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1

Identifying the genetic determinants of transcription factor activity  

Microsoft Academic Search

Analysis of parallel genotyping and expression profiling data has shown that mRNA expression levels are highly heritable. Currently, only a tiny fraction of this genetic variance can be mechanistically accounted for. The influence of trans-acting polymorphisms on gene expression traits is often mediated by transcription factors (TFs). We present a method that exploits prior knowledge about the in vitro DNA-binding

Eunjee Lee; Harmen J Bussemaker

2010-01-01

2

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

3

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

PubMed Central

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

Aguas, Ricardo; Ferguson, Neil M.

2013-01-01

4

Shortest-Path Network Analysis Is a Useful Approach toward Identifying Genetic Determinants of Longevity  

PubMed Central

Background Identification of genes that modulate longevity is a major focus of aging-related research and an area of intense public interest. In addition to facilitating an improved understanding of the basic mechanisms of aging, such genes represent potential targets for therapeutic intervention in multiple age-associated diseases, including cancer, heart disease, diabetes, and neurodegenerative disorders. To date, however, targeted efforts at identifying longevity-associated genes have been limited by a lack of predictive power, and useful algorithms for candidate gene-identification have also been lacking. Methodology/Principal Findings We have utilized a shortest-path network analysis to identify novel genes that modulate longevity in Saccharomyces cerevisiae. Based on a set of previously reported genes associated with increased life span, we applied a shortest-path network algorithm to a pre-existing protein–protein interaction dataset in order to construct a shortest-path longevity network. To validate this network, the replicative aging potential of 88 single-gene deletion strains corresponding to predicted components of the shortest-path longevity network was determined. Here we report that the single-gene deletion strains identified by our shortest-path longevity analysis are significantly enriched for mutations conferring either increased or decreased replicative life span, relative to a randomly selected set of 564 single-gene deletion strains or to the current data set available for the entire haploid deletion collection. Further, we report the identification of previously unknown longevity genes, several of which function in a conserved longevity pathway believed to mediate life span extension in response to dietary restriction. Conclusions/Significance This work demonstrates that shortest-path network analysis is a useful approach toward identifying genetic determinants of longevity and represents the first application of network analysis of aging to be extensively validated in a biological system. The novel longevity genes identified in this study are likely to yield further insight into the molecular mechanisms of aging and age-associated disease. PMID:19030232

Managbanag, J. R.; Witten, Tarynn M.; Bonchev, Danail; Fox, Lindsay A.; Tsuchiya, Mitsuhiro; Kennedy, Brian K.; Kaeberlein, Matt

2008-01-01

5

Identifying the Environmental Factors That Determine the Genetic Structure of Populations  

PubMed Central

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 FST 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

2006-01-01

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

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

9

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

10

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

11

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.

12

Genetic determinants of plasma triglycerides  

PubMed Central

Plasma triglyceride (TG) concentration is reemerging as an important cardiovascular disease risk factor. More complete understanding of the genes and variants that modulate plasma TG should enable development of markers for risk prediction, diagnosis, prognosis, and response to therapies and might help specify new directions for therapeutic interventions. Recent genome-wide association studies (GWAS) have identified both known and novel loci associated with plasma TG concentration. However, genetic variation at these loci explains only ?10% of overall TG variation within the population. As the GWAS approach may be reaching its limit for discovering genetic determinants of TG, alternative genetic strategies, such as rare variant sequencing studies and evaluation of animal models, may provide complementary information to flesh out knowledge of clinically and biologically important pathways in TG metabolism. Herein, we review genes recently implicated in TG metabolism and describe how some of these genes likely modulate plasma TG concentration. We also discuss lessons regarding plasma TG metabolism learned from various genomic and genetic experimental approaches. Treatment of patients with moderate to severe hypertriglyceridemia with existing therapies is often challenging; thus, gene products and pathways found in recent genetic research studies provide hope for development of more effective clinical strategies. PMID:21041806

Johansen, Christopher T.; Kathiresan, Sekar; Hegele, Robert A.

2011-01-01

13

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

14

Development and Use of an Efficient System for Random mariner Transposon Mutagenesis To Identify Novel Genetic Determinants of Biofilm Formation in the Core Enterococcus faecalis Genome  

Microsoft Academic Search

Enterococcus faecalis is a gram-positive commensal bacterium of the gastrointestinal tract and an important opportunistic pathogen. Despite the increasing clinical significance of the enterococci, most of the genetic analysis of these organisms has focused on mobile genetic elements, and existing tools for manipulation and analysis of the core E. faecalis chromosome are limited. We are interested in a comprehensive analysis

Christopher J. Kristich; Vy T. Nguyen; Thinh Le; Aaron M. T. Barnes; Suzanne Grindle; Gary M. Dunny

2008-01-01

15

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

16

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

17

Determining identifiable parameter combinations using subset profiling.  

PubMed

Identifiability is a necessary condition for successful parameter estimation of dynamic system models. A major component of identifiability analysis is determining the identifiable parameter combinations, the functional forms for the dependencies between unidentifiable parameters. Identifiable combinations can help in model reparameterization and also in determining which parameters may be experimentally measured to recover model identifiability. Several numerical approaches to determining identifiability of differential equation models have been developed, however the question of determining identifiable combinations remains incompletely addressed. In this paper, we present a new approach which uses parameter subset selection methods based on the Fisher Information Matrix, together with the profile likelihood, to effectively estimate identifiable combinations. We demonstrate this approach on several example models in pharmacokinetics, cellular biology, and physiology. PMID:25173434

Eisenberg, Marisa C; Hayashi, Michael A L

2014-10-01

18

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

19

Identifying Carriers of a Genetic Modifier Using Nonparametric  

E-print Network

Identifying Carriers of a Genetic Modifier Using Nonparametric Bayesian Methods Peter D. Hoff and Newton effects of Min. In order to genetically map the location of the modifier gene, it is necessary a mutant allele at a modifier gene, suppressing the tumor-causing #12;328 Hoff, Halberg, Shedlovsky, Dove

Dove, William

20

Newly Identified Genetic Variations May Affect Breast Cancer Risk  

Cancer.gov

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

21

Genetic Determinants of Psoriatic Arthritis.  

E-print Network

??Psoriatic Arthritis (PsA) is an inflammatory arthritis associated with psoriasis that leads to progressive joint damage. Genetic variants in the Major Histocompatibility Complex (MHC) region… (more)

Chandran, Vinod

2014-01-01

22

Identifying permethrin resistance loci in malaria vectors by genetic mapping.  

PubMed

Identification of the major loci responsible for insecticide resistance in malaria vectors would aid the development and implementation of effective resistance management strategies, which are urgently needed to tackle the growing threat posed by resistance to the limited insecticides available for malaria control. Genome-wide association studies in the major malaria vector, Anopheles gambiae, have been hindered by the high degree of within-population structuring and very low levels of linkage disequilibrium hence we revisited the use of quantitative trait loci (QTL) mapping to study resistance phenotypes in this vector species. Earlier work, identified two major QTL associated with pyrethroid resistance in A. gambiae s.s. from East Africa using genetic crossing of laboratory-colonized resistant and susceptible strains. In this study, we report the results from genetic mapping of pyrethroid resistance in three isofemale pedigrees established from wild-caught female A. gambiae s.s. mosquitoes from Benin. We identified two QTL on chromosomes 2L and 3R in these field populations, in similar genomic locations to the QTL identified in laboratory strains. The relative merits of two alternative study designs are discussed and suggestions made for future genetic mapping studies of insecticide resistance in mosquitoes. PMID:23448678

Witzig, Claudia; Wondji, Charles S; Strode, Clare; Djouaka, Rousseau; Ranson, Hilary

2013-10-01

23

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

24

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

25

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

26

Transcriptomic and genetic studies identify IL33 as a candidate gene for Alzheimer's disease  

Microsoft Academic Search

The only recognized genetic determinant of the common forms of Alzheimer's disease (AD) is the ?4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2741 genes in chromosomal regions of interest using brain tissue of AD cases and controls. From 82 differentially expressed genes, 1156 polymorphisms were genotyped in two

J Chapuis; D Hot; F Hansmannel; O Kerdraon; S Ferreira; C Hubans; C A Maurage; L Huot; F Bensemain; G Laumet; A M Ayral; N Fievet; J J Hauw; S T DeKosky; Y Lemoine; T Iwatsubo; F Wavrant-Devrièze; J F Dartigues; C Tzourio; L Buée; F Pasquier; C Berr; D Mann; C Lendon; A Alpérovitch; M I Kamboh; P Amouyel; J C Lambert

2009-01-01

27

Genetic and proteomic approaches to identify cancer drug targets  

PubMed Central

While target-based small-molecule discovery has taken centre-stage in the pharmaceutical industry, there are many cancer-promoting proteins not easily addressed with a traditional target-based screening approach. In order to address this problem, as well as to identify modulators of biological states in the absence of knowing the protein target of the state switch, alternative phenotypic screening approaches, such as gene expression-based and high-content imaging, have been developed. With this renewed interest in phenotypic screening, however, comes the challenge of identifying the binding protein target(s) of small-molecule hits. Emerging technologies have the potential to improve the process of target identification. In this review, we discuss the application of genomic (gene expression-based), genetic (short hairpin RNA and open reading frame screening), and proteomic approaches to protein target identification. PMID:22166799

Roti, G; Stegmaier, K

2012-01-01

28

Identifying interacting genetic variations by fish-swarm logic regression.  

PubMed

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

Zhang, Xuanping; Wang, Jiayin; Yang, Aiyuan; Yan, Chunxia; Zhu, Feng; Zhao, Zhongmeng; Cao, Zhi

2013-01-01

29

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

30

Identifying common genetic variants in blood pressure due to polygenic pleiotropy with associated phenotypes.  

PubMed

Blood pressure is a critical determinant of cardiovascular morbidity and mortality. It is affected by environmental factors, but has a strong heritable component. Despite recent large genome-wide association studies, few genetic risk factors for blood pressure have been identified. Epidemiological studies suggest associations between blood pressure and several diseases and traits, which may partly arise from a shared genetic basis (genetic pleiotropy). Using genome-wide association studies summary statistics and a genetic pleiotropy-informed conditional false discovery rate method, we systematically investigated genetic overlap between systolic blood pressure (SBP) and 12 comorbid traits and diseases. We found significant enrichment of single nucleotide polymorphisms associated with SBP as a function of their association with body mass index, low-density lipoprotein, waist/hip ratio, schizophrenia, bone mineral density, type 1 diabetes mellitus, and celiac disease. In contrast, the magnitude of enrichment due to shared polygenic effects was smaller with the other phenotypes (triglycerides, high-density lipoproteins, type 2 diabetes mellitus, rheumatoid arthritis, and height). Applying the conditional false discovery rate method to the enriched phenotypes, we identified 62 loci associated with SBP (false discovery rate <0.01), including 42 novel loci. The observed polygenic overlap between SBP and several related disorders indicates that the epidemiological associations are not mediated solely via lifestyle factors but also reflect an etiologic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to lipid biology and the immune system in SBP. PMID:24396023

Andreassen, Ole A; McEvoy, Linda K; Thompson, Wesley K; Wang, Yunpeng; Reppe, Sjur; Schork, Andrew J; Zuber, Verena; Barrett-Connor, Elizabeth; Gautvik, Kaare; Aukrust, Pål; Karlsen, Tom H; Djurovic, Srdjan; Desikan, Rahul S; Dale, Anders M

2014-04-01

31

Determining the genetic heritability of wood properties  

E-print Network

Determining the genetic heritability of wood properties of Sitka spruce critical to timber strength of wood properties critical to spruce timber quality and strength, to aid with future developments in the wood quality of Sitka spruce to be possible. #12;

32

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.

33

Genetic determinants of Sindbis virus neuroinvasiveness.  

PubMed

After peripheral inoculation of mice, Sindbis virus replicates in a variety of tissues, leading to viremia. In some cases, the virus can enter the central nervous system (CNS) and cause lethal encephalitis. The outcome of infection is age and virus strain dependent. Recently, two pairs of Sindbis virus variants differing in neurovirulence and neuroinvasiveness were derived by limited serial passaging in mouse brain. Two early passage isolates (SVA and SVB) were neurotropic but did not cause lethal encephalitis. SVB, but not SVA, was neuroinvasive. A second independent pair of isolates (SVN and SVNI), which had undergone more extensive mouse brain passaging, were highly neurotropic and caused lethal encephalitis. Only SVNI could reach the brain after peripheral inoculation. From these isolates, virion RNAs were obtained and used to construct full-length cDNA clones from which infectious RNA transcripts could be recovered. The strains recovered from these clones were shown to retain the appropriate phenotypes in weanling mice. Construction and analysis of recombinant viruses were used to define the genetic loci determining neuroinvasion. For SVB, neuroinvasiveness was determined by a single residue in the E2 glycoprotein (Gln-55). For SVNI, neuroinvasive loci were identified in both the 5' noncoding region (position 8) and the E2 glycoprotein (Met-190). Either of these changes on the SVN background was sufficient to confer a neuroinvasive phenotype, although these recombinants were less virulent. To completely mimic the SVNI phenotype, three SVNI-specific substitutions on the SVN background were required: G at position 8, E2 Met-190, and Lys-260, which by itself had no effect on neuroinvasion. These genetically defined strains should be useful for dissecting the molecular mechanisms leading to Sindbis virus invasion of the CNS. PMID:9060616

Dubuisson, J; Lustig, S; Ruggli, N; Akov, Y; Rice, C M

1997-04-01

34

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

PubMed

We developed a new computational technique called Step-Level Differential Response (SLDR) to identify genetic regulatory relationships. Our technique takes advantages of functional genomics data for the same species under different perturbation conditions, therefore complementary to current popular computational techniques. It can particularly identify "rare" activation/inhibition relationship events that can be difficult to find in experimental results. In SLDR, we model each candidate target gene as being controlled by N binary-state regulators that lead to ?2N observable states ("step-levels") for the target. We applied SLDR to the study of the GEO microarray data set GSE25644, which consists of 158 different mutant S. cerevisiae gene expressional profiles. For each target gene t, we first clustered ordered samples into various clusters, each approximating an observable step-level of t to screen out the "de-centric" target. Then, we ordered each gene x as a candidate regulator and aligned t to x for the purpose of examining the step-level correlations between low expression set of x (Ro) and high expression set of x (Rh) from the regulator x to t, by finding max f(t, x): |Ro-Rh| over all candidate × in the genome for each t. We therefore obtained activation and inhibitions events from different combinations of Ro and Rh. Furthermore, we developed criteria for filtering out less-confident regulators, estimated the number of regulators for each target t, and evaluated identified top-ranking regulator-target relationship. Our results can be cross-validated with the Yeast Fitness database. SLDR is also computationally efficient with o(N2) complexity. In summary, we believe SLDR can be applied to the mining of functional genomics big data for future network biology and network medicine applications. PMID:25350940

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

2014-10-21

35

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

36

Identifying Families with Likely Genetic Protective Factors against Alzheimer Disease  

Microsoft Academic Search

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

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

1999-01-01

37

Genetic determinants of "cognitive impairment, no dementia".  

PubMed

Dementia is a heritable condition with devastating effects on both patients and their caregivers. Studies have identified genetic variants associated with increased susceptibility to late-onset Alzheimer disease (AD)-related dementia; however, no studies have assessed whether genetic variation is associated with the early stages of cognitive decline. Given that cerebrovascular disease is an established mechanism in which chronic ischemia increases susceptibility to dementia, we assessed whether genetic variation associated with either cardio-metabolic or AD-related traits is associated with an early stage of cognitive decline called "cognitive impairment, no dementia" (CIND). We studied 484 CIND patients and 459 cognitively healthy controls selected from the Canadian Study of Health and Aging. We tested for association between ~200,000 genetic variants selected from genes associated with cardio-metabolic traits and CIND status using the Cardio-MetaboChip. We also assessed whether AD-related variants and APOE alleles were associated with CIND status, either individually or as part of a composite genetic risk score. We identified a potential association between the ZNF608/GRAMD3 locus, specifically the rs1439568 polymorphism and CIND status (major allele odds ratio [OR] = 1.51; p = 8.4 × 10(-6)). AD-related variants were not associated with CIND status, however APOE E4 allele frequency was significantly higher in CIND patients versus healthy controls (OR = 1.35; p = 0.044). We identified a potential association between the ZNF608/GRAMD3 locus and CIND status, although AD-related variants were not associated with CIND. Additional replication of this association signal is invited. PMID:23042215

Dubé, Joseph B; Johansen, Christopher T; Robinson, John F; Lindsay, Joan; Hachinski, Vladimir; Hegele, Robert A

2013-01-01

38

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

39

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

40

An Interactive Resource to Identify Cancer Genetic and Lineage Dependencies  

E-print Network

drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer hypotheses and to accelerate discovery of drugs matched to patients by their cancer genotype and lineage of specific genetic features and (2) small-molecule drugs that target the dependencies. Cancer cell

Stockwell, Brent R.

