associations (HLA-B8 positive and HLA-B15 negative) in AD. Conclusions: In 21OH-AA+ subjects, genetic risk is found mainly in MHC class II haplotypes DR3 and DR4 but not class I alleles (HLA-B8 or HLA-B15). This suggests a difference between autoantibody formation (class II dependent) and progression to overt disease (class I dependent) in AD. PMID:22723331

Baker, Peter; Fain, Pam; Kahles, Heinrich; Yu, Liping; Hutton, John; Wenzlau, Janet; Rewers, Marian; Badenhoop, Klaus

2012-01-01

318

Determining DNA Sequence Specificity of Natural and Artificial Transcription Factors by Cognate Site Identifier Analysis  

NASA Astrophysics Data System (ADS)

Artificial transcription factors (ATFs) are designed to mimic natural transcription factors in the control of gene expression and are comprised of domains for DNA binding and gene regulation. ATF domains are modular, interchangeable, and can be composed of protein-based or nonpeptidic moieties, yielding DNA-interacting regulatory molecules that can either activate or inhibit transcription. Sequence-specific targeting is a key determinant in ATF activity, and DNA-binding domains such as natural zinc fingers and synthetic polyamides have emerged as useful DNA targeting molecules. Defining the comprehensive DNA binding specificity of these targeting molecules for accurate manipulations of the genome can be achieved using cognate site identifier DNA microarrays to explore the entire sequence space of binding sites. Design of ATFs that regulate gene expression with temporal control will generate important molecular tools to probe cell- and tissue-specific gene regulation and to function as potential therapeutic agents.

Ozers, Mary S.; Warren, Christopher L.; Ansari, Aseem Z.

319

Antimicrobial resistance, virulence determinants and genetic profiles of clinical and nonclinical Enterococcus cecorum from poultry.  

PubMed

Enterococcus cecorum has been implicated as a possible cause of disease in poultry. However, the characteristics that contribute to pathogenesis of Ent. cecorum in poultry have not been defined. In this study, Ent. cecorum from carcass rinsates (n = 75) and diseased broilers and broiler breeders (n = 30) were compared based upon antimicrobial resistance phenotype, the presence of virulence determinants and genetic relatedness using pulsed-field gel electrophoresis (PFGE). Of the 16 antimicrobials tested, Ent. cecorum from carcass rinsates and clinical cases were resistant to ten and six of the antimicrobials, respectively. The majority of Ent. cecorum from carcass rinsates was resistant to lincomycin (54/75; 72%) and tetracycline (46/75; 61.3%) while the highest level of resistance among clinical Ent. cecorum was to tetracycline (22/30; 73.3%) and erythromycin (11/30; 36.7%). Multidrug resistance (resistance to ?2 antimicrobials) was identified in Ent. cecorum from carcass rinsates (53/75; 70.7%) and diseased poultry (18/30; 60%). Of the virulence determinants tested, efaAfm was present in almost all of the isolates (104/105; 99%). Using PFGE, the majority of clinical isolates clustered together; however, a few clinical isolates grouped with Ent. cecorum from carcass rinsates. These data suggest that distinguishing the two groups of isolates is difficult based upon the characterization criteria used. PMID:25470229

Jackson, C R; Kariyawasam, S; Borst, L B; Frye, J G; Barrett, J B; Hiott, L M; Woodley, T A

2015-02-01

320

Novel Determinants of Intestinal Colonization of Salmonella enterica Serotype Typhimurium Identified in Bovine Enteric Infection  

PubMed Central

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.

2013-01-01

321

Identifying the Prevalence, Trajectory, and Determinants of Psychological Distress in Extremity Sarcoma  

PubMed Central

Objective. Extremity sarcoma (ES) is a rare cancer that presents with unique challenges. This study was performed to identify the prevalence, trajectory, and determinants of distress and characterise sources of stress in this cohort. Methods. Consecutive patients with ES were prospectively recruited between May 2011 and December 2012. Questionnaires were administered during initial diagnosis and then six months and one year after surgery. Results. Distress was reported by about a third of our cohort and associated with poorer physical function, poorer quality of life, and pain. In addition to fears regarding mortality and life role changes, the most common sources of stress were centered on dissatisfaction with the healthcare system, such as frustrations with a lack of communication with the hospital regarding appointments and lack of education regarding management and outcomes. Conclusions. Psychological distress presents early in the cancer journey and persists up to one year after surgery. Distress is associated with negative outcomes. Active screening and effective interventions are necessary to improve outcomes. Sources of stress have been identified that may be amenable to targeted interventions. PMID:25767410

Tang, Melissa H.; Castle, David J.; Choong, Peter F. M.

2015-01-01

322

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

323

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

324

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

325

On the genetic determinism of muscular hypertrophy in the Belgian White and Blue cattle breed  

E-print Network

On the genetic determinism of muscular hypertrophy in the Belgian White and Blue cattle breed I-1070 Bruxelles, Belgique Summary The inheritance of muscle hypertrophy has been studied. It is concluded that a major gene is involved in the determination of muscle hypertrophy in the Belgian Blue

Paris-Sud XI, Université de

326

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

327

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

328

A Large-Scale Rheumatoid Arthritis Genetic Study Identifies Association at Chromosome 9q33.2  

PubMed Central

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (ORcommon?=?1.28, trend Pcomb?=?1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (Pcomb<0.01) spanned a large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified SNPs in a 70 kb region extending from the third intron of PHF19 across TRAF1 into the TRAF1-C5 intergenic region, but excluding the C5 coding region, as the most interesting (trend Pcomb: 1.45E-06 ? 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential. PMID:18648537

Chang, Monica; Rowland, Charles M.; Garcia, Veronica E.; Schrodi, Steven J.; Catanese, Joseph J.; van der Helm-van Mil, Annette H. M.; Ardlie, Kristin G.; Amos, Christopher I.; Criswell, Lindsey A.; Kastner, Daniel L.; Gregersen, Peter K.; Kurreeman, Fina A. S.; Toes, Rene E. M.; Huizinga, Tom W. J.; Seldin, Michael F.; Begovich, Ann B.

2008-01-01

329

Genetic and Molecular Characterization of Submergence Response Identifies Subtol6 as a Major Submergence Tolerance Locus in Maize  

PubMed Central

Maize is highly sensitive to short term flooding and submergence. Early season flooding reduces germination, survival and growth rate of maize seedlings. We aimed to discover genetic variation for submergence tolerance in maize and elucidate the genetic basis of submergence tolerance through transcriptional profiling and linkage analysis of contrasting genotypes. A diverse set of maize nested association mapping (NAM) founder lines were screened, and two highly tolerant (Mo18W and M162W) and sensitive (B97 and B73) genotypes were identified. Tolerant lines exhibited delayed senescence and lower oxidative stress levels compared to sensitive lines. Transcriptome analysis was performed on these inbreds to provide genome level insights into the molecular responses to submergence. Tolerant lines had higher transcript abundance of several fermentation-related genes and an unannotated Pyrophosphate-Dependent Fructose-6-Phosphate 1-Phosphotransferase gene during submergence. A coexpression network enriched for CBF (C-REPEAT/DRE BINDING FACTOR: C-REPEAT/DRE BINDING FACTOR) genes, was induced by submergence in all four inbreds, but was more activated in the tolerant Mo18W. A recombinant inbred line (RIL) population derived from Mo18W and B73 was screened for submergence tolerance. A major QTL named Subtol6 was mapped to chromosome 6 that explains 22% of the phenotypic variation within the RIL population. We identified two candidate genes (HEMOGLOBIN2 and RAV1) underlying Subtol6 based on contrasting expression patterns observed in B73 and Mo18W. Sources of tolerance identified in this study (Subtol6) can be useful to increase survival rate during flooding events that are predicted to increase in frequency with climate change. PMID:25806518

Campbell, Malachy T.; Proctor, Christopher A.; Dou, Yongchao; Schmitz, Aaron J.; Phansak, Piyaporn; Kruger, Greg R.; Zhang, Chi; Walia, Harkamal

2015-01-01

330

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

331

Genetic determinants of type 1 diabetes: immune response genes.  

PubMed

Type 1 diabetes (T1D) is a polygenic autoimmune disease. Susceptibility to T1D is strongly linked to a major genetic locus that is the MHC, and several other minor loci including insulin, cytotoxic T-lymphocyte-associated antigen-4, PTPN22 and others that contribute to diabetes risk in an epistatic way. We have observed that there are three sets of DR3-positive autoimmunity-favoring haplotypes in the north-Indian population, including B50-DR3, B58-DR3 and B8-DR3. The classical Caucasian autoimmunity favoring AH8.1 (HLA-A1-B8-DR3) is rare in the Indian population, and has been replaced by a variant AH8.1v, which differs from the Caucasian AH8.1 at several gene loci. Similarly, there are additional HLA-DR3 haplotypes, A26-B8-DR3 (AH8.2), A24-B8-DR3 (AH8.3), A3-B8-DR3 (AH8.4) and A31-B8-DR3 (AH8.5), of which AH8.2 is the most common. The fact that disease-associated DR3-positive haplotypes show heterogeneity in different populations suggests that these might possess certain shared components that are involved in the development of autoimmunity. PMID:20477508

Kumar, Neeraj; Kaur, Gurvinder; Mehra, Narinder

2009-04-01

332

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

333

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

334

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...

335

SOYBEAN UNIGENES – USING SNPS TO DETERMINE THEIR GENETIC MAP POSITION  

Technology Transfer Automated Retrieval System (TEKTRAN)

Single Nucleotide Polymorphisms (SNPs) were discovered in more than 1000 soybean unigenes via resequencing. Resequencing determined the presence of polymorphism in two of the five mapping populations used to develop the current simple sequence repeat-based soybean linkage map constructed using Join...

336

Genetic and functional analyses identify DISC1 as a novel callosal agenesis candidate gene.  

PubMed

Agenesis of the corpus callosum (AgCC) is a congenital brain malformation that occurs in approximately 1:1,000-1:6,000 births. Several syndromes associated with AgCC have been traced to single gene mutations; however, the majority of AgCC causes remain unidentified. We investigated a mother and two children who all shared complete AgCC and a chromosomal deletion at 1q42. We fine mapped this deletion and show that it includes Disrupted-in-Schizophrenia 1 (DISC1), a gene implicated in schizophrenia and other psychiatric disorders. Furthermore, we report a de novo chromosomal deletion at 1q42.13 to q44, which includes DISC1, in another individual with AgCC. We resequenced DISC1 in a cohort of 144 well-characterized AgCC individuals and identified 20 sequence changes, of which 4 are rare potentially pathogenic variants. Two of these variants were undetected in 768 control chromosomes. One of these is a splice site mutation at the 5' boundary of exon 11 that dramatically reduces full-length mRNA expression of DISC1, but not of shorter forms. We investigated the developmental expression of mouse DISC1 and find that it is highly expressed in the embryonic corpus callosum at a critical time for callosal formation. Taken together our results suggest a significant role for DISC1 in corpus callosum development. PMID:21739582

Osbun, Nathan; Li, Jiang; O'Driscoll, Mary C; Strominger, Zoe; Wakahiro, Mari; Rider, Eric; Bukshpun, Polina; Boland, Elena; Spurrell, Cailyn H; Schackwitz, Wendy; Pennacchio, Len A; Dobyns, William B; Black, Graeme C M; Sherr, Elliott H