41

Islet Transplantation in Genetically Determined Diabetes  

PubMed Central

Hyperglycemia induced in animals by beta cell toxins or by pancreatectomy can be reversed by pancreatic islet transplantation. Abnormal carbohydrate metabolism in juvenile onset human diabetics has also been corrected, albeit temporarily because of graft rejection, by pancreatic transplantation. It does not necessarily follow that naturally occurring diabetes in animals or adult onset diabetes in man would respond to similar treatment. Islet transplantation was studied in mice with chemically induced or genetically determined diabetes. Streptozotocin-induced diabetic mice were permanently cured by syngeneic islets and, when immunosuppressed, were rendered normoglycemic for six weeks after receiving xenogeneic rat islets. In contrast, histocompatible islets from normoglycemic coisogenic donors were ineffective in hyperglycemic db/db recipients as were xenogeneic rat islets in immunosuppressed db/db hosts. However, when islets were isolated from db/db donors and transplated to genetically normal coisogenic mice, which had been rendered hyperglycemic with streptozotocin, they became normoglycemic. Apparently the metabolic defect in the db/db mice, which is similar in some ways to human maturity onset diabetes, does not reside in their islets as these cells can function normally if transplanted to genetically nondiabetic hosts. In two other types of genetic diabetes (ob/ob and NZO) islet transplantation was more effective. Pancreatic transplantation is unlikely to be the proper treatment for all types of diabetes even if technical and immunological problems are overcome. PMID:143916

Barker, Clyde F.; Frangipane, Leo G.; Silvers, Willys K.

1977-01-01

42

Alphaviruses: Population genetics and determinants of emergence  

PubMed Central

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

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

2013-01-01

43

A proton current drives action potentials in genetically identified sour taste cells  

E-print Network

H. To identify acid- sensitive conductances unique to sour cells, we created genetically modified mice in which and safety of ingested food and is detected by a separate subset of cells within the taste bud (1). AlthoughA proton current drives action potentials in genetically identified sour taste cells Rui B. Chang

Liman, Emily

44

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

E-print Network

dependency in landscape genetic studies Melanie A. Murphy, Jeffrey S. Evans, Samuel A. Cushman and Andrew ecology and population genetics, has great potential to influence our understanding of habitat ecological data, spatial incorpora- tion of neutral multilocus genetic data presents two unique complexities

Storfer, Andrew

45

Genetic determinants of dietary antioxidant status.  

PubMed

Oxidative stress refers to a physiological state in which an imbalance between pro-oxidants and antioxidants results in oxidative damage. Oxidative stress has been associated with the development of numerous chronic diseases such as type 2 diabetes, cardiovascular disease (CVD), osteoporosis, and cancer. Endogenous production of free radicals occurs during normal physiological processes, such as aerobic metabolism, oxidation of biological molecules, and enzymatic activity. Environmental factors such as ultraviolet radiation, air pollution, and cigarette smoking can also contribute to the accumulation of free radicals in the body. Excess free radicals can damage tissues and promote the upregulation of disease-related pathways such as inflammation. Modulating oxidative stress by dietary supplementation with antioxidant micronutrients such as vitamins C and E or phytochemicals such as different carotenoids may help prevent or delay the development of certain diseases. However, research on antioxidant supplementation and disease has yielded inconsistent findings, which may be due, in part, to interindividual genetic variation. Polymorphisms in genes coding for endogenous antioxidant enzymes or proteins responsible for the absorption, transport, distribution, or metabolism of dietary antioxidants have been shown to affect antioxidant status and response to supplementation. These genetic variants may also interact with environmental factors, such as diet, to determine an individual's overall antioxidant status. This chapter examines current knowledge of the relationship between genetic variation and dietary antioxidant status. PMID:22656378

Da Costa, Laura A; García-Bailo, Bibiana; Badawi, Alaa; El-Sohemy, Ahmed

2012-01-01

46

Genetic-Genomic Replication to Identify Candidate Mouse Atherosclerosis Modifier Genes  

PubMed Central

Objective Genetics plays a large role in atherosclerosis susceptibility in humans and mice. We attempted to confirm previously determined mouse atherosclerosis?associated loci and use bioinformatics and transcriptomics to create a catalog of candidate atherosclerosis modifier genes at these loci. Methods and Results A strain intercross was performed between AKR and DBA/2 mice on the apoE?/? background generating 166 F2 progeny. Using the phenotype log10 of the aortic root lesion area, we identified 3 suggestive atherosclerosis quantitative trait loci (Ath QTLs). When combined with our prior strain intercross, we confirmed 3 significant Ath QTLs on chromosomes 2, 15, and 17, with combined logarithm of odds scores of 5.9, 5.3, and 5.6, respectively, which each met the genome?wide 5% false discovery rate threshold. We identified all of the protein coding differences between these 2 mouse strains within the Ath QTL intervals. Microarray gene expression profiling was performed on macrophages and endothelial cells from this intercross to identify expression QTLs (eQTLs), the loci that are associated with variation in the expression levels of specific transcripts. Cross tissue eQTLs and macrophage eQTLs that replicated from a prior strain intercross were identified. These bioinformatic and eQTL analyses produced a comprehensive list of candidate genes that may be responsible for the Ath QTLs. Conclusions Replication studies for clinical traits as well as gene expression traits are worthwhile in identifying true versus false genetic associations. We have replicated 3 loci on mouse chromosomes 2, 15, and 17 that are associated with atherosclerosis. We have also identified protein coding differences and multiple replicated eQTLs, which may be useful in the identification of atherosclerosis modifier genes. PMID:23525445

Hsu, Jeffrey; Smith, Jonathan D.

2013-01-01

47

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

48

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.

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

Copyright 2003 by the Genetics Society of America Mapping Determinants of Variation in Energy Metabolism,  

E-print Network

in recombinant inbred lines of Drosophila melanogaster. We identified QTL underlying variation in glycogenCopyright 2003 by the Genetics Society of America Mapping Determinants of Variation in Energy) mapping to dissect the genetic architecture of a hierarchy of functionally related physiological traits

Marden, James

51

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

52

Researchers Identify Genetic Variations That May Increase Risk of Breast Cancer  

Cancer.gov

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

53

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

E-print Network

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

2012-04-12

54

Harnessing genomics to identify environmental determinants of heritable disease  

EPA Science Inventory

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

55

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

56

Identifying Sequence Determinants of Reduction Potentials of Metalloproteins  

PubMed Central

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

Perrin, Bradley Scott; Ichiye, Toshiko

2013-01-01

57

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

58

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, Michigan 48105 Received December 14, 2006 Throughout the drug discovery process, discovery teams are asked to prioritize compounds for subsequent stages of the drug discovery process, given results from

Wu, Jeff

59

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.

60

Scientists Identify Genetic Cause of Previously Undefined Primary Immune Deficiency Disease  

Cancer.gov

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

61

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

62

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.

63

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...

64

Sphingolipids and Membrane Biology as Determined from Genetic Models  

PubMed Central

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

Rao, Raghavendra Pralhada; Acharya, Jairaj K

2008-01-01

65

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, D.; Scribner, K.T.

2000-01-01

66

DEVELOPMENTAL GENETICS 15297312 (1994) Temperature-DependentSex Determination in  

E-print Network

DEVELOPMENTAL GENETICS 15297312 (1994) Temperature-DependentSex Determination in Reptiles and intersexes are rarely formed. How is the exter- nal signal of temperature transduced into a genetic signal and modifying the endocrine microenvi- ronment in the embryo. The temperature experi- enced in development also

Crews, David

67

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

68

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

69

Determination of Mitochondrial Genetic Diversity in Mammals  

PubMed Central

Mitochondrial DNA (mtDNA) is one of the most popular population genetic markers. Its relevance as an indicator of population size and history has recently been questioned by several large-scale studies in animals reporting evidence for recurrent adaptive evolution, at least in invertebrates. Here we focus on mammals, a more restricted taxonomic group for which the issue of mtDNA near neutrality is crucial. By analyzing the distribution of mtDNA diversity across species and relating it to allozyme diversity, life-history traits, and taxonomy, we show that (i) mtDNA in mammals does not reject the nearly neutral model; (ii) mtDNA diversity, however, is unrelated to any of the 14 life-history and ecological variables that we analyzed, including body mass, geographic range, and The World Conservation Union (IUCN) categorization; (iii) mtDNA diversity is highly variable between mammalian orders and families; (iv) this taxonomic effect is most likely explained by variations of mutation rate between lineages. These results are indicative of a strong stochasticity of effective population size in mammalian species. They suggest that, even in the absence of selection, mtDNA genetic diversity is essentially unpredictable, knowing species biology, and probably uncorrelated to species abundance. PMID:18202378

Nabholz, Benoit; Mauffrey, Jean-Francois; Bazin, Eric; Galtier, Nicolas; Glemin, Sylvain

2008-01-01

70

Pooled Segregant Sequencing Reveals Genetic Determinants of Yeast Pseudohyphal Growth  

PubMed Central

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

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

2014-01-01

71

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

72

Functional Genomics Complements Quantitative Genetics in Identifying Disease-Gene Associations  

PubMed Central

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

73

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; Vinuela, Ana; Lappalainen, Tuuli; Zheng, Hou-Feng; Richards, J Brent; Small, Kerrin S; Spector, Timothy D; Dermitzakis, Emmanouil T; Durbin, Richard

2014-01-01

74

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

75

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

PubMed

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

2014-04-15

76

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

PubMed

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

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

2011-01-01

77

Quantiles Regression Approach to Identifying the Determinant of Breastfeeding Duration  

NASA Astrophysics Data System (ADS)

In this study, quantiles regression approach is applied to the data of Malaysian Family Life Survey (MFLS), to identify factors which are significantly related to the different conditional quantiles of the breastfeeding duration. It is known that the classical linear regression methods are based on minimizing residual sum of squared, but quantiles regression use a mechanism which are based on the conditional median function and the full range of other conditional quantile functions. Overall, it is found that the period of breastfeeding is significantly related to place of living, religion and total number of children in the family.

Mahdiyah; Norsiah Mohamed, Wan; Ibrahim, Kamarulzaman

78

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.

79

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.

80

Isoflavone determination in spontaneous legumes identified by DNA barcodes.  

PubMed

Isoflavones have been associated with several health protective effects. In this work spontaneous legume plants were screened as putative sources of dietary isoflavones. A molecular identification of the collected species was performed throughout DNA barcoding using ITS, rbcL, rpoC1 and matK sequences. The use of a multi-locus barcoding system complemented with basic morphological information allowed the unequivocal identification at the species level of 90% of the samples. The determination of isoflavone content was performed by high-performance liquid chromatography with diode-array detection. Total average contents in the studied species were significantly different, Ononis natrix and Cytisus scoparius possessing the highest total isoflavones content (396 and 273 mg kg(-1), respectively) and Lotus creticus, the lowest (20 mg kg(-1)). The correlation of total isoflavone content with the phylogeny of this set of plants as determined by the rpoC1 sequences was evaluated for the first time. PMID:23442684

Cunha, Sara C; Faria, Miguel A; Sousa, Tiago; Nunes, Eugénia

2012-10-15

81

Early Determinants of Obesity: Genetic, Epigenetic, and In Utero Influences  

PubMed Central

There is an emerging body of work indicating that genes, epigenetics, and the in utero environment can impact whether or not a child is obese. While certain genes have been identified that increase one's risk for becoming obese, other factors such as excess gestational weight gain, gestational diabetes mellitus, and smoking can also influence this risk. Understanding these influences can help to inform which behaviors and exposures should be targeted if we are to decrease the prevalence of obesity. By helping parents and young children change certain behaviors and exposures during critical time periods, we may be able to alter or modify one's genetic predisposition. However, further research is needed to determine which efforts are effective at decreasing the incidence of obesity and to develop new methods of prevention. In this paper, we will discuss how genes, epigenetics, and in utero influences affect the development of obesity. We will then discuss current efforts to alter these influences and suggest future directions for this work. PMID:22701495

Rhee, Kyung E.; Phelan, Suzanne; McCaffery, Jeanne

2012-01-01

82

Spatial and temporal determinants of genetic structure in Gentianella bohemica  

PubMed Central

The biennial plant Gentianella bohemica is a subendemic of the Bohemian Massif, where it occurs in seminatural grasslands. It has become rare in recent decades as a result of profound changes in land use. Using amplified fragment length polymorphisms (AFLP) fingerprint data, we investigated the genetic structure within and among populations of G. bohemica in Bavaria, the Czech Republic, and the Austrian border region. The aim of our study was (1) to analyze the genetic structure among populations and to discuss these findings in the context of present and historical patterns of connectivity and isolation of populations, (2) to analyze genetic structure among consecutive generations (cohorts of two consecutive years), and (3) to investigate relationships between intrapopulational diversity and effective population size (Ne) as well as plant traits. (1) The German populations were strongly isolated from each other (pairwise FST= 0.29–0.60) and from all other populations (FST= 0.24–0.49). We found a pattern of near panmixis among the latter (FST= 0.15–0.35) with geographical distance explaining only 8% of the genetic variance. These results were congruent with a principal coordinate analysis (PCoA) and analysis using STRUCTURE to identify genetically coherent groups. These findings are in line with the strong physical barrier and historical constraints, resulting in separation of the German populations from the others. (2) We found pronounced genetic differences between consecutive cohorts of the German populations (pairwise FST= 0.23 and 0.31), which can be explained by local population history (land use, disturbance). (3) Genetic diversity within populations (Shannon index, HSh) was significantly correlated with Ne (RS= 0.733) and reflected a loss of diversity due to several demographic bottlenecks. Overall, we found that the genetic structure in G. bohemica is strongly influenced by historical periods of high connectivity and isolation as well as by marked demographic fluctuations in declining populations. PMID:22822440

Königer, Julia; Rebernig, Carolin A; Brabec, Ji?í; Kiehl, Kathrin; Greimler, Josef

2012-01-01

83

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

84

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

PubMed

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

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

2014-04-01

85

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

86

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

PubMed Central

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

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

2008-01-01

87

Utility of RAPD markers in identifying genetic linkages to genes of economic interest in peach.  

PubMed

The identification of molecular markers linked to economically important traits for use in crop improvement is very important in long-lived perennial species. Three-hundred-and-sixty RAPD primers were used with bulked segregant analysis to identify markers linked to loci of specific interest in peach [(Prunus persica) L. Batch] and peach x almond [(Prunus dulcis) Batch] crosses. The traits analyzed included flesh color, adhesion, and texture; pollen fertility; plant stature; and three isozyme loci. The Mendelian behavior of the RAPD loci was established, and RAPD markers were mapped relative to the loci controlling flesh color, adhesion, and texture, and the isozyme loci Mdh-1, 6Pgd-2 and Aat-1, as well as the existing RFLP genetic linkage map constructed previously using a peach x almond F2 population. This technique has facilitated rapid identification of RAPD and RFLP markers that are linked to the traits under study. Loci controlling these traits mapped predominantly to linkage groups 2 and 3 of the peach genetic linkage map. Linkages to genes with both dominant and co-dominant alleles were identified, but linkages to dominant genes were more difficult to find. In several crosses, RAPD marker bands proved to be allelic. One co-dominant RAPD formed a heteroduplex band in heterozygous individuals and in mixtures of alternate homozygotes. The Mendelian behavior of the RAPD loci studied was established and the results suggest that RAPD markers will be useful for plant improvement in peach. PMID:24162426

Warburton, M L; Becerra-Velásquez, V L; Goffreda, J C; Bliss, F A

1996-10-01

88

Novel genetic associations with serum level metabolites identified by phenotype set enrichment analyses.  

PubMed

Availability of standardized metabolite panels and genome-wide single-nucleotide polymorphism data endorse the comprehensive analysis of gene-metabolite association. Currently, many studies use genome-wide association analysis to investigate the genetic effects on single metabolites (mGWAS) separately. Such studies have identified several loci that are associated not only with one but with multiple metabolites, facilitated by the fact that metabolite panels often include metabolites of the same or related pathways. Strategies that analyse several phenotypes in a combined way were shown to be able to detect additional genetic loci. One of those methods is the phenotype set enrichment analysis (PSEA) that tests sets of metabolites for enrichment at genes. Here we applied PSEA on two different panels of serum metabolites together with genome-wide data. All analyses were performed as a two-step identification-validation approach, using data from the population-based KORA cohort and the TwinsUK study. In addition to confirming genes that were already known from mGWAS, we were able to identify and validate 12 new genes. Knowledge about gene function was supported by the enriched metabolite sets. For loci with unknown gene functions, the results suggest a function that is interrelated with the metabolites, and hint at the underlying pathways. PMID:24927737

Ried, Janina S; Shin, So-Youn; Krumsiek, Jan; Illig, Thomas; Theis, Fabian J; Spector, Tim D; Adamski, Jerzy; Wichmann, H-Erich; Strauch, Konstantin; Soranzo, Nicole; Suhre, Karsten; Gieger, Christian

2014-11-01

89

A Genome-wide Analysis Identifies Genetic Variants in the RELN Gene Associated with Otosclerosis  

PubMed Central

Otosclerosis is a common form of progressive hearing loss, characterized by abnormal bone remodeling in the otic capsule. The etiology of the disease is largely unknown, and both environmental and genetic factors have been implicated. To identify genetic factors involved in otosclerosis, we used a case-control discovery group to complete a genome-wide association (GWA) study with 555,000 single-nucleotide polymorphisms (SNPs), utilizing pooled DNA samples. By individual genotyping of the top 250 SNPs in a stepwise strategy, we were able to identify two highly associated SNPs that replicated in two additional independent populations. We then genotyped 79 tagSNPs to fine map the two genomic regions defined by the associated SNPs. The region with the strongest association signal, pcombined = 6.23 × 10?10, is on chromosome 7q22.1 and spans intron 1 to intron 4 of reelin (RELN), a gene known for its role in neuronal migration. Evidence for allelic heterogeneity was found in this region. Consistent with the GWA data, expression of RELN was confirmed in the inner ear and in stapes footplate specimens. In conclusion, we provide evidence that implicates RELN in the pathogenesis of otosclerosis. PMID:19230858

Schrauwen, Isabelle; Ealy, Megan; Huentelman, Matthew J.; Thys, Melissa; Homer, Nils; Vanderstraeten, Kathleen; Fransen, Erik; Corneveaux, Jason J.; Craig, David W.; Claustres, Mireille; Cremers, Cor W.R.J.; Dhooge, Ingeborg; Van de Heyning, Paul; Vincent, Robert; Offeciers, Erwin; Smith, Richard J.H.; Van Camp, Guy

2009-01-01

90

A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis.  

PubMed

Otosclerosis is a common form of progressive hearing loss, characterized by abnormal bone remodeling in the otic capsule. The etiology of the disease is largely unknown, and both environmental and genetic factors have been implicated. To identify genetic factors involved in otosclerosis, we used a case-control discovery group to complete a genome-wide association (GWA) study with 555,000 single-nucleotide polymorphisms (SNPs), utilizing pooled DNA samples. By individual genotyping of the top 250 SNPs in a stepwise strategy, we were able to identify two highly associated SNPs that replicated in two additional independent populations. We then genotyped 79 tagSNPs to fine map the two genomic regions defined by the associated SNPs. The region with the strongest association signal, p(combined) = 6.23 x 10(-10), is on chromosome 7q22.1 and spans intron 1 to intron 4 of reelin (RELN), a gene known for its role in neuronal migration. Evidence for allelic heterogeneity was found in this region. Consistent with the GWA data, expression of RELN was confirmed in the inner ear and in stapes footplate specimens. In conclusion, we provide evidence that implicates RELN in the pathogenesis of otosclerosis. PMID:19230858

Schrauwen, Isabelle; Ealy, Megan; Huentelman, Matthew J; Thys, Melissa; Homer, Nils; Vanderstraeten, Kathleen; Fransen, Erik; Corneveaux, Jason J; Craig, David W; Claustres, Mireille; Cremers, Cor W R J; Dhooge, Ingeborg; Van de Heyning, Paul; Vincent, Robert; Offeciers, Erwin; Smith, Richard J H; Van Camp, Guy

2009-03-01

91

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

92

Genetic Determinants of Phosphate Response in Clemens Bergwitz1  

E-print Network

, we establish Drosophila melanogaster as a model system for the study of phosphate effects. We found-energy phosphate esters, and intracellular signaling. Cells and organisms have developed elaborate mechanismsGenetic Determinants of Phosphate Response in Drosophila Clemens Bergwitz1 *, Mark J. Wee1 , Sumi

Higgins, Darren

93

Intelligence and Race, Gender, Class: The Fallacy of Genetic Determinism.  

ERIC Educational Resources Information Center

Biological determinism represents a pseudo-scientific inquiry that is ultimately used to foster a scientific rationale for the maintenance of classism, racism, and sexism in general. Genetic diversity is an inescapable fact, but it is cultures that human brains have created that most severely limit potential. (SLD)

Belkhir, Jean Ait; Duyme, Michael

1998-01-01

94

Genetic Segregation of Brain Gene Expression Identifies Retinaldehyde Binding Protein 1 and Syntaxin 12 as Potential Contributors to Ethanol Preference in Mice  

Microsoft Academic Search

Genetic strains of mice represent an important resource for research on the biological determinants of complex diseases and behavioral phenotypes. To date, the approaches used have had little success in identifying causal genes. We have evaluated brain gene expression in C57BL\\/6J (B6) and DBA\\/2J (D2) inbred mouse strains using differential display to identify a number of sequences showing significant expression

Julie A. Treadwell; Kara B. Pagniello; Shiva M. Singh

2004-01-01

95

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

PubMed

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

2013-10-01

96

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

97

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

PubMed Central

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

2014-01-01

98

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.

99

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

100

A reverse genetics approach identifies novel mutants in light responses and anthocyanin metabolism in petunia.  

PubMed

Flower color and plant architecture are important commercially valuable features for ornamental petunias (Petunia x hybrida Vilm.). Photoperception and light signaling are the major environmental factors controlling anthocyanin and chlorophyll biosynthesis and shade-avoidance responses in higher plants. The genetic regulators of these processes were investigated in petunia by in silico analyses and the sequence information was used to devise a reverse genetics approach to probe mutant populations. Petunia orthologs of photoreceptor, light-signaling components and anthocyanin metabolism genes were identified and investigated for functional conservation by phylogenetic and protein motif analyses. The expression profiles of photoreceptor gene families and of transcription factors regulating anthocyanin biosynthesis were obtained by bioinformatic tools. Two mutant populations, generated by an alkalyting agent and by gamma irradiation, were screened using a phenotype-independent, sequence-based method by high-throughput PCR-based assay. The strategy allowed the identification of novel mutant alleles for anthocyanin biosynthesis (CHALCONE SYNTHASE) and regulation (PH4), and for light signaling (CONSTANS) genes. PMID:24554834

Berenschot, Amanda S; Quecini, Vera

2014-01-01

101

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, Harriette; Munoz, 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

102

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

103

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

104

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

PubMed

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

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

2014-07-01

105

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

106

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

107

A Model for Genetic and Epigenetic Regulatory Networks Identifies Rare Pathways for Transcription Factor Induced Pluripotency  

PubMed Central

With relatively low efficiency, differentiated cells can be reprogrammed to a pluripotent state by ectopic expression of a few transcription factors. An understanding of the mechanisms that underlie data emerging from such experiments can help design optimal strategies for creating pluripotent cells for patient-specific regenerative medicine. We have developed a computational model for the architecture of the epigenetic and genetic regulatory networks which describes transformations resulting from expression of reprogramming factors. Importantly, our studies identify the rare temporal pathways that result in induced pluripotent cells. Further experimental tests of predictions emerging from our model should lead to fundamental advances in our understanding of how cellular identity is maintained and transformed. PMID:20485562

Artyomov, Maxim N.; Meissner, Alexander; Chakraborty, Arup K.

2010-01-01

108

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

PubMed

Complex clinical outcomes, such as adverse reaction to vaccination, arise from the concerted interactions among the myriad components of a biological system. Therefore, comprehensive etiological models can be developed only through the integrated study of multiple types of experimental data. In this study, we apply this paradigm to high-dimensional genetic and proteomic data collected to elucidate the mechanisms underlying the development of adverse events (AEs) in patients after smallpox vaccination. As vaccination was successful in all of the patients under study, the AE outcomes reported likely represent the result of interactions among immune system components that result in excessive or prolonged immune stimulation. In this study, we examined 1442 genetic variables (single nucleotide polymorphisms) and 108 proteomic variables (serum cytokine concentrations) to model AE risk. To accomplish this daunting analytical task, we employed the Random Forests (RF) method to filter the most important attributes, then we used the selected attributes to build a final decision tree model. This strategy is well suited to integrated analysis, as relevant attributes may be selected from categorical or continuous data. Importantly, RF is a natural approach for studying the type of gene-gene, gene-protein and protein-protein interactions we hypothesize to be involved in the development of clinical AEs. RF importance scores for particular attributes take interactions into account, and there may be interactions across data types. Combining information from previous studies on AEs related to smallpox vaccination with the genetic and proteomic attributes identified by RF, we built a comprehensive model of AE development that includes the cytokines intercellular adhesion molecule-1 (ICAM-1 or CD54), interleukin-10 (IL-10), and colony stimulating factor-3 (CSF-3 or G-CSF) and a genetic polymorphism in the cytokine gene interleukin-4 (IL4). The biological factors included in the model support our hypothesized mechanism for the development of AEs involving prolonged stimulation of inflammatory pathways and an imbalance of normal tissue damage repair pathways. This study shows the utility of RF for such analytical tasks, while both enhancing and reinforcing our working model of AE development after smallpox vaccination. PMID:18923431

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

2009-03-01

109

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

110

Focal-Mechanism Determination in Taiwan by Genetic Algorithm  

Microsoft Academic Search

Abstract We determined the focal-mechanism solutions for earthquakes with mag- nitude ML ?4:0 that occurred in the Taiwan region between,1991 and 2005. First- motion polarities of P waves recorded at over 700 seismic stations in Taiwan were used. Because of the large number of events and stations involved, we implemented the genetic algorithm in a nonlinear global search for the

Y.-M. Wu; L. Zhao; C.-H. Chang; Y.-J. Hsu

2008-01-01

111

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

PubMed

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

2013-11-01

112

Identifying Genetic Traces of Historical Expansions: Phoenician Footprints in the Mediterranean  

PubMed Central

The Phoenicians were the dominant traders in the Mediterranean Sea two thousand to three thousand years ago and expanded from their homeland in the Levant to establish colonies and trading posts throughout the Mediterranean, but then they disappeared from history. We wished to identify their male genetic traces in modern populations. Therefore, we chose Phoenician-influenced sites on the basis of well-documented historical records and collected new Y-chromosomal data from 1330 men from six such sites, as well as comparative data from the literature. We then developed an analytical strategy to distinguish between lineages specifically associated with the Phoenicians and those spread by geographically similar but historically distinct events, such as the Neolithic, Greek, and Jewish expansions. This involved comparing historically documented Phoenician sites with neighboring non-Phoenician sites for the identification of weak but systematic signatures shared by the Phoenician sites that could not readily be explained by chance or by other expansions. From these comparisons, we found that haplogroup J2, in general, and six Y-STR haplotypes, in particular, exhibited a Phoenician signature that contributed > 6% to the modern Phoenician-influenced populations examined. Our methodology can be applied to any historically documented expansion in which contact and noncontact sites can be identified. PMID:18976729

Zalloua, Pierre A.; Platt, Daniel E.; El Sibai, Mirvat; Khalife, Jade; Makhoul, Nadine; Haber, Marc; Xue, Yali; Izaabel, Hassan; Bosch, Elena; Adams, Susan M.; Arroyo, Eduardo; Lopez-Parra, Ana Maria; Aler, Mercedes; Picornell, Antonia; Ramon, Misericordia; Jobling, Mark A.; Comas, David; Bertranpetit, Jaume; Wells, R. Spencer; Tyler-Smith, Chris

2008-01-01

113

An event-specific DNA microarray to identify genetically modified organisms in processed foods.  

PubMed

We developed an event-specific DNA microarray system to identify 19 genetically modified organisms (GMOs), including two GM soybeans (GTS-40-3-2 and A2704-12), thirteen GM maizes (Bt176, Bt11, MON810, MON863, NK603, GA21, T25, TC1507, Bt10, DAS59122-7, TC6275, MIR604, and LY038), three GM canolas (GT73, MS8xRF3, and T45), and one GM cotton (LLcotton25). The microarray included 27 oligonucleotide probes optimized to identify endogenous reference targets, event-specific targets, screening targets (35S promoter and nos terminator), and an internal target (18S rRNA gene). Thirty-seven maize-containing food products purchased from South Korean and US markets were tested for the presence of GM maize using this microarray system. Thirteen GM maize events were simultaneously detected using multiplex PCR coupled with microarray on a single chip, at a limit of detection of approximately 0.5%. Using the system described here, we detected GM maize in 11 of the 37 food samples tested. These results suggest that an event-specific DNA microarray system can reliably detect GMOs in processed foods. PMID:20438128

Kim, Jae-Hwan; Kim, Su-Youn; Lee, Hyungjae; Kim, Young-Rok; Kim, Hae-Yeong

2010-05-26

114

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

115

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

116

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

PubMed Central

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

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

2009-01-01

117

Genetic risk identifies multiple myeloma patients who do not benefit from autologous stem cell transplantation  

Microsoft Academic Search

Genetic aberrations have emerged as major prognostic factors for patients with multiple myeloma (MM). We evaluated 126 MM patients for t(4;14) or t(11;14), 13q or p53 deletions and correlated the number of genetic aberrations with patient's clinical outcome following undergoing autologous stem cell transplantation. We demonstrate the significance of genetic-based risk classification that clearly segregate patients into low (no genetic

H Chang; X Y Qi; S Samiee; Q-L Yi; C Chen; S Trudel; J Mikhael; D Reece; A K Stewart

2005-01-01

118

Developmental and genetic determinants of leadership role occupancy among women.  

PubMed

The genetic and developmental influences on leadership role occupancy were investigated using a sample of 178 fraternal and 214 identical female twins. Two general developmental factors were identified, one involving formal work experiences and the other a family experiences factor hypothesized to influence whether women move into positions of leadership in organizations. Results indicated that 32% of the variance in leadership role occupancy was associated with heritability. The 2 developmental factors also showed significant correlations with leadership role occupancy. However, after genetic factors were partialed out, only the work experience factor was significantly related to leadership role occupancy. Results are discussed in terms of prior life events and experiences that may trigger leadership development and the limitations of this study. PMID:17484551

Arvey, Richard D; Zhang, Zhen; Avolio, Bruce J; Krueger, Robert F

2007-05-01

119

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

120

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

121

A screen for genetic suppressor elements of hepatitis C virus identifies a supercharged protein inhibitor of viral replication  

E-print Network

A Screen for Genetic Suppressor Elements of Hepatitis C Virus Identifies a Supercharged Protein Inhibitor of Viral Replication Rudo L. Simeon1, Zhilei Chen1,2* 1 Artie McFerrin Department of Chemical Engineering, Texas A&M University, College... Station, Texas, United States of America, 2 Department of Microbial and Molecular Pathogenesis, Texas A&M Health Science Center, College Station, Texas, United States of America Abstract Genetic suppressor elements (GSEs) are biomolecules derived from a...

Simeon, Rudo L.; Chen, Zhilei

2013-12-31

122

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

123

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

124

Cumulative effect of genome-wide association study-identified genetic variants for bladder cancer.  

PubMed

Recent genome-wide association studies have identified 14 genetic variants associated with bladder cancer in Caucasians. The effects of these risk variants and their cumulative effects in Asian populations are unknown. We genotyped these newly identified variants in a case-control study of 1,050 patients diagnosed with bladder cancer and 1,404 controls in the Chinese population. Odds rations (ORs) and 95% confidence intervals (CIs) were computed by logistic regression, and cumulative effect of risk alleles were evaluated. Overall, seven of the 14 variants were significantly associated with bladder cancer risk (p?=?9.763?×?10(-3) for rs9642880 at 8q24.21, p?=?3.004?×?10(-3) for rs2294008 at 8q24.3, p?=?0.012 for rs798766 at 4p16.3, p?=?0.034 for rs1495741 at 8p22, p?=?2.306?×?10(-4) for GSTM1, p?=?8.507?×?10(-8) for rs17674580 at 18q12.3, p?=?7.179?×?10(-4) for rs10936599 at 3q26.2) and the odds ratios (ORs) ranged from 1.13 to 1.65. Moreover, there were a significant increased risk for bladder cancer positively correlated numbers of risk alleles and smoking status (Ptrend ?=?7.060?×?10(-16) ). However, no allelic interaction effects on bladder cancer risk were observed between cumulative effects of variants and clinical characteristics. These findings suggest that seven bladder cancer risk-associated variants (rs9642880, rs2294008, rs798766, rs1495741, GSTM1 null, rs17674580 and rs10936599) may be used, collectively, to effectively measure inherited risk for bladder cancer. PMID:24740636

Wang, Meilin; Chu, Haiyan; Lv, Qiang; Wang, Li; Yuan, Lin; Fu, Guangbo; Tong, Na; Qin, Chao; Yin, Changjun; Zhang, Zhengdong; Xu, Jianfeng

2014-12-01

125

Evolution of a Pathogen: A Comparative Genomics Analysis Identifies a Genetic Pathway to Pathogenesis in Acinetobacter  

PubMed Central

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

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

2013-01-01

126

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

PubMed

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

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

2013-01-01

127

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, Tonu; 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, Andre 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

128

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

PubMed Central

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

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

2013-01-01

129

Polynesian genetic affinities with Southeast Asian populations as identified by mtDNA analysis.  

PubMed Central

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(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 "Polynesian motif" 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. PMID:7668267

Melton, T; Peterson, R; Redd, A J; Saha, N; Sofro, A S; Martinson, J; Stoneking, M

1995-01-01

130

An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules  

PubMed Central

Summary The high rate of clinical response to protein kinase-targeting drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer cell-line (CCL) profiling to identify additional biomarkers of small-molecule sensitivities. We have quantitatively measured the sensitivity of 242 genomically characterized CCLs to an Informer Set of 354 small molecules that target many nodes in cell circuitry, uncovering protein dependencies that: 1) associate with specific cancer-genomic alterations and 2) can be targeted by small molecules. We have created the Cancer Therapeutics Response Portal (www.broadinstitute.org/ctrp) to enable users to correlate genetic features to sensitivity in individual lineages and control for confounding factors of CCL profiling. We report a candidate dependency, associating activating mutations in the oncogene ?-catenin with sensitivity to the Bcl2-family antagonist, navitoclax. The resource can be used to develop novel therapeutic hypotheses and accelerate discovery of drugs matched to patients by their cancer genotype and lineage. PMID:23993102

Basu, Amrita; Bodycombe, Nicole E.; Cheah, Jaime H.; Price, Edmund V.; Liu, Ke; Schaefer, Giannina I.; Ebright, Richard Y.; Stewart, Michelle L.; Ito, Daisuke; Wang, Stephanie; Bracha, Abigail L.; Liefeld, Ted; Wawer, Mathias; Gilbert, Joshua C.; Wilson, Andrew J.; Stransky, Nicolas; Kryukov, Gregory V.; Dancik, Vlado; Barretina, Jordi; Garraway, Levi A.; Hon, C. Suk-Yee; Munoz, Benito; Bittker, Joshua A.; Stockwell, Brent R.; Khabele, Dineo; Stern, Andrew M.; Clemons, Paul A.; Shamji, Alykhan F.; Schreiber, Stuart L.