2011-08-01

337

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

338

A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates  

PubMed Central

Injury to the central nervous system (CNS) can result in lifelong loss of function due in part to the regenerative failure of CNS neurons. Inhibitory proteins derived from myelin and the astroglial scar are major barriers for the successful regeneration of injured CNS neurons. Previously, we described the identification of a novel compound, F05, which promotes neurite growth from neurons challenged with inhibitory substrates in vitro, and promotes axonal regeneration in vivo (Usher et al., 2010). To identify additional regeneration-promoting compounds, we used F05-induced gene expression profiles to query the Broad Institute Connectivity Map, a gene expression database of cells treated with >1,300 compounds. Despite no shared chemical similarity, F05-induced changes in gene expression were remarkably similar to those seen with a group of piperazine phenothiazine antipsychotics (PhAPs). In contrast to antipsychotics of other structural classes, PhAPs promoted neurite growth of CNS neurons challenged with two different glial derived inhibitory substrates. Our pharmacological studies suggest a mechanism whereby PhAPs promote growth through antagonism of calmodulin signaling, independent of dopamine receptor antagonism. These findings shed light on mechanisms underlying neurite-inhibitory signaling, and suggest that clinically approved antipsychotic compounds may be repurposed for use in CNS injured patients. PMID:22561309

Johnstone, AL; Reierson, GW; Smith, RP; Goldberg, JL; Lemmon, VP; Bixby, JL

2012-01-01

339

A High Throughput Genetic Screen Identifies New Early Meiotic Recombination Functions in Arabidopsis thaliana  

PubMed Central

Meiotic recombination is initiated by the formation of numerous DNA double-strand breaks (DSBs) catalysed by the widely conserved Spo11 protein. In Saccharomyces cerevisiae, Spo11 requires nine other proteins for meiotic DSB formation; however, unlike Spo11, few of these are conserved across kingdoms. In order to investigate this recombination step in higher eukaryotes, we took advantage of a high-throughput meiotic mutant screen carried out in the model plant Arabidopsis thaliana. A collection of 55,000 mutant lines was screened, and spo11-like mutations, characterised by a drastic decrease in chiasma formation at metaphase I associated with an absence of synapsis at prophase, were selected. This screen led to the identification of two populations of mutants classified according to their recombination defects: mutants that repair meiotic DSBs using the sister chromatid such as Atdmc1 or mutants that are unable to make DSBs like Atspo11-1. We found that in Arabidopsis thaliana at least four proteins are necessary for driving meiotic DSB repair via the homologous chromosomes. These include the previously characterised DMC1 and the Hop1-related ASY1 proteins, but also the meiotic specific cyclin SDS as well as the Hop2 Arabidopsis homologue AHP2. Analysing the mutants defective in DSB formation, we identified the previously characterised AtSPO11-1, AtSPO11-2, and AtPRD1 as well as two new genes, AtPRD2 and AtPRD3. Our data thus increase the number of proteins necessary for DSB formation in Arabidopsis thaliana to five. Unlike SPO11 and (to a minor extent) PRD1, these two new proteins are poorly conserved among species, suggesting that the DSB formation mechanism, but not its regulation, is conserved among eukaryotes. PMID:19763177

Vezon, Daniel; Chelysheva, Liudmila; Gendrot, Ghislaine; Chambon, Aurélie; Lainé-Choinard, Sandrine; Pelletier, Georges; Mercier, Raphaël; Nogué, Fabien; Grelon, Mathilde

2009-01-01

340

Genome-wide association study identifies three novel genetic markers associated with elite endurance performance  

PubMed Central

To investigate the association between multiple single-nucleotide polymorphisms (SNPs), aerobic performance and elite endurance athlete status in Russians. By using GWAS approach, we examined the association between 1,140,419 SNPs and relative maximal oxygen consumption rate (V.O2max) in 80 international-level Russian endurance athletes (46 males and 34 females). To validate obtained results, we further performed case-control studies by comparing the frequencies of the most significant SNPs (with P < 10?5-10?8) between 218 endurance athletes and opposite cohorts (192 Russian controls, 1367 European controls, and 230 Russian power athletes). Initially, six ‘endurance alleles’ were identified showing discrete associations with V.O2max both in males and females. Next, case-control studies resulted in remaining three SNPs (NFIA-AS2 rs1572312, TSHR rs7144481, RBFOX1 rs7191721) associated with endurance athlete status. The C allele of the most significant SNP, rs1572312, was associated with high values of V.O2max (males: P = 0.0051; females: P = 0.0005). Furthermore, the frequency of the rs1572312 C allele was significantly higher in elite endurance athletes (95.5%) in comparison with non-elite endurance athletes (89.8%, P = 0.0257), Russian (88.8%, P = 0.007) and European (90.6%, P = 0.0197) controls and power athletes (86.2%, P = 0.0005). The rs1572312 SNP is located on the nuclear factor I A antisense RNA 2 (NFIA-AS2) gene which is supposed to regulate the expression of the NFIA gene (encodes transcription factor involved in activation of erythropoiesis and repression of the granulopoiesis). Our data show that the NFIA-AS2 rs1572312, TSHR rs7144481 and RBFOX1 rs7191721 polymorphisms are associated with aerobic performance and elite endurance athlete status. PMID:25729143

Kulemin, NA; Popov, DV; Naumov, VA; Akimov, EB; Bravy, YR; Egorova, ES; Galeeva, AA; Generozov, EV; Kostryukova, ES; Larin, AK; Mustafina, LJ; Ospanova, EA; Pavlenko, AV; Starnes, LM; ?mijewski, P; Alexeev, DG; Vinogradova, OL; Govorun, VM

2014-01-01

341

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

342

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

343

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

344

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

345

Linking Genetics to Structural Biology: Complex Heterozygosity Screening with Actin Alanine Scan Alleles Identifies Functionally Related Surfaces on Yeast Actin  