2014-01-01

131

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; Leeuw, Christiaan de; 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

132

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

133

Genetic modifier loci of mouse Mfrp(rd6) identified by quantitative trait locus analysis.  

PubMed

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 Mfrp(rd6) mice, which exhibit a slowly progressive photoreceptor degeneration. A cohort of 63 F2 homozygous Mfrp(rd6) mice from a (B6.C3Ga-Mfrp(rd6)/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 Mfrp(rd6) retinal degenerative phenotype in mice depends on the strain genetic background and that a significant modifier locus on CAST/EiJ Chromosome 1 protects against Mfrp(rd6)-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

134

Harnessing gene expression to identify the genetic basis of drug resistance  

PubMed Central

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

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

2009-01-01

135

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

PubMed Central

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

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

2010-01-01

136

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

137

A Constant Light-Genetic Screen Identifies KISMET as a Regulator of Circadian Photoresponses  

PubMed Central

Circadian pacemakers are essential to synchronize animal physiology and behavior with the day?night cycle. They are self-sustained, but the phase of their oscillations is determined by environmental cues, particularly light intensity and temperature cycles. In Drosophila, light is primarily detected by a dedicated blue-light photoreceptor: CRYPTOCHROME (CRY). Upon light activation, CRY binds to the pacemaker protein TIMELESS (TIM) and triggers its proteasomal degradation, thus resetting the circadian pacemaker. To understand further the CRY input pathway, we conducted a misexpression screen under constant light based on the observation that flies with a disruption in the CRY input pathway remain robustly rhythmic instead of becoming behaviorally arrhythmic. We report the identification of more than 20 potential regulators of CRY-dependent light responses. We demonstrate that one of them, the chromatin-remodeling enzyme KISMET (KIS), is necessary for normal circadian photoresponses, but does not affect the circadian pacemaker. KIS genetically interacts with CRY and functions in PDF-negative circadian neurons, which play an important role in circadian light responses. It also affects daily CRY-dependent TIM oscillations in a peripheral tissue: the eyes. We therefore conclude that KIS is a key transcriptional regulator of genes that function in the CRY signaling cascade, and thus it plays an important role in the synchronization of circadian rhythms with the day?night cycle. PMID:20041201

Dubruille, Raphaelle; Murad, Alejandro; Rosbash, Michael; Emery, Patrick

2009-01-01

138

Genetic Approach to Identifying Signal Transduction Mechanisms Initiated by Receptors for TGF-B-Related Factors.  

National Technical Information Service (NTIS)

A genetic screen for new mutations affecting the signaling pathway by which cells respond to TGF-beta-related factors in Drosophila was carried out. The genetic background was sensitized using a mutation in the Type I receptor gene. New mutations affectin...

F. M. Hoffman

1996-01-01

139

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

PubMed Central

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

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

2012-01-01

140

Genetic and environmental determinants of risk for cholangiocarcinoma in Thailand  

PubMed Central

Cholangiocarcinoma (CCA) is a difficult cancer to diagnose in the early stage and to treat by curative resection. The incidence of CCA in the northeast of Thailand is the highest in the world. To make progress in detecting a high risk group and in the prevention and detection of CCA, we have been analyzing the risk factors for CCA. Although liver fluke infection is known to be a risk factor, there are patients who are not infected with the liver fluke and not all people infected with the liver fluke will suffer from the disease. Therefore, it is of the utmost importance to analyze the risk factors and the mechanism to prevent the disease and also to detect the disease in its early stage to save patients’ lives. Through collaboration among Thai and Japanese researchers, we analyzed the genetic and environmental determinants of risks for CCA. Also, we have been trying to develop methods to detect the disease in a non-invasive way. Without repeating findings reported in various reviews on CCA, we will first discuss the environmental and genetic determinants of the risks for CCA. Second, we will discuss the properties of CCA, including the etiological agents and the mechanism of cholangiocarcinogenesis, and finally, we will discuss future approaches to prevent and cure CCA from the standpoint of evidence-based medicine. We will discuss these points by including the data from our laboratories. We would like to emphasize the importance of the genetic data, especially whole genome approaches, to understand the properties of CCA, to find a high risk population for CCA and to develop effective preventative methods to stop the carcinogenic steps toward CCA in the near future. In addition, it is of the upmost importance to develop a non-invasive, specific and sensitive method to detect CCA in its early stage for the application of modern medical approaches to help patients with CCA. PMID:25401000

Miwa, Masanao; Honjo, Satoshi; You, Gyokukou; Tanaka, Masakazu; Uchida, Kazuhiko; Srivatanakul, Petcharin; Khuhaprema, Thiravud; Loilome, Watcharin; Techasen, Anchalee; Wongkham, Chaisiri; Limpaiboon, Temduang; Yongvanit, Puangrat; Wongkham, Sopit

2014-01-01

141

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

142

Genetic and environmental determinants of risk for cholangiocarcinoma in Thailand.  

PubMed

Cholangiocarcinoma (CCA) is a difficult cancer to diagnose in the early stage and to treat by curative resection. The incidence of CCA in the northeast of Thailand is the highest in the world. To make progress in detecting a high risk group and in the prevention and detection of CCA, we have been analyzing the risk factors for CCA. Although liver fluke infection is known to be a risk factor, there are patients who are not infected with the liver fluke and not all people infected with the liver fluke will suffer from the disease. Therefore, it is of the utmost importance to analyze the risk factors and the mechanism to prevent the disease and also to detect the disease in its early stage to save patients' lives. Through collaboration among Thai and Japanese researchers, we analyzed the genetic and environmental determinants of risks for CCA. Also, we have been trying to develop methods to detect the disease in a non-invasive way. Without repeating findings reported in various reviews on CCA, we will first discuss the environmental and genetic determinants of the risks for CCA. Second, we will discuss the properties of CCA, including the etiological agents and the mechanism of cholangiocarcinogenesis, and finally, we will discuss future approaches to prevent and cure CCA from the standpoint of evidence-based medicine. We will discuss these points by including the data from our laboratories. We would like to emphasize the importance of the genetic data, especially whole genome approaches, to understand the properties of CCA, to find a high risk population for CCA and to develop effective preventative methods to stop the carcinogenic steps toward CCA in the near future. In addition, it is of the upmost importance to develop a non-invasive, specific and sensitive method to detect CCA in its early stage for the application of modern medical approaches to help patients with CCA. PMID:25401000

Miwa, Masanao; Honjo, Satoshi; You, Gyokukou; Tanaka, Masakazu; Uchida, Kazuhiko; Srivatanakul, Petcharin; Khuhaprema, Thiravud; Loilome, Watcharin; Techasen, Anchalee; Wongkham, Chaisiri; Limpaiboon, Temduang; Yongvanit, Puangrat; Wongkham, Sopit

2014-11-15

143

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

144

Gene networks associated with conditional fear in mice identified using a systems genetics approach  

Microsoft Academic Search

Background  Our understanding of the genetic basis of learning and memory remains shrouded in mystery. To explore the genetic networks\\u000a governing the biology of conditional fear, we used a systems genetics approach to analyze a hybrid mouse diversity panel (HMDP)\\u000a with high mapping resolution.\\u000a \\u000a \\u000a \\u000a \\u000a Results  A total of 27 behavioral quantitative trait loci were mapped with a false discovery rate of 5%.

Christopher C Park; Greg D Gale; Simone de Jong; Anatole Ghazalpour; Brian J Bennett; Charles R Farber; Peter Langfelder; Andy Lin; Arshad H Khan; Eleazar Eskin; Steve Horvath; Aldons J Lusis; Roel A Ophoff; Desmond J Smith

2011-01-01

145

Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations  

PubMed Central

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic ?-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08×10?66. The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1–3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p?=?10?4 or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases. PMID:19798445

Pramstaller, Peter P.; Rudan, Igor; Franklin, Christopher S.; Liebisch, Gerhard; Erdmann, Jeanette; Jonasson, Inger; Zorkoltseva, Irina V.; Pattaro, Cristian; Hayward, Caroline; Isaacs, Aaron; Hengstenberg, Christian; Campbell, Susan; Gnewuch, Carsten; Janssens, A. CecileJ.W.; Kirichenko, Anatoly V.; Konig, Inke R.; Marroni, Fabio; Polasek, Ozren; Demirkan, Ayse; Kolcic, Ivana; Schwienbacher, Christine; Igl, Wilmar; Biloglav, Zrinka; Witteman, Jacqueline C. M.; Pichler, Irene; Zaboli, Ghazal; Axenovich, Tatiana I.; Peters, Annette; Schreiber, Stefan; Wichmann, H.-Erich; Schunkert, Heribert; Hastie, Nick; Oostra, Ben A.; Wild, Sarah H.; Meitinger, Thomas; Gyllensten, Ulf; van Duijn, Cornelia M.; Wilson, James F.; Wright, Alan; Schmitz, Gerd; Campbell, Harry

2009-01-01

146

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

147

Sex Differences in the Genetic Basis of Morning Serum Cortisol Levels: Genome-Wide Screen Identifies Two  

E-print Network

Sex Differences in the Genetic Basis of Morning Serum Cortisol Levels: Genome-Wide Screen, Massachusetts 02115 Context: Relatively little is known about the influence of specific genes on cortisol levels, particularly morning cortisol levels. Objective: The objective of this study was to identify quantitative trait

Abney, Mark

148

Mouse Genome-Wide Association and Systems Genetics Identify Asxl2 As a Regulator of Bone Mineral Density and Osteoclastogenesis  

Microsoft Academic Search

Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis were used in the recently described Hybrid Mouse Diversity Panel (HMDP) to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of

Charles R. Farber; Brian J. Bennett; Luz Orozco; Wei Zou; Ana Lira; Emrah Kostem; Hyun Min Kang; Nicholas Furlotte; Ani Berberyan; Anatole Ghazalpour; Jaijam Suwanwela; Thomas A. Drake; Eleazar Eskin; Q. Tian Wang; Steven L. Teitelbaum; Aldons J. Lusis

2011-01-01

149

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

Microsoft Academic Search

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

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

2010-01-01

150

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); Ferdinand Noble (College de Frence); Anne Eichmann (College de France)

2006-10-01

151

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

152

Genetic Determinants Influencing Human Serum Metabolome among African Americans  

PubMed Central

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

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

2014-01-01

153

Genetic and nongenetic determinants of cell growth variation assessed by high-throughput microscopy.  

PubMed

In microbial populations, growth initiation and proliferation rates are major components of fitness and therefore likely targets of selection. We used a high-throughput microscopy assay, which enables simultaneous analysis of tens of thousands of microcolonies, to determine the sources and extent of growth rate variation in the budding yeast (Saccharomyces cerevisiae) in different glucose environments. We find that cell growth rates are regulated by the extracellular concentration of glucose as proposed by Monod (1949), but that significant heterogeneity in growth rates is observed among genetically identical individuals within an environment. Yeast strains isolated from different geographic locations and habitats differ in their growth rate responses to different glucose concentrations. Inheritance patterns suggest that the genetic determinants of growth rates in different glucose concentrations are distinct. In addition, we identified genotypes that differ in the extent of variation in growth rate within an environment despite nearly identical mean growth rates, providing evidence that alleles controlling phenotypic variability segregate in yeast populations. We find that the time to reinitiation of growth (lag) is negatively correlated with growth rate, yet this relationship is strain-dependent. Between environments, the respirative activity of individual cells negatively correlates with glucose abundance and growth rate, but within an environment respirative activity and growth rate show a positive correlation, which we propose reflects differences in protein expression capacity. Our study quantifies the sources of genetic and nongenetic variation in cell growth rates in different glucose environments with unprecedented precision, facilitating their molecular genetic dissection. PMID:23938868

Ziv, Naomi; Siegal, Mark L; Gresham, David

2013-12-01

154

An EHW Architecture for Real-Time GPS Attitude Determination Based on Parallel Genetic Algorithm  

Microsoft Academic Search

The paper describes a parallel genetic algorithm for the VLSI implementation of real-time GPS attitude determination systems. The genetic algorithm is based on a fine-grained model and utilises AFM (Ambiguity Function Method) for GPS attitude determination. The paper describes various implementation choices with for the genetic algorithm in order to achieve both functionality and practical performance constraints such as speed,

Jiangning Xu; Tughrul Arslan; Qing Wang; Dejun Wan

2002-01-01

155

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

156

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

157

[Spatial organization of EEG in rats with genetically determined emotionality].  

PubMed

In order to study the possibility of EEG discrimination of genetically determined emotionality (increased propensity to emotional and stress reactions and anxiety) brain electrical activity was recorded in rats of two strains: Maudsley Reactive and Maudsley Nonreactive (24 derivations from the convexital skull surface were used). The program package "Synchro-EEG" was used for EEG processing. It was demonstrated that the two rat strains were significantly different in 120 EEG parameters of 840 ones analyzed. On the basis of 37 parameters, each rat was correctly recognized as belonging to the respective group with the error of 4.89%. The analysis of the detected signs allowed their classification to be performed in accordance with the peculiarities of the emotional and cognitive processes and the level of nonspecific activation. Specific forms of interaction between these components in the system of emotional reactions were revealed. PMID:10923382

Sviderskaia, N E; Seredenin, S B; Korol'kova, T A; Kozhechkin, S N; Koshtoiants, O Kh; Kozhedub, R G

2000-01-01

158

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

159

Pharmacogenetics: A Tool for Identifying Genetic Factors in Drug Dependence and Response to Treatment  

PubMed Central

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

Mroziewicz, Margaret; Tyndale, Rachel F.

2010-01-01

160

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

161

Orbit determination by genetic algorithm and application to GEO observation  

NASA Astrophysics Data System (ADS)

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

Hinagawa, Hideaki; Yamaoka, Hitoshi; Hanada, Toshiya

2014-02-01

162

Species boundaries and genetic diversity among Hawaiian crickets of the genus Laupala identified using amplified fragment length polymorphism  

Microsoft Academic Search

Crickets of the genus Laupala represent one of the many morphologically cryptic groups of insects, with the most closely related species distinguished only by the male calling song. Cryptic groups provide a challenge in determining the genetic boundaries between closely related populations and species. We have addressed the question of species boundaries in the Hawaiian cricket, Laupala , using nuclear

Y. M. PA RSONS; K. L. S H AW

163

A genetic linkage study in Brazil identifies a new locus for persistent developmental stuttering on chromosome 10.  

PubMed

Although twin, adoption, and family studies demonstrate that genetic factors are involved in the origins of stuttering, the mode of transmission of the disorder in families is not well defined and stuttering is considered a genetically complex trait. We performed a genome-wide linkage scan in a group of 43 Brazilian families, each containing multiple cases of persistent developmental stuttering. Linkage analysis under a dominant model of inheritance generated significant evidence of linkage in two Brazilian families, with a combined maximum single-point LOD score of 4.02 and a multipoint LOD score of 4.28 on chromosome 10q21. This demonstrated the presence of a novel variant gene at this locus that predisposes individuals to stuttering, which provides an opportunity to identify novel genetic mechanisms that underlie this disorder. PMID:24737434

Domingues, C E F; Olivera, C M C; Oliveira, B V; Juste, F S; Andrade, C R F; Giacheti, C M; Moretti-Ferreira, D; Drayna, D

2014-01-01

164

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

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

2014-09-01

165

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; Lopez, Cesar G.; Senior, M. Lynn; Borras, Lucas

2014-01-01

166

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

167

Towards identifying populations that increase the likelihood of success in genetic programming  

Microsoft Academic Search

This paper presents a comprehensive, multivariate account of how initial population material is used over the course of a genetic programming run as while various factors influencing problem difficulty are changed. The results corroborate both theoretical and empirical studies on factors that influence population dynamics. The results also indicate a clue for a possible empirical measurement that could be used

Jason M. Daida

2005-01-01

168

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

Cancer.gov

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

169

Comparative Genomics to Identify Genetic Variabilities Associated with Salmonella Typhimurium DT104  

E-print Network

the epidemic period, to interrogate the genetic changes that may have contributed to the strain epidemicity. Two novel techniques, optical mapping and the Biolog phenotypic microarray, were used to confirm by phenotypic assay and confirmatory techniques. Overall the picture of DT104 epidemicity is complex

Chittka, Lars

170

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

171

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

Microsoft Academic Search

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

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

2005-01-01

172

Identifying genetic marker sets associated with phenotypes via an efficient adaptive score test.  

PubMed

In recent years, genome-wide association studies (GWAS) and gene-expression profiling have generated a large number of valuable datasets for assessing how genetic variations are related to disease outcomes. With such datasets, it is often of interest to assess the overall effect of a set of genetic markers, assembled based on biological knowledge. Genetic marker-set analyses have been advocated as more reliable and powerful approaches compared with the traditional marginal approaches (Curtis and others, 2005. Pathways to the analysis of microarray data. TRENDS in Biotechnology 23, 429-435; Efroni and others, 2007. Identification of key processes underlying cancer phenotypes using biologic pathway analysis. PLoS One 2, 425). Procedures for testing the overall effect of a marker-set have been actively studied in recent years. For example, score tests derived under an Empirical Bayes (EB) framework (Liu and others, 2007. Semiparametric regression of multidimensional genetic pathway data: least-squares kernel machines and linear mixed models. Biometrics 63, 1079-1088; Liu and others, 2008. Estimation and testing for the effect of a genetic pathway on a disease outcome using logistic kernel machine regression via logistic mixed models. BMC bioinformatics 9, 292-2; Wu and others, 2010. Powerful SNP-set analysis for case-control genome-wide association studies. American Journal of Human Genetics 86, 929) have been proposed as powerful alternatives to the standard Rao score test (Rao, 1948. Large sample tests of statistical hypotheses concerning several parameters with applications to problems of estimation. Mathematical Proceedings of the Cambridge Philosophical Society, 44, 50-57). The advantages of these EB-based tests are most apparent when the markers are correlated, due to the reduction in the degrees of freedom. In this paper, we propose an adaptive score test which up- or down-weights the contributions from each member of the marker-set based on the Z-scores of their effects. Such an adaptive procedure gains power over the existing procedures when the signal is sparse and the correlation among the markers is weak. By combining evidence from both the EB-based score test and the adaptive test, we further construct an omnibus test that attains good power in most settings. The null distributions of the proposed test statistics can be approximated well either via simple perturbation procedures or via distributional approximations. Through extensive simulation studies, we demonstrate that the proposed procedures perform well in finite samples. We apply the tests to a breast cancer genetic study to assess the overall effect of the FGFR2 gene on breast cancer risk. PMID:22734045

Cai, Tianxi; Lin, Xihong; Carroll, Raymond J

2012-09-01

173

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

174

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

175

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

176

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

PubMed

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), r(2) = 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), r(2) = 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

177

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

PubMed Central

Background Identifying causal relationships in phylogeographic and landscape genetic investigations is notoriously difficult, but can be facilitated by use of multispecies comparisons. Methodology/Principal Findings We 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: Pinus monticola). Visualizations suggested that, despite occupying the same geographical region and habitats, species responded differently to prevailing historical processes. S. o. caurina and P. monticola demonstrated directional patterns of spatial genetic structure where genetic distances and diversity were greater in southern versus northern locales. A. longicaudus and R. variegatus displayed opposite patterns where genetic distances were greater in northern versus southern regions. Statistical analyses of directional patterns subsequently confirmed observations from visualizations. Based upon regional climatological history, we hypothesized that observed latitudinal patterns may have been produced by range expansions. Subsequent computer simulations confirmed that directional patterns can be produced by expansion events. Conclusions/Significance We discuss phylogeographic hypotheses regarding historical processes that may have produced observed patterns. Inferential methods used here may become increasingly powerful as detailed simulations of organisms and historical scenarios become plausible. We further suggest that inter-specific comparisons of historical patterns take place prior to drawing conclusions regarding effects of current anthropogenic change within landscapes. PMID:21060824

Miller, Mark P.; Haig, Susan M.

2010-01-01

178

Genetic Determinants of Emphysema Distribution in the National Emphysema Treatment Trial  

PubMed Central

Rationale: Computed tomography (CT) scanning of the lung may reduce phenotypic heterogeneity in defining subjects with chronic obstructive pulmonary disease (COPD), and allow identification of genetic determinants of emphysema severity and distribution. Objectives: We sought to identify genes associated with CT scan distribution of emphysema in individuals without ?1-antitrypsin deficiency but with severe COPD. Methods: We evaluated baseline CT densitometry phenotypes in 282 individuals with emphysema enrolled in the Genetics Ancillary Study of the National Emphysema Treatment Trial, and used regression models to identify genetic variants associated with emphysema distribution. Measurements and Main Results: Emphysema distribution was assessed by two methods—assessment by radiologists and by computerized density mask quantitation, using a threshold of ?950 Hounsfield units. A total of 77 polymorphisms in 20 candidate genes were analyzed for association with distribution of emphysema. GSTP1, EPHX1, and MMP1 polymorphisms were associated with the densitometric, apical-predominant distribution of emphysema (p value range = 0.001–0.050). When an apical-predominant phenotype was defined by the radiologist scoring method, GSTP1 and EPHX1 single-nucleotide polymorphisms were found to be significantly associated. In a case–control analysis of COPD susceptibility limited to cases with densitometric upper-lobe–predominant cases, the EPHX1 His139Arg single-nucleotide polymorphism was associated with COPD (p = 0.005). Conclusions: Apical and basal emphysematous destruction appears to be influenced by different genes. Polymorphisms in the xenobiotic enzymes, GSTP1 and EPHX1, are associated with apical-predominant emphysema. Altered detoxification of cigarette smoke metabolites may contribute to emphysema distribution, and these findings may lead to further insight into genetic determinants of emphysema. PMID:17363767

DeMeo, Dawn L.; Hersh, Craig P.; Hoffman, Eric A.; Litonjua, Augusto A.; Lazarus, Ross; Sparrow, David; Benditt, Joshua O.; Criner, Gerard; Make, Barry; Martinez, Fernando J.; Scanlon, Paul D.; Sciurba, Frank C.; Utz, James P.; Reilly, John J.; Silverman, Edwin K.

2007-01-01

179

Identifying Determinants of Academic Self-Confidence among Science, Math, Engineering, and Technology Students.  

ERIC Educational Resources Information Center

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 point to perceived respect from professors as the strongest determinant of female academic self-confidence whereas the perceived quality of teaching is…

Huang, Penelope M.; Brainard, Suzanne G.

2001-01-01

180

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

PubMed

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

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

2014-01-01

181

Identifying the genomic determinants of aging and longevity in human population studies: Progress and challenges  

PubMed Central

Human lifespan variation is mainly determined by environmental factors, whereas the genetic contribution is 25–30% and expected to be polygenic. Two complementary fields go hand in hand in order to unravel the mechanisms of biological aging: genomic and biomarker research. Explorative and candidate gene studies of the human genome by genetic, transcriptomic, and epigenomic approaches have resulted in the identification of a limited number of interesting positive linkage regions, genes, and pathways that contribute to lifespan variation. The possibilities to further exploit these findings are rapidly increasing through the use of novel technologies, such as next-generation sequencing. Genomic research is progressively being integrated with biomarker studies on aging, including the application of (noninvasive) deep phenotyping and omics data – generated using novel technologies – in a wealth of studies in human populations. Hence, these studies may assist in obtaining a more holistic perspective on the role of the genome in aging and lifespan regulation. PMID:23423909

Deelen, Joris; Beekman, Marian; Capri, Miriam; Franceschi, Claudio; Slagboom, P Eline

2013-01-01

182

Genetic modifiers of Hb E\\/?0 thalassemia identified by a two-stage genome-wide association study  

Microsoft Academic Search

BACKGROUND: Patients with Hb E\\/?0 thalassemia display remarkable variability in disease severity. To identify genetic modifiers influencing disease severity, we conducted a two-stage genome scan in groups of 207 mild and 305 severe unrelated patients from Thailand with Hb E\\/?0 thalassemia and normal ?-globin genes. METHODS: First, we estimated and compared the allele frequencies of approximately 110,000 gene-based single nucleotide

Richard Sherva; Orapan Sripichai; Kenneth Abel; Qianli Ma; Johanna Whitacre; Vach Angkachatchai; Wattanan Makarasara; Pranee Winichagoon; Saovaros Svasti; Suthat Fucharoen; Andreas Braun; Lindsay A Farrer

2010-01-01

183

Identifying genetic loci and spleen gene coexpression networks underlying immunophenotypes in BXD recombinant inbred mice  

PubMed Central

The immune system plays a pivotal role in the susceptibility to and progression of a variety of diseases. Due to a strong genetic basis, heritable differences in immune function may contribute to differential disease susceptibility between individuals. Genetic reference populations, such as the BXD (C57BL/6J × DBA/2J) panel of recombinant inbred (RI) mouse strains, provide unique models through which to integrate baseline phenotypes in healthy individuals with heritable risk for disease because of the ability to combine data collected from these populations across both multiple studies and time. We performed basic immunophenotyping (e.g., percentage of circulating B and T lymphocytes and CD4+ and CD8+ T cell subpopulations) in peripheral blood of healthy mice from 41 BXD RI strains to define the immunophenotypic variation in this strain panel and to characterize the genetic architecture that underlies these traits. Significant QTL models that explained the majority (50–77%) of phenotypic variance were derived for each trait and for the T:B cell and CD4+:CD8+ ratios. Combining QTL mapping with spleen gene expression data uncovered two quantitative trait transcripts, Ptprk and Acp1, as candidates for heritable differences in the relative abundance of helper and cytotoxic T cells. These data will be valuable in extracting genetic correlates of the immune system in the BXD panel. In addition, they will be a useful resource for prospective, phenotype-driven model selection to test hypotheses about differential disease or environmental susceptibility between individuals with baseline differences in the composition of the immune system. PMID:20179155

Lynch, Rachel M.; Naswa, Sudhir; Rogers, Gary L.; Kania, Stephen A.; Das, Suchita; Chesler, Elissa J.; Saxton, Arnold M.; Langston, Michael A.

2010-01-01

184

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

Microsoft Academic Search

A recently recognized human rhinovirus species C (HRV-C) is associated with up to half of HRV infections in young children. Here we propagated two HRV-C isolates ex vivo in organ culture of nasal epithelial cells, sequenced a new C15 isolate and developed the first, to our knowledge, reverse genetics system for HRV-C. Using contact points for the known HRV receptors,

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

2011-01-01

185

Solving genetic heterogeneity in extended families by identifying sub-types of complex diseases  

Microsoft Academic Search

The study of genetic properties of a disease requires the collection of information concerning the subjects in a set of pedigrees.\\u000a The main focus of this study was the detection of susceptible genes. However, even with large pedigrees, the heterogeneity\\u000a of phenotypes in complex diseases such as Schizophrenia, Bipolar and Autism, makes the detection of susceptible genes difficult\\u000a to accomplish.

Arafat Tayeb; Aurélie Labbe; Alexandre Bureau; Chantal Mérette

2011-01-01

186

Susceptibility and Prevention Recent Natural Selection Identifies a Genetic Variant in a Regulatory  

E-print Network

: Studies of human genetic variants in the p53 tumor suppressor gene and MDM2 oncogene have shown- ied are found in the p53 and MDM2 genes (p53 codon72; ref. 6, rs1042522, C/G; MDM2 SNP309; ref. 7, rs populations. For example, the G allele of MDM2 SNP309 was found to be at 10% in African Americans (8), 33

Vazquez, Alexei

187

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

Microsoft Academic Search

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

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

2012-01-01

188

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

189

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

190

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

PubMed Central

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

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

2013-01-01

191

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

192

Genetic Determinants of Intrinsic Colistin Tolerance in Acinetobacter baumannii  

PubMed Central

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

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

2013-01-01

193

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

194

Gold causes genetically determined autoimmune and immunostimulatory responses in mice  

PubMed Central

Natrium aurothiomaleate (GSTM) is a useful disease-modifying anti-rheumatic drug, but causes a variety of immune-mediated adverse effects in many patients. A murine model was used to study further the interaction of GSTM with the immune system, including induction of systemic autoimmunity. Mice were given weekly intramuscular injections of GSTM and controls equimolar amounts of sodium thiomaleate. The effects of gold on lymphocyte subpopulations were determined by flow cytometry. Humoral autoimmunity was measured by indirect immunofluorescence and immunoblotting, and deposition of immunoglobulin and C3 used to assess immunopathology. Gold, in the form of GSTM, stimulated the murine immune system causing strain-dependent lymphoproliferation and autoimmunity, including a major histocompatibility complex (MHC)-restricted autoantibody response against the nucleolar protein fibrillarin. GSTM did not cause glomerular or vessel wall IgG deposits. However, it did elicit a strong B cell-stimulating effect, including both T helper 1 (Th1)- and Th2-dependent isotypes. All these effects on the immune system were dependent on the MHC genotype, emphasizing the clinical observations of a strong genetic linkage for the major adverse immune reactions seen with GSTM treatment. PMID:17680821

Havarinasab, S; Johansson, U; Pollard, K M; Hultman, P

2007-01-01

195

Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping  

PubMed Central

A venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism is a major concern in the treatment of patients with multiple myeloma with thalidomide. The susceptibility to developing a VTE in response to thalidomide therapy is likely to be influenced by both genetic and environmental factors. To test genetic variation associated with treatment related VTE in patient peripheral blood DNA, we used a custom-built molecular inversion probe (MIP)–based single nucleotide polymorphism (SNP) chip containing 3404 SNPs. SNPs on the chip were selected in “functional regions” within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and side effects associated with myeloma therapy. Patients and controls were taken from 3 large clinical trials: Medical Research Council (MRC) Myeloma IX, Hovon-50, and Eastern Cooperative Oncology Group (ECOG) EA100, which compared conventional treatments with thalidomide in patients with myeloma. Our analysis showed that the set of SNPs associated with thalidomide-related VTE were enriched in genes and pathways important in drug transport/metabolism, DNA repair, and cytokine balance. The effects of the SNPs associated with thalidomide-related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111; Hovon-50: NCT00028886; and ECOG EA100: NCT00033332. PMID:18805967

Johnson, David C.; Corthals, Sophie; Ramos, Christine; Hoering, Antje; Cocks, Kim; Dickens, Nicholas J.; Haessler, Jeff; Goldschmidt, Harmut; Child, J. Anthony; Bell, Sue E.; Jackson, Graham; Baris, Dalsu; Rajkumar, S. Vincent; Davies, Faith E.; Durie, Brian G. M.; Crowley, John; Sonneveld, Pieter; Van Ness, Brian

2008-01-01

196

Genetic structuring of nine Indian domestic goat breeds based on SNPs identified in IGF-1 gene.  

PubMed

The caprine Insulin like Growth Factor1 (IGF1) gene was analyzed for identification of single nucleotide polymorphisms (SNPs) and genetic structuring of Indian goat breeds. A panel of 80 samples belonging to nine Indian goat breeds (Capra hircus) including three large sized breeds (Jamunapari, Beetal and Jakhrana); three medium sized breeds (Sirohi, Barbari, and Osmanabadi) and three small sized breeds (Black Bengal, Changthangi, and Gaddi) were screened for SNP identification and diversity analysis. The comparative gene sequence analysis of all the nine goat breeds studied revealed a total of 18 SNPs in IGF1 gene. All the nucleotide changes were found to be synonymous. The mean observed heterozygosity was found to be maximum (0.074) in Sirohi, Beetal, Osmanabadi, and Gaddi breeds of goat, whereas it is found to be minimum (0.019) in Black Bengal breed of goat. The rest of the breeds were intermediate in terms of heterozygosity. The same has been confirmed by allele frequency distribution across the studied loci. Barbari and Gaddi were found to be more differentiated (0.0123), Changthangi and Jamunapari were least differentiated (0.00110) based on Nei's genetic distance. PMID:23534960

Sharma, Anurodh; Dutt, Gautam; Jayakumar, S; Saroha, Vinita; Verma, N K; Dixit, S P

2013-01-01

197

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

198

Genetic Essentialism: On the Deceptive Determinism of DNA  

Microsoft Academic Search

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 regarding those conditions: they are more likely to be perceived as (a)

Ilan Dar-Nimrod; Steven J. Heine

2011-01-01

199

DRAFT DO NOT CITE OR DISTRIBUTE -INITIAL COMPILATION OF INFORMATION PRESENTED TO DATE TO IDENTIFY INFORMATION GAPS Acoustic Genetic Markers (PBT) Genetic Markers (GSI) Pit Tags Coded Wire tags  

E-print Network

INFORMATION GAPS Acoustic Genetic Markers (PBT) Genetic Markers (GSI) Pit Tags Coded Wire tags 3a What fishDRAFT DO NOT CITE OR DISTRIBUTE - INITIAL COMPILATION OF INFORMATION PRESENTED TO DATE TO IDENTIFY and age. Genetic markers can be applied to any species of fish to allow for individual or stock

200

A Genetic Screen to Discover Pathways Affecting Cohesin Function in Schizosaccharomyces pombe Identifies Chromatin Effectors  

PubMed Central

Cohesion, the force that holds sister chromatids together from the time of DNA replication until separation at the metaphase to anaphase transition, is mediated by the cohesin complex. This complex is also involved in DNA damage repair, chromosomes condensation, and gene regulation. To learn more about the cellular functions of cohesin, we conducted a genetic screen in Schizosaccharomyces pombe with two different cohesin mutants (eso1-G799D and mis4-242). We found synthetic negative interactions with deletions of genes involved in DNA replication and heterochromatin formation. We also found a few gene deletions that rescued the growth of eso1-G799D at the nonpermissive temperature, and these genes partially rescue the lagging chromosome phenotype. These genes are all chromatin effectors. Overall, our screen revealed an intimate association between cohesin and chromatin. PMID:23050226

Chen, Zhiming; McCroskey, Scott; Guo, Weichao; Li, Hua; Gerton, Jennifer L.

2012-01-01

201

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

202

Genetic and environmental determinants of the susceptibility of Amerindian derived populations for having hypertriglyceridemia.  