PubMed Central

Previous genome-level genetic interaction screens with the single essential actin gene of yeast identified 238 nonessential genes that upon deletion result in deleterious, digenic complex haploinsufficiences with an actin null allele. Deletion alleles of these 238 genes were tested for complex heterozygous interactions with 32 actin alanine scan alleles, which target clusters of residues on the surface of actin. A total of 891 deleterious digenic combinations were identified with 203 of the 238 genes. Two-dimensional hierarchical cluster analysis of the interactions identified nine distinct groups, and the alleles within clusters tended to affect localized regions on the surface of actin. The mutants in one cluster all affect electrostatic interactions between stacked subunits in the long pitch helix of the actin filament. A second cluster that contains the most highly interactive alleles may disrupt the tropomyosin/myosin system, as one of the mutants in that cluster cannot support Type V myosin-dependent movement of secretory vesicles in haploids and causes processivity defects in heterozygous diploids. These examples suggest the clusters represent mutations with shared protein?protein interaction defects. These results show that complex heterozygous interaction screens have benefit for detecting actin-related genes and suggest that having actin filaments of mixed composition, containing both mutant and wild-type subunits, presents unique challenges to the cell. PMID:24938290

DiPrima, Stephanie; Haarer, Brian; Viggiano, Susan; Pons, Carles; Myers, Chad L.; Amberg, David C.

2014-01-01

346

Patterns and mechanisms of evolutionary transitions between genetic sex-determining systems.  

PubMed

The diversity and patchy phylogenetic distribution of genetic sex-determining mechanisms observed in some taxa is thought to have arisen by the addition, modification, or replacement of regulators at the upstream end of the sex-determining pathway. Here, I review the various evolutionary forces acting on upstream regulators of sexual development that can cause transitions between sex-determining systems. These include sex-ratio selection and pleiotropic benefits, as well as indirect selection mechanisms involving sex-linked sexually antagonistic loci or recessive deleterious mutations. Most of the current theory concentrates on the population-genetic aspects of sex-determination transitions, using models that do not reflect the developmental mechanisms involved in sex determination. However, the increasing availability of molecular data creates opportunities for the development of mechanistic models that can clarify how selection and developmental architecture interact to direct the evolution of sex-determination genes. PMID:24993578

Sander van Doorn, G

2014-08-01

347

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

348

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, Tõnu; 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, Åsa; 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.; Ferrières, 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

349

A microsatellite-based genetic linkage map and putative sex-determining genomic regions in Lake Victoria cichlids.  

PubMed

Cichlid fishes in East Africa have undergone extensive adaptive radiation, which has led to spectacular diversity in their morphology and ecology. To date, genetic linkage maps have been constructed for several tilapias (riverine), Astatotilapia burtoni (Lake Tanganyika), and hybrid lines of Lake Malawi cichlids to facilitate genome-wide comparative analyses. In the present study, we constructed a genetic linkage map of the hybrid line of Lake Victoria cichlids, so that maps of cichlids from all the major areas of East Africa will be available. The genetic linkage map shown here is derived from the F2 progeny of an interspecific cross between Haplochromis chilotes and Haplochromis sauvagei and is based on 184 microsatellite and two single-nucleotide polymorphism (SNP) markers. Most of the microsatellite markers used in the present study were originally designed for other genetic linkage maps, allowing us to directly compare each linkage group (LG) among different cichlid groups. We found 25 LGs, the total length of which was 1133.2cM with an average marker spacing of about 6.09cM. Our subsequent linkage mapping analysis identified two putative sex-determining loci in cichlids. Interestingly, one of these two loci is located on cichlid LG5, on which the female heterogametic ZW locus and several quantitative trait loci (QTLs) related to adaptive evolution have been reported in Lake Malawi cichlids. We also found that V1R1 and V1R2, candidate genes for the fish pheromone receptor, are located very close to the recently detected sex-determining locus on cichlid LG5. The genetic linkage map study presented here may provide a valuable foundation for studying the chromosomal evolution of East African cichlids and the possible role of sex chromosomes in generating their genomic diversity. PMID:25639358

Kudo, Yu; Nikaido, Masato; Kondo, Azusa; Suzuki, Hikoyu; Yoshida, Kohta; Kikuchi, Kiyoshi; Okada, Norihiro

2015-04-15

350

Birth of healthy female twins after preimplantation genetic diagnosis of cystic fibrosis combined with gender determination  

Microsoft Academic Search

Two healthy sisters with a familial history of mental retardation were referred to our centre for preimplantation genetic diagnosis (PGD). Their two brothers showed severe mental retardation. The molecular basis for their disorder could not be identified, but one of the sisters and the mother presented a highly skewed pattern of X-inactivation reinforcing the likelihood of an X-linked mode of

Pierre F. Ray; Nelly Frydman; Tania Attie ´; Samir Hamamah; Violaine Kerbrat; Gerard Tachdjian; Serge Romana; Michel Vekemans; Arnold Munnich

2002-01-01

351

Transcriptional profiling identifies physicochemical properties of nanomaterials that are determinants of the in vivo pulmonary response.  

PubMed

We applied transcriptional profiling to elucidate the mechanisms associated with pulmonary responses to titanium dioxide (TiO2 ) nanoparticles (NPs) of different sizes and surface coatings, and to determine if these responses are modified by NP size, surface area, surface modification, and embedding in paint matrices. Adult C57BL/6 mice were exposed via single intratracheal instillations to free forms of TiO2 NPs (10, 20.6, or 38 nm in diameter) with different surface coatings, or TiO2 NPs embedded in paint matrices. Controls were exposed to dispersion medium devoid of NPs. TiO2 NPs were characterized for size, surface area, chemical impurities, and agglomeration state in the exposure medium. Pulmonary transcriptional profiles were generated using microarrays from tissues collected one and 28 d postexposure. Property-specific pathway effects were identified. Pulmonary protein levels of specific inflammatory cytokines and chemokines were confirmed by ELISA. The data were collapsed to 659 differentially expressed genes (P ? 0.05; fold change ? 1.5). Unsupervised hierarchical clustering of these genes revealed that TiO2 NPs clustered mainly by postexposure timepoint followed by particle type. A pathway-based meta-analysis showed that the combination of smaller size, large deposited surface area, and surface amidation contributes to TiO2 NP gene expression response. Embedding of TiO2 NP in paint dampens the overall transcriptional effects. The magnitude of the expression changes associated with pulmonary inflammation differed across all particles; however, the underlying pathway perturbations leading to inflammation were similar, suggesting a generalized mechanism-of-action for all TiO2 NPs. Thus, transcriptional profiling is an effective tool to determine the property-specific biological/toxicity responses induced by nanomaterials. Environ. Mol. Mutagen. 56:245-264, 2015. © 2014 Wiley Periodicals, Inc. PMID:25504612

Halappanavar, Sabina; Saber, Anne Thoustrup; Decan, Nathalie; Jensen, Keld Alstrup; Wu, Dongmei; Jacobsen, Nicklas Raun; Guo, Charles; Rogowski, Jacob; Koponen, Ismo K; Levin, Marcus; Madsen, Anne Mette; Atluri, Rambabu; Snitka, Valentinas; Birkedal, Renie K; Rickerby, David; Williams, Andrew; Wallin, Håkan; Yauk, Carole L; Vogel, Ulla

2015-03-01

352

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

353

Pathways to obesity: identifying local, modifiable determinants of physical activity and diet.  

PubMed

Many studies document small area inequalities in morbidity and mortality and show associations between area deprivation and health. However, few studies unpack the "black box" of area deprivation to show which specific local social and physical environmental characteristics impact upon health, and might be amenable to modification. We theorised a model of the potential causal pathways to obesity and employed path analysis using a rich data set from national studies in England and Scotland to test the model empirically. Significant associations between obesity and neighbourhood disorder and access to local high street facilities (local shops, financial services and health-related stores found in a typical small UK town) were found. There was a tendency for lower levels of obesity in areas with more swimming pools and supermarkets. In turn, policing levels, physical dereliction and recorded violent crime were associated with neighbourhood disorder. The analysis identifies several factors that are associated with (and are probably determinants of) obesity and which are outside the standard remit of the healthcare sector. They highlight the role that public and private sector organisations have in promoting the nation's health. Public health professionals should seek to work alongside or within these organisations to capitalise on opportunities to improve health. PMID:17640787

Stafford, Mai; Cummins, Steven; Ellaway, Anne; Sacker, Amanda; Wiggins, Richard D; Macintyre, Sally

2007-11-01

354

Genetic subtraction profiling identifies genes essential for Arabidopsis reproduction and reveals interaction between the female gametophyte and the maternal sporophyte  

PubMed Central

Background The embryo sac contains the haploid maternal cell types necessary for double fertilization and subsequent seed development in plants. Large-scale identification of genes expressed in the embryo sac remains cumbersome because of its inherent microscopic and inaccessible nature. We used genetic subtraction and comparative profiling by microarray between the Arabidopsis thaliana wild-type and a sporophytic mutant lacking an embryo sac in order to identify embryo sac expressed genes in this model organism. The influences of the embryo sac on the surrounding sporophytic tissues were previously thought to be negligible or nonexistent; we investigated the extent of these interactions by transcriptome analysis. Results We identified 1,260 genes as embryo sac expressed by analyzing both our dataset and a recently reported dataset, obtained by a similar approach, using three statistical procedures. Spatial expression of nine genes (for instance a central cell expressed trithorax-like gene, an egg cell expressed gene encoding a kinase, and a synergid expressed gene encoding a permease) validated our approach. We analyzed mutants in five of the newly identified genes that exhibited developmental anomalies during reproductive development. A total of 527 genes were identified for their expression in ovules of mutants lacking an embryo sac, at levels that were twofold higher than in the wild type. Conclusion Identification of embryo sac expressed genes establishes a basis for the functional dissection of embryo sac development and function. Sporophytic gain of expression in mutants lacking an embryo sac suggests that a substantial portion of the sporophytic transcriptome involved in carpel and ovule development is, unexpectedly, under the indirect influence of the embryo sac. PMID:17915010

Johnston, Amal J; Meier, Patrick; Gheyselinck, Jacqueline; Wuest, Samuel EJ; Federer, Michael; Schlagenhauf, Edith; Becker, Jörg D; Grossniklaus, Ueli

2007-01-01

355

Chemical and Synthetic Genetic Array Analysis Identifies Genes that Suppress Xylose Utilization and Fermentation in Saccharomyces cerevisiae.  

PubMed

Though highly efficient at fermenting hexose sugars, Saccharomyces cerevisiae has limited ability to ferment five-carbon sugars. As a significant portion of sugars found in cellulosic biomass is the five-carbon sugar xylose, S. cerevisiae must be engineered to metabolize pentose sugars, commonly by the addition of exogenous genes from xylose fermenting fungi. However, these recombinant strains grow poorly on xylose and require further improvement through rational engineering or evolutionary adaptation. To identify unknown genes that contribute to improved xylose fermentation in these recombinant S. cerevisiae, we performed genome-wide synthetic interaction screens to identify deletion mutants that impact xylose utilization of strains expressing the xylose isomerase gene XYLA from Piromyces sp. E2 alone or with an additional copy of the endogenous xylulokinase gene XKS1. We also screened the deletion mutant array to identify mutants whose growth is affected by xylose. Our genetic network reveals that more than 80 nonessential genes from a diverse range of cellular processes impact xylose utilization. Surprisingly, we identified four genes, ALP1, ISC1, RPL20B, and BUD21, that when individually deleted improved xylose utilization of both S. cerevisiae S288C and CEN.PK strains. We further characterized BUD21 deletion mutant cells in batch fermentations and found that they produce ethanol even the absence of exogenous XYLA. We have demonstrated that the ability of laboratory strains of S. cerevisiae to utilize xylose as a sole carbon source is suppressed, which implies that S. cerevisiae may not require the addition of exogenous genes for efficient xylose fermentation. PMID:22384336