PubMed

Here, we discuss potential explanations for the higher prevalence of hypertriglyceridemia in populations with an Amerindian background. Although environmental factors are the triggers, the search for the ethnic related factors that explain the increased susceptibility of the Amerindians is a promising area for research. The study of the genetics of hypertriglyceridemia in Hispanic populations faces several challenges. Ethnicity could be a major confounding variable to prove genetic associations. Despite that, the study of hypertriglyceridemia in Hispanics has resulted in significant contributions. Two GWAS reports have exclusively included Mexican mestizos. Fifty percent of the associations reported in Caucasians could be generalized to the Mexicans, but in many cases the Mexican lead SNP was different than that reported in Europeans. Both reports included new associations with apo B or triglycerides concentrations. The frequency of susceptibility alleles in Mexicans is higher than that found in Europeans for several of the genes with the greatest effect on triglycerides levels. An example is the SNP rs964184 in APOA5. The same trend was observed for ANGPTL3 and TIMD4 variants. In summary, we postulate that the study of the genetic determinants of hypertriglyceridemia in Amerindian populations which have major changes in their lifestyle, may prove to be a great resource to identify new genes and pathways associated with hypertriglyceridemia. PMID:24768220

Aguilar-Salinas, Carlos A; Tusie-Luna, Teresa; Pajukanta, Päivi

2014-07-01

203

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

PubMed

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

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

2009-05-01

204

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

205

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...

206

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...

207

Genetic Determination of Colles' Fracture and Differential Bone Mass in Women With and Without Colles' Fracture  

Microsoft Academic Search

Osteoporotic fractures (OFs) are a major public health problem. Direct evidence of the importance and, particularly, the magnitude of genetic determination of OF per se is essentially nonexistent. Colles' fractures (CFs) are a common type of OF. In a metropolitan white female population in the midwestern United States, we found significant genetic determination of CF. The prevalence (K) of CF

HONG-WEN DENG; WEI-MIN CHEN; SUSAN RECKER; MARY RUTH STEGMAN; JIN-LONG LI; K. MICHAEL DAVIES; YAN ZHOU; HONGYI DENG; ROBERT HEANEY; ROBERT R. RECKER

2000-01-01

208

Using genetic programming to determine Che` zy resistance coefficient in corrugated channels  

E-print Network

INTRODUCTION Three artificially corrugated channels have been experi- mentally studied. Laboratory tests aimUsing genetic programming to determine Che` zy resistance coefficient in corrugated channels Orazio Genetic Programming has been used to determine Che` zy resistance coefficient for full circular corrugated

Fernandez, Thomas

209

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

PubMed

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

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

2014-01-01

210

Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies  

PubMed Central

Recently, genome-wide association studies (GWAS) have linked the human LIN28B locus to height and timing of menarche [1-5]. LIN28B and its homolog LIN28 (hereafter, LIN28A) are functionally redundant RNA-binding proteins that block let-7 microRNA (miRNA) biogenesis [6-9]. lin-28 and let-7 were discovered in C. elegans as heterochronic regulators of larval and vulval development, but recently have been implicated in cancer, stem cell aging, and pluripotency [10-13]. The let-7 targets Myc, Kras, Igf2bp1 and Hmga2 are known regulators of mammalian body size and metabolism [14-18]. To explore the Lin28/let-7 pathway in vivo, we engineered transgenic mice to express Lin28a and observed increased body size, crown-rump length, and a delayed onset of puberty. While investigating metabolic and endocrine mechanisms of overgrowth, we observed increased glucose metabolism and insulin sensitivity in these transgenic mice. We report a mouse that models the human phenotypes associated with genetic variation in the Lin28/let-7 pathway. PMID:20512147

Zhu, Hao; Shah, Samar; Shyh-Chang, Ng; Shinoda, Gen; Einhorn, William S.; Viswanathan, Srinivas R.; Takeuchi, Ayumu; Grasemann, Corinna; Rinn, John L.; Lopez, Mary F.; Hirschhorn, Joel N.; Palmert, Mark R.; Daley, George Q.

2010-01-01

211

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

212

Whole-Genome Sequencing Identifies Genetic Variances in Culture-Expanded Human Mesenchymal Stem Cells  

PubMed Central

Summary Culture-expanded human mesenchymal stem cells (MSCs) are increasingly used in clinics, yet full characterization of the genomic compositions of these cells is lacking. We present a whole-genome investigation on the genetic dynamics of cultured MSCs under ex vivo establishment (passage 1 [p1]) and serial expansion (p8 and p13). We detected no significant changes in copy-number alterations (CNAs) and low levels of single-nucleotide changes (SNCs) until p8. Strikingly, a significant number (677) of SNCs were found in p13 MSCs. Using a sensitive Droplet Digital PCR assay, we tested the nonsynonymous SNCs detected by whole-genome sequencing and found that they were preexisting low-frequency mutations in uncultured mononuclear cells (?0.01%) and early-passage MSCs (0.1%–1% at p1 and p8) but reached 17%–36% in p13. Our data demonstrate that human MSCs maintain a stable genomic composition in the early stages of ex vivo culture but are subject to clonal growth upon extended expansion. PMID:25254336

Cai, Jun; Miao, Xuexia; Li, Yueying; Smith, Cory; Tsang, Kitman; Cheng, Linzhao; Wang, Qian-fei

2014-01-01

213

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

PubMed

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

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

2014-07-01

214

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

215

Identifying Modifiers of Tamoxifen Sensitivity Using High-Throughput Genetic and Chemical Screens  

Microsoft Academic Search

Endocrine therapies, which inhibit estrogen receptor (ER?) signalling, are the most common and effective treatments for ER?\\u000a positive breast cancer. However, the utility of these agents is limited by the frequent development of resistance. The precise\\u000a mechanisms underlying endocrine therapy resistance remain incompletely understood. In our laboratory, an RNA interference\\u000a (RNAi) screen was used to identify modifiers of sensitivity to

Elizabeth Iorns; Christopher J. Lord; Alan Ashworth

216

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

217

DREAM4: Combining Genetic and Dynamic Information to Identify Biological Networks and Dynamical Models  

PubMed Central

Background Current technologies have lead to the availability of multiple genomic data types in sufficient quantity and quality to serve as a basis for automatic global network inference. Accordingly, there are currently a large variety of network inference methods that learn regulatory networks to varying degrees of detail. These methods have different strengths and weaknesses and thus can be complementary. However, combining different methods in a mutually reinforcing manner remains a challenge. Methodology We investigate how three scalable methods can be combined into a useful network inference pipeline. The first is a novel t-test–based method that relies on a comprehensive steady-state knock-out dataset to rank regulatory interactions. The remaining two are previously published mutual information and ordinary differential equation based methods (tlCLR and Inferelator 1.0, respectively) that use both time-series and steady-state data to rank regulatory interactions; the latter has the added advantage of also inferring dynamic models of gene regulation which can be used to predict the system's response to new perturbations. Conclusion/Significance Our t-test based method proved powerful at ranking regulatory interactions, tying for first out of methods in the DREAM4 100-gene in-silico network inference challenge. We demonstrate complementarity between this method and the two methods that take advantage of time-series data by combining the three into a pipeline whose ability to rank regulatory interactions is markedly improved compared to either method alone. Moreover, the pipeline is able to accurately predict the response of the system to new conditions (in this case new double knock-out genetic perturbations). Our evaluation of the performance of multiple methods for network inference suggests avenues for future methods development and provides simple considerations for genomic experimental design. Our code is publicly available at http://err.bio.nyu.edu/inferelator/. PMID:21049040

Ostrer, Harry; Bonneau, Richard

2010-01-01

218

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

219

PPARA: a novel genetic determinant of CYP3A4 in vitro and in vivo.  

PubMed

Interindividual variability in cytochrome P450 3A4 (CYP3A4) is believed to be largely heritable; however, predictive genetic factors have remained scarce. Using a candidate-gene approach in a human liver bank, we identified single-nucleotide polymorphisms (SNPs) in the Ah-receptor nuclear translocator (ARNT), glucocorticoid receptor (GR), progesterone receptor membrane component 2 (PGRMC2), and peroxisome proliferator-activated receptor-? (PPARA) that are associated with CYP3A4 phenotype. Validation in atorvastatin-treated volunteers confirmed a decrease in atorvastatin-2-hydroxylation in carriers of PPARA SNP rs4253728. Homozygous carriers expressed significantly less PPAR-? protein in the liver. Moreover, shRNA-mediated PPARA gene knockdown in primary human hepatocytes decreased expression levels of the PPAR-? target ACOX1 and of CYP3A4 by more than 50%. In conclusion, this study identified novel genetic determinants of CYP3A4 that, together with nongenetic factors, explained 52, 55, and 33% of hepatic CYP3A4 mRNA, protein, and atorvastatin-2-hydroxylase activity, respectively. These findings have implications for variability in response to drug substrates of CYP3A4. PMID:22510778

Klein, Kathrin; Thomas, Maria; Winter, Stefan; Nussler, Andreas K; Niemi, Mikko; Schwab, Matthias; Zanger, Ulrich M

2012-06-01

220

An investigation of folate-related genetic factors in the determination of birthweight.  

PubMed

Recent evidence suggests that maternal folate status in early gestation is a significant determinant of infant birthweight. Folate metabolism is known to be controlled by genetic factors, with a number of polymorphic variations in folate metabolising genes identified, several of which have well-documented functional effects. The current study investigated whether folate-related polymorphic variation, in association with low maternal folate status, influences birthweight. Red blood cell (RBC) folate analysis and genotyping of five polymorphisms in folate-related genes [Methylenetetrahydrofolate reductase (MTHFR) 677C>T; MTHFR 1298A>C; cystathionine-beta-synthase (CbetaS) 844ins68bp; serine hydroxymethyltransferase (SHMT) 1420C>T; reduced folate carrier-1 (RFC-1) 80G>A] were undertaken in mothers and infants from 998 pregnancies. These data were analysed in relation to infant birthweight, adjusted for gender and gestational age (z-score). Low maternal RBC folate status was associated with reduced infant birthweight. None of the genetic variants studied showed an independent association with infant birthweight. However, two genetic variants were shown to have a significant effect on birthweight when found in association with low maternal RBC folate status. When individuals with variant genotypes and mothers with folate in the lowest quintile were compared with wild-type individuals and mothers with folate in the highest quintile, the following differences in mean birthweight (z-score) were observed; maternal MTHFR 677C>T (-0.56 [95% CI -1.00, -0.12]P=0.01) and infant CbetaS 844ins68bp (-0.71 [95% CI -1.97, -0.07]P=0.03). The findings of this study suggest that folate-related genetic polymorphisms do not directly influence infant birthweight. However, when placed on a background of deficient maternal nutritional status, they may detrimentally affect fetal growth. PMID:16115288

Relton, Caroline L; Pearce, Mark S; Burn, John; Parker, Louise

2005-09-01

221

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

222

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

NASA Astrophysics Data System (ADS)

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 determinant of female academic self-confidence, whereas the perceived quality of teaching is the strongest predictor among male students. Results from multivariate regression analyses of the Undergraduate Retention Study, a longitudinal study of nine cohorts of female undergraduates interested in SMET study at UW, support the finding that female students’ selfconfidence levels tend more than those of male students to be influenced by external factors. Analyses also reveal the determinants of math self-confidence to be different from factors that determine science self-confidence. These factors are found to vary by class level as well.

Huang, Penelope M.; Brainard, Suzanne G.

223

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

PubMed Central

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

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

2008-01-01

224

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

225

Utilization of an EMR-biorepository to identify the genetic predictors of calcineurin-inhibitor toxicity in heart transplant recipients.  

PubMed

Calcineurin-inhibitors CI are immunosuppressive agents prescribed to patients after solid organ transplant to prevent rejection. Although these drugs have been transformative for allograft survival, long-term use is complicated by side effects including nephrotoxicity. Given the narrow therapeutic index of CI, therapeutic drug monitoring is used to prevent acute rejection from underdosing and acute toxicity from overdosing, but drug monitoring does not alleviate long-term side effects. Patients on calcineurin-inhibitors for long periods almost universally experience declines in renal function, and a subpopulation of transplant recipients ultimately develop chronic kidney disease that may progress to end stage renal disease attributable to calcineurin inhibitor toxicity (CNIT). Pharmacogenomics has the potential to identify patients who are at high risk for developing advanced chronic kidney disease caused by CNIT and providing them with existing alternate immunosuppressive therapy. In this study we utilized BioVU, Vanderbilt University Medical Center's DNA biorepository linked to de-identified electronic medical records to identify a cohort of 115 heart transplant recipients prescribed calcineurin-inhibitors to identify genetic risk factors for CNIT We identified 37 cases of nephrotoxicity in our cohort, defining nephrotoxicity as a monthly median estimated glomerular filtration rate (eGFR)<30 mL/min/1.73 m2 at least six months post-transplant for at least three consecutive months. All heart transplant patients were genotyped on the Illumina ADME Core Panel, a pharmacogenomic genotyping platform that assays 184 variants across 34 genes. In Cox regression analysis adjusting for age at transplant, pre-transplant chronic kidney disease, pre-transplant diabetes, and the three most significant principal components (PCAs), we did not identify any markers that met our multiple-testing threshold. As a secondary analysis we also modeled post-transplant eGFR directly with linear mixed models adjusted for age at transplant, cyclosporine use, median BMI, and the three most significant principal components. While no SNPs met our threshold for significance, a SNP previously identified in genetic studies of the dosing of tacrolimus CYP34A rs776746, replicated in an adjusted analysis at an uncorrected p-value of 0.02 (coeff(S.E.)=14.60(6.41)). While larger independent studies will be required to further validate this finding, this study underscores the EMRs usefulness as a resource for longitudinal pharmacogenetic study designs. PMID:24297552

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

2014-01-01

226

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

227

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

228

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

PubMed

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

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

2013-02-01

229

A Genetic Screen in Myxococcus xanthus Identifies Mutants That Uncouple Outer Membrane Exchange from a Downstream Cellular Response.  

PubMed

Upon physical contact with sibling cells, myxobacteria transiently fuse their outer membranes (OMs) and exchange OM proteins and lipids. From previous work, TraA and TraB were identified to be essential factors for OM exchange (OME) in donor and recipient cells. To define the genetic complexity of OME, we carried out a comprehensive forward genetic screen. The screen was based on the observation that Myxococcus xanthus nonmotile cells, by a Tra-dependent mechanism, block swarm expansion of motile cells when mixed. Thus, mutants defective in OME or a downstream responsive pathway were readily identified as escape flares from mixed inocula seeded on agar. This screen was surprisingly powerful, as we found >50 mutants defective in OME. Importantly, all of the mutations mapped to the traAB operon, suggesting that there may be few, if any, proteins besides TraA and TraB directly required for OME. We also found a second and phenotypically different class of mutants that exhibited wild-type OME but were defective in a responsive pathway. This pathway is postulated to control inner membrane homeostasis by covalently attaching amino acids to phospholipids. The identified proteins are homologous to the Staphylococcus aureus MprF protein, which is involved in membrane adaptation and antibiotic resistance. Interestingly, we also found that a small number of nonmotile cells were sufficient to block the swarming behavior of a large gliding-proficient population. This result suggests that an OME-derived signal could be amplified from a few nonmotile producers to act on many responder cells. PMID:25266387

Dey, Arup; Wall, Daniel

2014-12-15

230

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, Natalia 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

231

Sexual differentiation in the spiny softshell turtle (Apalone spinifera), a species with genetic sex determination  

Microsoft Academic Search

It is hypothesized on the basis of sex determination theory that species exhibiting genetic sex determination (GSD) may undergo sexual differentiation earlier in development than species with environmental sex determination (ESD). Most turtle species exhibit a form of ESD known as temperature-dependent sex determination (TSD), and in such species the chronology of sex differentiation is well studied. Apalone spinifera is

Eli Greenbaum; John L. Carr

2001-01-01

232

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

233

A clinical genetic method to identify mechanisms by which pain causes depression and anxiety  

PubMed Central

Background Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year. Results We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood – the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery. Conclusion Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts. PMID:16623937

Max, Mitchell B; Wu, Tianxia; Atlas, Steven J; Edwards, Robert R; Haythornthwaite, Jennifer A; Bollettino, Antonella F; Hipp, Heather S; McKnight, Colin D; Osman, Inge A; Crawford, Erin N; Pao, Maryland; Nejim, Jemiel; Kingman, Albert; Aisen, Daniel C; Scully, Michele A; Keller, Robert B; Goldman, David; Belfer, Inna

2006-01-01

234

Genetic Screening in C. Elegans Identifies Rho-GTPAse Activating Protein 6 as Novel HERG Regulator  

PubMed Central

The human ether-a-go-go related gene (HERG) constitutes the pore forming subunit of IKr, a K+ current involved in repolarization of the cardiac action potential. While mutations in HERG predispose patients to cardiac arrhythmias (Long QT syndrome; LQTS), altered function of HERG regulators are undoubtedly LQTS risk factors. We have combined RNA interference with behavioral screening in Caenorhabditis elegans to detect genes that influence function of the HERG homolog, UNC-103. One such gene encodes the worm ortholog of the rho-GTPase activating protein 6 (ARHGAP6). In addition to its GAP function, ARHGAP6 induces cytoskeletal rearrangements and activates phospholipase C (PLC). Here we show that IKr recorded in cells co-expressing HERG and ARHGAP6 was decreased by 43% compared to HERG alone. Biochemical measurements of cell-surface associated HERG revealed that ARHGAP6 reduced membrane expression of HERG by 35%, which correlates well with the reduction in current. In an atrial myocyte cell line, suppression of endogenous ARHGAP6 by virally transduced shRNA led to a 53 % enhancement of IKr. ARHGAP6 effects were maintained when we introduced a dominant negative rho-GTPase, or ARHGAP6 devoid of rhoGAP function, indicating ARHGAP6 regulation of HERG is independent of rho activation. However, ARHGAP6 lost effectiveness when PLC was inhibited. We further determined that ARHGAP6 effects are mediated by a consensus SH3 binding domain within the C-terminus of HERG, although stable ARHGAP6-HERG complexes were not observed. These data link a rhoGAP-activated PLC pathway to HERG membrane expression and implicate this family of proteins as candidate genes in disorders involving HERG. PMID:19038263

Potet, Franck; Petersen, Christina I.; Boutaud, Olivier; Shuai, Wen; Stepanovic, Svetlana Z.; Balser, Jeffrey R.; Kupershmidt, Sabina

2009-01-01

235

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

PubMed

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

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

2013-08-30

236

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

E-print Network

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

Antonovics, Janis

237

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

PubMed

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

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

2014-10-01

238

Genetic algorithms for determining the topological structure of metallic clusters  

Microsoft Academic Search

Genetic algorithms (GA) are applied for the optimization of the structure of metallic clusters by the calculation of the ground-state energies from a tight-binding (Hückel) Hamiltonian. The optimum topology or graph is searched by the use of the adjacency matrix A ij as a natural coding. The initial populations for N-atom clusters are generated from a representative group of fit

R. Poteau; G. M. Pastor

1999-01-01

239

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

PubMed

Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted a genome-wide association study of CRC in East Asians with 14,963 cases and 31,945 controls and identified 6 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 transcriptional 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-associated loci. Our study provides insights into the genetic basis of CRC and suggests the involvement of 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

2014-06-01

240

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

241

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

242

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; Malarstig, Anders; Folkersen, Lasse; Soler Artigas, Maria; Baldassarre, Damiano; Kavousi, Maryam; Almgren, Peter; Veglia, Fabrizio; Brusselle, Guy; Hofman, Albert; Engstrom, 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

243

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

PubMed

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

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

2014-12-01

244

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

245

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

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

2014-01-01

246

Ethnic and genetic determinants of cardiovascular response to the selective alpha 2-adrenoceptor agonist dexmedetomidine.  