Usher, Jane; Balderas-Hernandez, Victor; Quon, Peter; Gold, Nicholas D; Martin, Vincent J J; Mahadevan, Radhakrishnan; Baetz, Kristin

2011-09-01

356

Chemical and Synthetic Genetic Array Analysis Identifies Genes that Suppress Xylose Utilization and Fermentation in Saccharomyces cerevisiae  

PubMed Central

Though highly efficient at fermenting hexose sugars, Saccharomyces cerevisiae has limited ability to ferment five-carbon sugars. As a significant portion of sugars found in cellulosic biomass is the five-carbon sugar xylose, S. cerevisiae must be engineered to metabolize pentose sugars, commonly by the addition of exogenous genes from xylose fermenting fungi. However, these recombinant strains grow poorly on xylose and require further improvement through rational engineering or evolutionary adaptation. To identify unknown genes that contribute to improved xylose fermentation in these recombinant S. cerevisiae, we performed genome-wide synthetic interaction screens to identify deletion mutants that impact xylose utilization of strains expressing the xylose isomerase gene XYLA from Piromyces sp. E2 alone or with an additional copy of the endogenous xylulokinase gene XKS1. We also screened the deletion mutant array to identify mutants whose growth is affected by xylose. Our genetic network reveals that more than 80 nonessential genes from a diverse range of cellular processes impact xylose utilization. Surprisingly, we identified four genes, ALP1, ISC1, RPL20B, and BUD21, that when individually deleted improved xylose utilization of both S. cerevisiae S288C and CEN.PK strains. We further characterized BUD21 deletion mutant cells in batch fermentations and found that they produce ethanol even the absence of exogenous XYLA. We have demonstrated that the ability of laboratory strains of S. cerevisiae to utilize xylose as a sole carbon source is suppressed, which implies that S. cerevisiae may not require the addition of exogenous genes for efficient xylose fermentation. PMID:22384336

Usher, Jane; Balderas-Hernandez, Victor; Quon, Peter; Gold, Nicholas D.; Martin, Vincent J. J.; Mahadevan, Radhakrishnan; Baetz, Kristin

2011-01-01

357

Comparison of multilevel modeling and the family-based association test for identifying genetic variants associated with systolic and diastolic blood pressure using Genetic Analysis Workshop 18 simulated data.  

PubMed

Identifying genetic variants associated with complex diseases is an important task in genetic research. Although association studies based on unrelated individuals (ie, case-control genome-wide association studies) have successfully identified common single-nucleotide polymorphisms for many complex diseases, these studies are not so likely to identify rare genetic variants. In contrast, family-based association studies are particularly useful for identifying rare-variant associations. Recently, there has been some interest in employing multilevel models in family-based genetic association studies. However, the performance of such models in these studies, especially for longitudinal family-based sequence data, has not been fully investigated. Therefore, in this study, we investigated the performance of the multilevel model in the family-based genetic association analysis and compared it with the conventional family-based association test, by examining the powers and type I error rates of the 2 approaches using 3 data sets from the Genetic Analysis Workshop 18 simulated data: genome-wide association single-nucleotide polymorphism data, sequence data, and rare-variants-only data. Compared with the univariate family-based association test, the multilevel model had slightly higher power to identify most of the causal genetic variants using the genome-wide association single-nucleotide polymorphism data and sequence data. However, both approaches had low power to identify most of the causal single-nucleotide polymorphisms, especially those among the relatively rare genetic variants. Therefore, we suggest a unified method that combines both approaches and incorporates collapsing strategy, which may be more powerful than either approach alone for studying genetic associations using family-based data. PMID:25519380

Wang, Jian; Yu, Robert; Shete, Sanjay

2014-01-01

358

Genetics  

MedlinePLUS

... Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

359

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

360

Determinants of genetic structure in a nonequilibrium metapopulation of the plant Silene latifolia.  

PubMed

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

361

A Tyrosine-Rich Cell Surface Protein in the Diatom Amphora coffeaeformis Identified through Transcriptome Analysis and Genetic Transformation  

PubMed Central

Diatoms are single-celled eukaryotic microalgae that are ubiquitously found in almost all aquatic ecosystems, and are characterized by their intricately structured SiO2 (silica)-based cell walls. Diatoms with a benthic life style are capable of attaching to any natural or man-made submerged surface, thus contributing substantially to both microbial biofilm communities and economic losses through biofouling. Surface attachment of diatoms is mediated by a carbohydrate- and protein- based glue, yet no protein involved in diatom underwater adhesion has been identified so far. In the present work, we have generated a normalized transcriptome database from the model adhesion diatom Amphora coffeaeformis. Using an unconventional bioinformatics analysis we have identified five proteins that exhibit unique amino acid sequences resembling the amino acid composition of the tyrosine-rich adhesion proteins from mussel footpads. Establishing the first method for the molecular genetic transformation of A. coffeaeformis has enabled investigations into the function of one of these proteins, AC3362, through expression as YFP fusion protein. Biochemical analysis and imaging by fluorescence microscopy revealed that AC3362 is not involved in adhesion, but rather plays a role in biosynthesis and/or structural stability of the cell wall. The methods established in the present study have paved the way for further molecular studies on the mechanisms of underwater adhesion and biological silica formation in the diatom A. coffeaeformis. PMID:25372470

Buhmann, Matthias T.; Poulsen, Nicole; Klemm, Jennifer; Kennedy, Matthew R.; Sherrill, C. David; Kröger, Nils