PubMed

The alpha(2)-adrenoceptor agonist clonidine reduces blood pressure more effectively in White than Black Americans despite similar degrees of sympatholysis. Functional genetic variation in receptor signaling mechanisms, for example in the beta 3 G-protein subunit (GNB3 C825T) and in the alpha(2C)-adrenoceptor subtype (ADRA2C del322-325), may affect drug responses. We examined the hypothesis that there are ethnic differences in the responses to the highly selective alpha(2)-agonist, dexmedetomidine, and that these genetic variants contribute to interindividual variability in drug responses. In a placebo-controlled, single-masked study, 73 healthy subjects (37 whites and 36 blacks) received 3 placebo infusions and then 3 incremental doses of dexmedetomidine (cumulative dose, 0.4 microg/kg), each separated by 30 minutes. Blood pressure, heart rate, and plasma catecholamine concentrations were determined after each infusion. We measured dexmedetomidine concentrations after the last infusion and determined ADRA2C del322-325 and GNB3 C825T genotypes. Dexmedetomidine lowered blood pressure and plasma catecholamine concentrations significantly (all P<0.001). There was substantial interindividual variability in the reduction of systolic blood pressure (range, 1 to 34 mm Hg) and plasma norepinephrine concentrations (range, 24 to 424 pg/mL). However, there were no differences between black and white subjects in dexmedetomidine responses (P>0.16 for all outcomes) before or after adjustment for covariates. Neither ADRA2C del322-325 nor GNB3 C825T genotypes affected the responses to dexmedetomidine (all P>0.66). There is large interindividual variability in response to the selective alpha(2)-AR agonist dexmedetomidine, and neither ethnicity nor ADRA2C and GNB3 genotypes contribute to it. Further studies to identify determinants of alpha(2)-AR-mediated responses will be of interest. PMID:18071056

Kurnik, Daniel; Muszkat, Mordechai; Sofowora, Gbenga G; Friedman, Eitan A; Dupont, William D; Scheinin, Mika; Wood, Alastair J J; Stein, C Michael

2008-02-01

247

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

ERIC Educational Resources Information Center

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

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

2009-01-01

248

Shadow autozygosity mapping by linkage exclusion (SAMPLE): a simple strategy to identify the genetic basis of lethal autosomal recessive disorders.  

PubMed

Autozygosity mapping has been invaluable for determining the genetic basis of lethal autosomal recessive disorders, but this approach remains challenging because DNA from affected individuals may often be unavailable or of insufficient quality for extensive molecular genetic studies. To circumvent these difficulties, we developed a computer program called "SAMPLE" (for shadow autozygosity mapping by linkage exclusion) to enhance autozygosity mapping through the empirical analysis of haplotypes of unaffected individuals in consanguineous families. Single nucleotide polymorphism (SNP) genotyping of unaffected individuals in complex consanguineous pedigrees is used to infer limited chromosomal regions compatible with linkage to a potential disease locus, and to allow the immediate prioritization of potential regions of interest. Further limited genotyping then enables the rapid confirmation and fine mapping of a disease locus. We demonstrate the utility of this strategy by using genotyping data from only parents and unaffected siblings, in three consanguineous families affected with Meckel-Gruber syndrome, to correctly infer the location of the MKS3/TMEM67 locus on chromosome 8q22.1. This strategy is practicable only with the recent advances in whole genome genotyping by high-density SNP microarrays, and could not be easily implemented in approaches that rely on microsatellite markers. SAMPLE is available at http://dna.leeds.ac.uk/sample/. PMID:19842213

Carr, Ian M; Szymanska, Katarzyna; Sheridan, Eamonn; Markham, Alexander F; Bonthron, David T; Johnson, Colin A

2009-12-01

249

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

250

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

251

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; Kroger, Nils

2014-01-01

252

Genetic regulators of a pluripotent adult stem cell system in planarians identified by RNAi and clonal analysis  

PubMed Central

Summary Pluripotency is a central, well-studied feature of embryonic development, but the role of pluripotent cell regulation in somatic tissue regeneration remains poorly understood. In planarians, regeneration of entire animals from tissue fragments is promoted by the activity of adult pluripotent stem cells (cNeoblasts). We utilized transcriptional profiling to identify planarian genes expressed in adult proliferating, regenerative cells (neoblasts). We also developed quantitative clonal analysis methods for expansion and differentiation of cNeoblast descendants that, together with RNAi, revealed gene roles in stem cell biology. Genes encoding two zinc finger proteins, Vasa, a LIM domain protein, Sox and Jun-like transcription factors, two candidate RNA-binding proteins, a Setd8-like protein, and PRC2 (Polycomb) were required for proliferative expansion and/or differentiation of cNeoblast-derived clones. These findings suggest that planarian stem cells utilize molecular mechanisms found in germ cells and other pluripotent cell types, and identify novel genetic regulators of the planarian stem cell system. PMID:22385657

Wagner, Daniel E.; Ho, Jaclyn J.

2012-01-01

253

Genetic determinants of hair and eye colours in the Scottish and Danish populations  

PubMed Central

Background Eye and hair colour is highly variable in the European population, and is largely genetically determined. Both linkage and association studies have previously been used to identify candidate genes underlying this variation. Many of the genes found were previously known as underlying mutant mouse phenotypes or human genetic disease, but others, previously unsuspected as pigmentation genes, have also been discovered. Results We assayed the hair of a population of individuals of Scottish origin using tristimulus colorimetry, in order to produce a quantitative measure of hair colour. Cluster analysis of this data defined two groups, with overlapping borders, which corresponded to visually assessed dark versus red/light hair colour. The Danish population was assigned into categorical hair colour groups. Both cohorts were also assessed for eye colour. DNA from the Scottish group was genotyped at SNPs in 33 candidate genes, using 384 SNPs identified by HapMap as representatives of each gene. Associations found between SNPs and colorimetric hair data and eye colour categories were replicated in a cohort of the Danish population. The Danish population was also genotyped with SNPs in 4 previously described pigmentation genes. We found replicable associations of hair colour with the KITLG and OCA2 genes. MC1R variation correlated, as expected, with the red dimension of colorimetric hair colour in Scots. The Danish analysis excluded those with red hair, and no associations were found with MC1R in this group, emphasising that MC1R regulates the colour rather than the intensity of pigmentation. A previously unreported association with the HPS3 gene was seen in the Scottish population. However, although this replicated in the smaller cohort of the Danish population, no association was seen when the whole study population was analysed. Conclusions We have found novel associations with SNPs in known pigmentation genes and colorimetrically assessed hair colour in a Scottish and a Danish population. PMID:20042077

2009-01-01

254

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

255

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

PubMed

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

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

2014-11-15

256

Development of a decision-support tool for identifying the most suitable approach to achieve nitrate source determination.  

PubMed

Numerous approaches have been suggested for differentiating point and diffuse sources of nitrate contamination, including nitrate stable isotopes, microbiological analyses, genetic markers and chemical markers. Each approach has its own strengths and limitations. As a result, the most appropriate approach to use largely depends upon the scenario and the context of the study. However, available data on nitrate source determination is highly fragmented and approach dependent, with very little if any interface between the different techniques. This makes it difficult for stakeholders to identify the most suitable approach to adopt in a specific scenario. Therefore, this paper examines the development and application of a decision-support tool to support environmental forensics studies for nitrate contamination. In particular, this tool can support policy makers, regulators and operators within the field in understanding the environmental hazards and processes resulting from nitrate contamination, and to implement appropriate actions for limiting the impacts that may arise from such contamination. The tool was developed using the IDEF0 modeling system, and evaluated by interviewing key stakeholders who suggested a number of important implications for practice. PMID:25232953

Fenech, C; Nolan, K; Rock, L; Morrissey, A

2014-10-20

257

Genetic determinants of Tibetan high-altitude adaptation.  

PubMed

Some highland populations have genetic adaptations that enable their successful existence in a hypoxic environment. Tibetans are protected against many of the harmful responses exhibited by non-adapted populations upon exposure to severe hypoxia, including elevated hemoglobin concentration (i.e., polycythemia). Recent studies have highlighted several genes subject to natural selection in native high-altitude Tibetans. Three of these genes, EPAS1, EGLN1 and PPARA, regulate or are regulated by hypoxia inducible factor, a principal controller of erythropoiesis and other organismal functions. Uncovering the molecular basis of hypoxic adaptation should have implications for understanding hematological and other adaptations involved in hypoxia tolerance. Because the hypoxia response involves a variety of cardiovascular, pulmonary and metabolic functions, this knowledge would improve our understanding of disease mechanisms and could ultimately be translated into targeted therapies for oxygen deprivation, cardiopulmonary and cerebral pathologies, and metabolic disorders such as diabetes and obesity. PMID:22068265

Simonson, Tatum S; McClain, Donald A; Jorde, Lynn B; Prchal, Josef T

2012-04-01

258

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

259

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

PubMed

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

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

2014-07-01

260

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

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

2013-01-01

261

Application of genomic and quantitative genetic tools to identify candidate resistance genes for brown rot resistance in peach.  

PubMed

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

262

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, Jorg; Psaty, Bruce M.; Lorentzon, Mattias; Foroud, Tatiana; Harris, Tamara B.; Hofman, Albert; Jansson, John-Olov; Cauley, Jane A.; Uitterlinden, Andre G.; Gibson, Quince; Jarvelin, 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

263

In Vivo RNAi Screening Identifies Regulators of Actin Dynamics as Key Determinants of Lymphoma Progression  

E-print Network

Mouse models have markedly improved our understanding of cancer development and tumor biology. However, these models have shown limited efficacy as tractable systems for unbiased genetic experimentation. Here, we report ...

Ho, Emily E.

264

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

PubMed

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

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

2013-11-01

265

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

PubMed Central

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

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

2014-01-01

266

Identity-by-descent approaches identify regions of importance for genetic susceptibility to hereditary esophageal squamous cell carcinoma.  

PubMed

Worldwide, the highest prevalence of esophageal cancer (EC) occurs in Northern China. High-density SNP arrays allow identification of identity-by-descent (IBD) segments in genomic DNAs representative of shared common ancestral regions. We utilized IBD approaches to map susceptibility loci associated with low-penetrance SNPs in high-risk Henan hereditary esophageal squamous cell carcinoma (ESCC) patients. Affymetrix GeneChip Human mapping SNP array IBD analysis was performed in 32 Henan family history-positive (FH+) ESCC patients, 18 Henan healthy unrelated individuals, and 45 Chinese individuals from a CHB HapMap dataset using PLink (scoring IBD segments individually) and Beagle (scoring of shared IBD segments among case/case vs. control/control pairs) software. Both analyses identified longer IBD segment lengths associated with FH+ ESCC compared to controls. However, there was no strong evidence for a genetic founder effect. Pairing IBD analysis with BEAGLE identified 8 critical IBD segments residing at 2q32.1-q32.2, 3p22.3-p22.2, 4q21.1-q21.21, 7p22.2, 8q23.2-q23.3, 10q23.33-q24.1, 14q24.3 and 16q11.2-q12.1, which were more significantly shared among case/case compared to control/control. The shared IBD segments in FH+ ESCC samples with no overlap with control/CHB Hapmap may encompass potential cancer susceptibility loci. Selected targeted genes, PLCE1, GPT2, SIAH1 and CYP2C-18, residing within the IBD segments at 10q23.33-q24.1 and 16q11.2-q12.1, had statistically significant differential expression in primary ESCC tissues and are likely involved in ESCC carcinogenesis. The importance of these IBD segments to the etiology and development of ESCC in high-risk areas requires further study with expanded sample sizes. This is the first report employing the pairing IBD approach for elucidation of the genetic basis of hereditary ESCC in Henan by applying high throughput SNP array analysis. PMID:24890309

Ko, Josephine My; Zhang, Peng; Law, Simon; Fan, Yanhui; Song, You-Qiang; Zhao, Xue Ke; Wong, Elibe H W; Tang, Sa; Song, Xin; Lung, Maria Li; Wang, Li Dong

2014-08-01

267

Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate  

PubMed Central

Background Understanding the molecular control of cell lineages and fate determination in complex tissues is key to not only understanding the developmental biology and cellular homeostasis of such tissues but also for our understanding and interpretation of the molecular pathology of diseases such as cancer. The prerequisite for such an understanding is detailed knowledge of the cell types that make up such tissues, including their comprehensive molecular characterisation. In the mammary epithelium, the bulk of the tissue is composed of three cell lineages, namely the basal/myoepithelial, luminal epithelial estrogen receptor positive and luminal epithelial estrogen receptor negative cells. However, a detailed molecular characterisation of the transcriptomic differences between these three populations has not been carried out. Results A whole transcriptome analysis of basal/myoepithelial cells, luminal estrogen receptor negative cells and luminal estrogen receptor positive cells isolated from the virgin mouse mammary epithelium identified 861, 326 and 488 genes as highly differentially expressed in the three cell types, respectively. Network analysis of the transcriptomic data identified a subpopulation of luminal estrogen receptor negative cells with a novel potential role as non-professional immune cells. Analysis of the data for potential paracrine interacting factors showed that the basal/myoepithelial cells, remarkably, expressed over twice as many ligands and cell surface receptors as the other two populations combined. A number of transcriptional regulators were also identified that were differentially expressed between the cell lineages. One of these, Sox6, was specifically expressed in luminal estrogen receptor negative cells and functional assays confirmed that it maintained mammary epithelial cells in a differentiated luminal cell lineage. Conclusion The mouse mammary epithelium is composed of three main cell types with distinct gene expression patterns. These suggest the existence of a novel functional cell type within the gland, that the basal/myoepithelial cells are key regulators of paracrine signalling and that there is a complex network of differentially expressed transcription factors controlling mammary epithelial cell fate. These data will form the basis for understanding not only cell fate determination and cellular homeostasis in the normal mammary epithelium but also the contribution of different mammary epithelial cell types to the etiology and molecular pathology of breast disease. PMID:19063729

Kendrick, Howard; Regan, Joseph L; Magnay, Fiona-Ann; Grigoriadis, Anita; Mitsopoulos, Costas; Zvelebil, Marketa; Smalley, Matthew J

2008-01-01

268

Genetically determined dopamine availability predicts disposition for depression  

PubMed Central

Although prominent personality theories postulate orthogonality between traits of positive emotionality (PEM) and negative emotionality (NEM), empirical evidence often demonstrates the opposite indicating a negative relationship. Therefore, it is not surprising that dopaminergic (DA) gene loci have been related to traits of positive and of NEM. The present genetic association study investigates the influence of two functional DA gene polymorphisms on Sadness as defined by the Affective Neuroscience Personality Scales (ANPS) in healthy Caucasians (n = 1041). We observed a significant interaction effect between the 10-repeat (10R) allele of the dopamine transporter (DAT1) gene and the methionine (Met) allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism (F(1,1018) = 11.11; P < 0.001). Carriers of the 9R/9R and the Val/Val genotype showed dramatically reduced Sadness scores in comparison to the other three genotype configurations. Both the 9R/9R and the Val/Val genotypes characterized by reduced transporter density and high dopamine catabolism, respectively, have been separately related to personality traits of PEM and externalizing behavior in the past. The present findings indicate that gene variations of the DA system previously associated with PEM are at the same time protective against high NEM and can therefore constitute a resilience factor against depression. PMID:22399090

Felten, Andrea; Montag, Christian; Markett, Sebastian; Walter, Nora T; Reuter, Martin

2011-01-01

269

Genetically determined dopamine availability predicts disposition for depression.  

PubMed

Although prominent personality theories postulate orthogonality between traits of positive emotionality (PEM) and negative emotionality (NEM), empirical evidence often demonstrates the opposite indicating a negative relationship. Therefore, it is not surprising that dopaminergic (DA) gene loci have been related to traits of positive and of NEM. The present genetic association study investigates the influence of two functional DA gene polymorphisms on Sadness as defined by the Affective Neuroscience Personality Scales (ANPS) in healthy Caucasians (n = 1041). We observed a significant interaction effect between the 10-repeat (10R) allele of the dopamine transporter (DAT1) gene and the methionine (Met) allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism (F((1,1018)) = 11.11; P < 0.001). Carriers of the 9R/9R and the Val/Val genotype showed dramatically reduced Sadness scores in comparison to the other three genotype configurations. Both the 9R/9R and the Val/Val genotypes characterized by reduced transporter density and high dopamine catabolism, respectively, have been separately related to personality traits of PEM and externalizing behavior in the past. The present findings indicate that gene variations of the DA system previously associated with PEM are at the same time protective against high NEM and can therefore constitute a resilience factor against depression. PMID:22399090

Felten, Andrea; Montag, Christian; Markett, Sebastian; Walter, Nora T; Reuter, Martin

2011-11-01

270

Overview of the genetic determinants of primary aldosteronism.  

PubMed

Primary aldosteronism is the most common cause of secondary hypertension. The syndrome accounts for 10% of all cases of hypertension and is primarily caused by bilateral adrenal hyperplasia or aldosterone-producing adenoma. Over the last few years, the use of exome sequencing has significantly improved our understanding of this syndrome. Somatic mutations in the KCNJ5, ATP1A1, ATP2B3 or CACNA1D genes are present in more than half of all cases of aldosterone-producing adenoma (~40%, ~6%, ~1% and ~8%, respectively). Germline gain-of-function mutations in KCNJ5 are now known to cause familial hyperaldosteronism type III, and an additional form of genetic hyperaldosteronism has been reported in patients with germline mutations in CACNA1D. These genes code for channels that control ion homeostasis across the plasma membrane of zona glomerulosa cells. Moreover, all these mutations modulate the same pathway, in which elevated intracellular calcium levels lead to aldosterone hyperproduction and (in some cases) adrenal cell proliferation. From a clinical standpoint, the discovery of these mutations has potential implications for patient management. The mutated channels could be targeted by drugs, in order to control hormonal and overgrowth-related manifestations. Furthermore, some of these mutations are associated with high cell turnover and may be amenable to diagnosis via the sequencing of cell-free (circulating) DNA. However, genotype-phenotype correlations in patients harboring these mutations have yet to be characterized. Despite this recent progress, much remains to be done to elucidate the yet unknown mechanisms underlying sporadic bilateral adrenal hyperplasia. PMID:24817817

Al-Salameh, Abdallah; Cohen, Régis; Desailloud, Rachel

2014-01-01

271

Overview of the genetic determinants of primary aldosteronism  

PubMed Central

Primary aldosteronism is the most common cause of secondary hypertension. The syndrome accounts for 10% of all cases of hypertension and is primarily caused by bilateral adrenal hyperplasia or aldosterone-producing adenoma. Over the last few years, the use of exome sequencing has significantly improved our understanding of this syndrome. Somatic mutations in the KCNJ5, ATP1A1, ATP2B3 or CACNA1D genes are present in more than half of all cases of aldosterone-producing adenoma (~40%, ~6%, ~1% and ~8%, respectively). Germline gain-of-function mutations in KCNJ5 are now known to cause familial hyperaldosteronism type III, and an additional form of genetic hyperaldosteronism has been reported in patients with germline mutations in CACNA1D. These genes code for channels that control ion homeostasis across the plasma membrane of zona glomerulosa cells. Moreover, all these mutations modulate the same pathway, in which elevated intracellular calcium levels lead to aldosterone hyperproduction and (in some cases) adrenal cell proliferation. From a clinical standpoint, the discovery of these mutations has potential implications for patient management. The mutated channels could be targeted by drugs, in order to control hormonal and overgrowth-related manifestations. Furthermore, some of these mutations are associated with high cell turnover and may be amenable to diagnosis via the sequencing of cell-free (circulating) DNA. However, genotype-phenotype correlations in patients harboring these mutations have yet to be characterized. Despite this recent progress, much remains to be done to elucidate the yet unknown mechanisms underlying sporadic bilateral adrenal hyperplasia. PMID:24817817

Al-Salameh, Abdallah; Cohen, Regis; Desailloud, Rachel

2014-01-01

272

Genetic Modifiers of Neurofibromatosis Type 1-Associated Caf?-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

273

Determining Relative Importance and Best Settings for Genetic Algorithm Control  

E-print Network

applied to steer a population of cloud-computing simulators into behavioral directions that reveal is infeasible because the cloud-computing simulators we are exploring require significant computation. Instead computation algorithm and (2) we determine the relative importance and best settings for the control

274

The ends of a continuum: genetic and temperature-dependent sex determination in reptiles  

Microsoft Academic Search

Summary Two prevailing paradigms explain the diversity of sex- determining modes in reptiles. Many researchers, parti- cularly those who study reptiles, consider genetic and environmental sex-determining mechanisms to be fun- damentally different, and that one can be demonstrat- ed experimentally to the exclusion of the other. Other researchers, principally those who take a broader taxo- nomic perspective, argue that no

Stephen D. Sarre; Arthur Georges; Alex Quinn

2004-01-01

275

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

276

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

PubMed Central

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

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

2012-01-01

277

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

PubMed Central

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

Muniz, Luis M.; Gomez, Elisa; Guyon, Virginie; Lopez, Maribel; Khbaya, Bouchaib; Sellam, Olivier; Perez, Pascual; Hueros, Gregorio

2014-01-01

278

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

PubMed

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

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

2013-12-01

279

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

PubMed

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism. PMID:23202124

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

2013-01-01

280

Global Genetic Determinants of Mitochondrial DNA Copy Number  

PubMed Central

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

Zhang, Hengshan; Singh, Keshav K.

2014-01-01

281

Virulence determinants in the obligate intracellular pathogen Chlamydia trachomatis revealed by forward genetic approaches.  

PubMed

Chlamydia trachomatis, a pathogen responsible for diseases of significant clinical and public health importance, remains poorly characterized because of its intractability to routine molecular genetic manipulation. We have developed a combinatorial approach to rapidly generate a comprehensive library of genetically defined mutants. Chemical mutagenesis, coupled with whole-genome sequencing (WGS) and a system for DNA exchange within infected cells, was used to generate Chlamydia mutants with distinct phenotypes, map the underlying genetic lesions, and generate isogenic strains. As a result, we identified mutants with altered glycogen metabolism, including an attenuated strain defective for type II secretion. The coupling of chemically induced gene variation and WGS to establish genotype-phenotype associations should be broadly applicable to the large list of medically and environmentally important microorganisms currently intractable to genetic analysis. PMID:22232666

Nguyen, Bidong D; Valdivia, Raphael H

2012-01-24

282

Genetic Determinants of Time Perception Mediated by the Serotonergic System  

Microsoft Academic Search

BackgroundThe present study investigates neurobiological underpinnings of individual differences in time perception.MethodologyForty-four right-handed Russian Caucasian males (18–35 years old) participated in the experiment. The polymorphism of the genes related to the activity of serotonin (5-HT) and dopamine (DA)-systems (such as 5-HTT, 5HT2a, MAOA, DAT, DRD2, COMT) was determined upon the basis of DNA analysis according to a standard procedure. Time

Olga V. Sysoeva; Alexander G. Tonevitsky; Ji?í Wackermann

2010-01-01

283

Genetic Determinants of Tetracycline Resistance in Vibrio harveyi  

PubMed Central

Isolates of Vibrio harveyi, a prawn pathogen, have demonstrated multiple antibiotic resistance to commonly used antimicrobial agents, such as oxytetracycline. In this paper, we describe the cloning and characterization of two tetracycline resistance determinants from V. harveyi strain M3.4L. The first resistance determinant, cloned as a 4,590-bp fragment, was identical to tetA and flanking sequences encoded on transposon Tn10 from Shigella flexneri. The second determinant, cloned as a 3,358-bp fragment in pATJ1, contains two open reading frames, designated tet35 and txr. tet35 encodes a 369-amino-acid protein that was predicted to have nine transmembrane regions. It is a novel protein which has no homology to any other drug resistance protein but has low levels of homology (28%) to Na+/H+ antiporters. Transposon mutagenesis showed that tet35 and txr were required for tetracycline resistance in a heterologous Escherichia coli host. Tetracycline accumulation studies indicate that E. coli carrying tet35 and txr can function as an energy-dependent tetracycline efflux pump but is less efficient than TetA. PMID:11897587

Teo, Jeanette W. P.; Tan, Theresa M. C.; Poh, Chit Laa

2002-01-01

284

Genetic Approaches Identify Differential Roles for  4beta2* Nicotinic Receptors in Acute Models of Antinociception in Mice  

Microsoft Academic Search

The effects of nicotine on the tail-flick and hot-plate tests were determined to identify nicotinic receptor subtypes responsible for spinally and supraspinally mediated nicotine analgesia in knockin mice expressing hypersensitive 4 nicotinic receptors (L9S), in seven inbred mouse strains (C57BL\\/6, DBA\\/2, A\\/2, CBA\\/2, BALB\\/ cByJ, C3H\\/HeJ, and 129\\/SvEv), and in two F1 hybrids (B6CBAF1 and B6D2F1). L9S heterozygotes were 6-fold

M. I. Damaj; C. Fonck; M. J. Marks; P. Deshpande; C. Labarca; H. A. Lester; A. C. Collins; B. R. Martin

2007-01-01

285

Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients  

PubMed Central

A whole-genome approach was used to investigate the genetic determinants of cytarabine-induced cytotoxicity. We performed a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines (LCLs) from individuals of European, African, Asian, and African American ancestry. Several of the highest-ranked single-nucleotide polymorphisms (SNPs) were within the mutated in colorectal cancers (MCC) gene. MCC expression was induced by cytarabine treatment from 1.7- to 26.6-fold in LCLs. A total of 33 SNPs ranked at the top of the meta-analysis (P < 10?5) were successfully tested in a clinical trial of patients randomized to receive low-dose or high-dose cytarabine plus daunorubicin and etoposide; of these, 18 showed association (P < .05) with either cytarabine 50% inhibitory concentration in leukemia cells or clinical response parameters (minimal residual disease, overall survival (OS), and treatment-related mortality). This count (n = 18) was significantly greater than expected by chance (P = .016). For rs1203633, LCLs with AA genotype were more sensitive to cytarabine-induced cytotoxicity (P = 1.31 × 10?6) and AA (vs GA or GG) genotype was associated with poorer OS (P = .015), likely as a result of greater treatment-related mortality (P = .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084. PMID:23538338

Gamazon, Eric R.; Lamba, Jatinder K.; Pounds, Stanley; Stark, Amy L.; Wheeler, Heather E.; Cao, Xueyuan; Im, Hae K.; Mitra, Amit K.; Rubnitz, Jeffrey E.; Ribeiro, Raul C.; Raimondi, Susana; Campana, Dario; Crews, Kristine R.; Wong, Shan S.; Welsh, Marleen; Hulur, Imge; Gorsic, Lidija; Hartford, Christine M.; Zhang, Wei; Cox, Nancy J.; Dolan, M. Eileen

2013-01-01

286

Genetic determination of male sterility in gynodioecious Silene nutans.  

PubMed

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

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

2011-05-01

287

Genetic determination of male sterility in gynodioecious Silene nutans  

PubMed Central

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

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

2011-01-01

288

Congenic interval mapping of RNO10 reveals a complex cluster of closely-linked genetic determinants of blood pressure.  

PubMed

Genetic dissection of the rat genome for identifying alleles that cause abnormalities in blood pressure (BP) resulted in the mapping of a significant number of BP quantitative trait loci (QTLs). In this study we mapped at least one such BP QTL on rat chromosome 10 (RNO10) as being within the introgressed segment of a S.LEW congenic strain S.LEWx12x2x3x8 spanning 1.34 Mb from 70,725,437 bp to 72,063,232 bp. BP of 3 congenic strains that span shorter segments of this region was additionally examined. Results obtained indicate that LEW alleles that comprise a 375-kb introgressed segment of the congenic strain S.LEWx12x2x3x5 (70,725,437 bp to 71,100,513 bp) increase BP. The magnitude of change in BP exhibited by the 2 strains, S.LEWx12x2x3x8 and S.LEWx12x2x3x5, is the net phenotypic effect of the underlying genetic determinants of BP. In this respect, the current data are superior to previous QTL localization of BP QTL1, which was hypothesized based on differential congenic segments. Genetic dissection using these 2 congenic strains as tools is expected to facilitate further dissection of the regions. Meanwhile, differential congenic segments were used to predict and thereby prioritize regions for candidate gene analysis. Using this approach, 2 distinct regions of 401 kb and 409 kb within S.LEWx12x2x3x8 and a 104 kb region within S.LEWx12x2x3x5 were prioritized for further consideration. Because all of these genetic elements are located within a 1.06-Mb region of RNO10, our study has revealed a remarkable insight into a genomic module comprising very closely-linked, opposing genetic determinants of BP. PMID:17893371

Saad, Yasser; Yerga-Woolwine, Shane; Saikumar, Jagannath; Farms, Phyllis; Manickavasagam, Ezhilarasi; Toland, Edward J; Joe, Bina

2007-11-01

289

Genetic and Biochemical Dissection of a HisKA Domain Identifies Residues Required Exclusively for Kinase and Phosphatase Activities  

PubMed Central

Two-component signal transduction systems, composed of histidine kinases (HK) and response regulators (RR), allow bacteria to respond to diverse environmental stimuli. The HK can control both phosphorylation and subsequent dephosphorylation of its cognate RR. The majority of HKs utilize the HisKA subfamily of dimerization and histidine phosphotransfer (DHp) domains, which contain the phospho-accepting histidine and directly contact the RR. Extensive genetics, biochemistry, and structural biology on several prototypical TCS systems including NtrB-NtrC and EnvZ-OmpR have provided a solid basis for understanding the function of HK–RR signaling. Recently, work on NarX, a HisKA_3 subfamily protein, indicated that two residues in the highly conserved region of the DHp domain are responsible for phosphatase activity. In this study we have carried out both genetic and biochemical analyses on Myxococcus xanthus CrdS, a member of the HisKA subfamily of bacterial HKs. CrdS is required for the regulation of spore formation in response to environmental stress. Following alanine-scanning mutagenesis of the ?1 helix of the DHp domain of CrdS, we determined the role for each mutant protein for both kinase and phosphatase activity. Our results indicate that the conserved acidic residue (E372) immediately adjacent to the site of autophosphorylation (H371) is specifically required for kinase activity but not for phosphatase activity. Conversely, we found that the conserved Thr/Asn residue (N375) was required for phosphatase activity but not for kinase activity. We extended our biochemical analyses to two CrdS homologs from M. xanthus, HK1190 and HK4262, as well as Thermotoga maritima HK853. The results were similar for each HisKA family protein where the conserved acidic residue is required for kinase activity while the conserved Thr/Asn residue is required for phosphatase activity. These data are consistent with conserved mechanisms for kinase and phosphatase activities in the broadly occurring HisKA family of sensor kinases in bacteria. PMID:23226719

Willett, Jonathan W.; Kirby, John R.

2012-01-01

290

Extensive Genetic Diversity Identified among Sporadic Methicillin-Resistant Staphylococcus aureus Isolates Recovered in Irish Hospitals between 2000 and 2012  

PubMed Central

Clonal replacement of predominant nosocomial methicillin-resistant Staphylococcus aureus (MRSA) strains has occurred several times in Ireland during the last 4 decades. However, little is known about sporadically occurring MRSA in Irish hospitals or in other countries. Eighty-eight representative pvl-negative sporadic MRSA isolates recovered in Irish hospitals between 2000 and 2012 were investigated. These yielded unusual pulsed-field gel electrophoresis and antibiogram-resistogram typing patterns distinct from those of the predominant nosocomial MRSA clone, ST22-MRSA-IV, during the study period. Isolates were characterized by spa typing and DNA microarray profiling for multilocus sequence type (MLST) clonal complex (CC) and/or sequence type (ST) and SCCmec type assignment, as well as for detection of virulence and antimicrobial resistance genes. Conventional PCR-based SCCmec subtyping was undertaken when necessary. Extensive diversity was detected, including 38 spa types, 13 MLST-CCs (including 18 STs among 62 isolates assigned to STs), and 25 SCCmec types (including 2 possible novel SCCmec elements and 7 possible novel SCCmec subtypes). Fifty-four MLST-spa-SCCmec type combinations were identified. Overall, 68.5% of isolates were assigned to nosocomial lineages, with ST8-t190-MRSA-IID/IIE ± SCCM1 predominating (17.4%), followed by CC779/ST779-t878-MRSA-?SCCmec-SCC-SCCCRISPR (7.6%) and CC22/ST22-t032-MRSA-IVh (5.4%). Community-associated clones, including CC1-t127/t386/t2279-MRSA-IV, CC59-t216-MRSA-V, CC8-t008-MRSA-IVa, and CC5-t