2014-01-01

362

Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study  

PubMed Central

We conducted a genome-wide association study (GWAS) to discover single nucleotide polymorphisms (SNPs) associated with the severity of sickle cell anemia in 1,265 patients with either “severe” or “mild” disease based on a network model of disease severity. We analyzed data using single SNP analysis and a novel SNP set enrichment analysis (SSEA) developed to discover clusters of associated SNPs. Single SNP analysis discovered 40 SNPs that were strongly associated with sickle cell severity (odds for association >1,000); of the 32 that we could analyze in an independent set of 163 patients, five replicated, eight showed consistent effects although failed to reach statistical significance, whereas 19 did not show any convincing association. Among the replicated associations are SNPs in KCNK6 a K+ channel gene. SSEA identified 27 genes with a strong enrichment of significant SNPs (P < 10?6); 20 were replicated with varying degrees of confidence. Among the novel findings identified by SSEA is the telomere length regulator gene TNKS. These studies are the first to use GWAS to understand the genetic diversity that accounts the phenotypic heterogeneity sickle cell anemia as estimated by an integrated model of severity. Additional validation, resequencing, and functional studies to understand the biology and reveal mechanisms by which candidate genes might have their effects are the future goals of this work. PMID:20029952

Sebastiani, Paola; Solovieff, Nadia; Hartley, Stephen W.; Milton, Jacqueline N.; Riva, Alberto; Dworkis, Daniel A.; Melista, Efthymia; Klings, Elizabeth S.; Garrett, Melanie E.; Telen, Marilyn J.; Ashley-Koch, Allison; Baldwin, Clinton T.; Steinberg, Martin H.

2010-01-01

363

Identifying causal rare variants of disease through family-based analysis of Genetics Analysis Workshop 17 data set.  

PubMed

Linkage- and association-based methods have been proposed for mapping disease-causing rare variants. Based on the family information provided in the Genetic Analysis Workshop 17 data set, we formulate a two-pronged approach that combines both methods. Using the identity-by-descent information provided for eight extended pedigrees (n = 697) and the simulated quantitative trait Q1, we explore various traditional nonparametric linkage analysis methods; the best result is obtained by assuming between-family heterogeneity and applying the Haseman-Elston regression to each pedigree separately. We discover strong signals from two genes in two different families and weaker signals for a third gene from two other families. As an exploratory approach, we apply an association test based on a modified family-based association test statistic to all rare variants (frequency < 1% or < 3%) designated as causal for Q1. Family-based association tests correctly identified causal single-nucleotide polymorphisms for four genes (KDR, VEGFA, VEGFC, and FLT1). Our results suggest that both linkage and association tests with families show promise for identifying rare variants. PMID:22373204

Yip, Wai-Ki; De, Gourab; Raby, Benjamin A; Laird, Nan

2011-01-01

364

Genetic determinants of sensitivity to beryllium in mice.  

PubMed

Chronic beryllium disease (CBD), an irreversible, debilitating granulomatous lung disease is caused by exposure to beryllium. This occupational hazard occurs in primary production and machining of Be-metal, BeO, beryllium - containing alloys, and other beryllium products. CBD begins as an MHC Class II-restricted, T(H)1 hypersensitivity, and the Human Leukocyte Antigen, HLA-DPB1E(69), is associated with risk of developing CBD. Because inbred strains of mice have not provided good models of CBD to date, three strains of HLA-DPB1 transgenic mice in an FVB/N background were developed; each contains a single allele of HLA-DPB1 that confers a different magnitude of risk for chronic beryllium disease: HLA-DPB1*0401 (OR approximately 0.2), HLA-DPB1*0201 (OR approximately 3), and HLA-DPB1*1701 (OR approximately 46). The mouse ear swelling test (MEST) was employed to determine if these different alleles would support a hypersensitivity response to beryllium. Mice were first sensitized on the back and subsequently challenged on the ear. In separate experiments, mice were placed into one of three groups (sensitization/challenge): C/C, C/Be, and Be/Be. In the HLA-DPB1*1701 mice, the strain with the highest risk transgene, the Be/Be group was the only group that displayed significant maximum increased ear thickness of 19.6% +/- 3.0% over the baseline measurement (p < 0.05). No significant changes were observed in the other transgenic strains for any treatment condition. In addition, inter-strain differences in response to beryllium in seven inbred strains were investigated through use of the MEST, these included: FVB/N, AKR, Balb/c, C3H/HeJ, C57/BL6, DBA/2, and SJL/J. The FVB/N strain was least responsive, while the SJL/J and C57/BL6 strains were the highest responders. Our results suggest that the HLA-DPB1*1701 transgene product is an important risk factor for induction of the beryllium-sensitive phenotype. This model should be a useful tool for investigating beryllium sensitization. PMID:19589099

Tarantino-Hutchison, Lauren M; Sorrentino, Claudio; Nadas, Arthur; Zhu, Yiwen; Rubin, Edward M; Tinkle, Sally S; Weston, Ainsley; Gordon, Terry

2009-06-01

365

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

366

A High-Density Genetic Map Identifies a Novel Major QTL for Boron Efficiency in Oilseed Rape (Brassica napus L.)  

PubMed Central

Low boron (B) seriously limits the growth of oilseed rape (Brassica napus L.), a high B demand species that is sensitive to low B conditions. Significant genotypic variations in response to B deficiency have been observed among B. napus cultivars. To reveal the genetic basis for B efficiency in B. napus, quantitative trait loci (QTLs) for the plant growth traits, B uptake traits and the B efficiency coefficient (BEC) were analyzed using a doubled haploid (DH) population derived from a cross between a B-efficient parent, Qingyou 10, and a B-inefficient parent, Westar 10. A high-density genetic map was constructed based on single nucleotide polymorphisms (SNPs) assayed using Brassica 60 K Infinium BeadChip Array, simple sequence repeats (SSRs) and amplified fragment length polymorphisms (AFLPs). The linkage map covered a total length of 2139.5 cM, with 19 linkage groups (LGs) and an average distance of 1.6 cM between adjacent markers. Based on hydroponic evaluation of six B efficiency traits measured in three separate repeated trials, a total of 52 QTLs were identified, accounting for 6.14–46.27% of the phenotypic variation. A major QTL for BEC, qBEC-A3a, was co-located on A3 with other QTLs for plant growth and B uptake traits under low B stress. Using a subset of substitution lines, qBEC-A3a was validated and narrowed down to the interval between CNU384 and BnGMS436. The results of this study provide a novel major locus located on A3 for B efficiency in B. napus that will be suitable for fine mapping and marker-assisted selection breeding for B efficiency in B. napus. PMID:25375356

Wang, Xiaohua; Zhao, Hua; Shi, Lei; Xu, Fangsen

2014-01-01

367

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, Lounès

2012-01-01

368

Copyright 1998 by the Genetics Society of America Evidence for a Genomic Imprinting Sex Determination Mechanism  

E-print Network

harboring the paternal sex ratio chromosome (PSR). The results of this study support the GISD modelCopyright © 1998 by the Genetics Society of America Evidence for a Genomic Imprinting Sex different models have been proposed for the sex determination mechanism of Chalcidoidea (Hymenoptera

Dobson, Stephen L.

369

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

NASA Astrophysics Data System (ADS)

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 interviewed teachers' conceptions. This illustrates that innatism is present in two distinct ways: in relation to individuals (e.g. genetic determinism to justify intellectual likeness between individuals such as twins) or in relation to groups of humans (e.g. genetic determinism to justify gender differences or the superiority of some human ethnic groups). A between-factor analysis discriminates between countries, showing very significant differences. There is more innatism among teachers' conceptions in African countries and Lebanon than in European countries, Brazil and Australia. Among the other controlled parameters, only two are significantly independent of the country: the level of training and the level of knowledge of biology. A co-inertia analysis shows a strong correlation between non-citizen attitudes towards and innatist conceptions of genetic determinism regarding human groups. We discuss these findings and their implications for education.

Castéra, Jérémy; Clément, Pierre

2012-07-01

370

Search for genetic determinants of individual variability of the erythropoietin response to high altitude  

Microsoft Academic Search

There is marked variability in the erythropoietin (Epo) and erythrocytic response to extreme high altitude among mountain dwellers, as well as to hypoxic training among athletes, at least in part because of the variation in the erythropoietic response to hypoxia. We hypothesized that this may be genetically determined. Forty-eight athletes were exposed to 24 h of simulated altitude to 2800

Katerina Jedlickova; David W. Stockton; Hua Chen; James Stray-Gundersen; Sarah Witkowski; Ge Ri-Li; Jaroslav Jelinek; Benjamin D. Levine; Josef T. Prchala

2003-01-01

371

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

372

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

373

The HapMap project has raised high hopes for mapping genetic determinants of complex human  

E-print Network

The HapMap project has raised high hopes for mapping genetic determinants of complex human disease for mapping studies in human populations around the world. The HapMap project has characterized haplotype structures across the genome for four human populations with the goal of enabling genome-wide sets of SNPs

Rosenberg, Noah

374

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

375

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

376

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

377

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

378

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

379

Genetic screening identifies cyanogenesis-deficient mutants of Lotus japonicus and reveals enzymatic specificity in hydroxynitrile glucoside metabolism.  

PubMed

Cyanogenesis, the release of hydrogen cyanide from damaged plant tissues, involves the enzymatic degradation of amino acid-derived cyanogenic glucosides (alpha-hydroxynitrile glucosides) by specific beta-glucosidases. Release of cyanide functions as a defense mechanism against generalist herbivores. We developed a high-throughput screening method and used it to identify cyanogenesis deficient (cyd) mutants in the model legume Lotus japonicus. Mutants in both biosynthesis and catabolism of cyanogenic glucosides were isolated and classified following metabolic profiling of cyanogenic glucoside content. L. japonicus produces two cyanogenic glucosides: linamarin (derived from Val) and lotaustralin (derived from Ile). Their biosynthesis may involve the same set of enzymes for both amino acid precursors. However, in one class of mutants, accumulation of lotaustralin and linamarin was uncoupled. Catabolic mutants could be placed in two complementation groups, one of which, cyd2, encoded the beta-glucosidase BGD2. Despite the identification of nine independent cyd2 alleles, no mutants involving the gene encoding a closely related beta-glucosidase, BGD4, were identified. This indicated that BGD4 plays no role in cyanogenesis in L. japonicus in vivo. Biochemical analysis confirmed that BGD4 cannot hydrolyze linamarin or lotaustralin and in L. japonicus is specific for breakdown of related hydroxynitrile glucosides, such as rhodiocyanoside A. By contrast, BGD2 can hydrolyze both cyanogenic glucosides and rhodiocyanosides. Our genetic analysis demonstrated specificity in the catabolic pathways for hydroxynitrile glucosides and implied specificity in their biosynthetic pathways as well. In addition, it has provided important tools for elucidating and potentially modifying cyanogenesis pathways in plants. PMID:20453117

Takos, Adam; Lai, Daniela; Mikkelsen, Lisbeth; Abou Hachem, Maher; Shelton, Dale; Motawia, Mohammed Saddik; Olsen, Carl Erik; Wang, Trevor L; Martin, Cathie; Rook, Fred

2010-05-01

380

Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis  

PubMed Central

Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count. PMID:25329635

Pemov, Alexander; Sung, Heejong; Hyland, Paula L.; Sloan, Jennifer L.; Ruppert, Sarah L.; Baldwin, Andrea M.; Boland, Joseph F.; Bass, Sara E.; Lee, Hyo Jung; Jones, Kristine M.; Zhang, Xijun; Mullikin, James C.; Widemann, Brigitte C.; Wilson, Alexander F.; Stewart, Douglas R.

2014-01-01

381

Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis.  

PubMed

Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognos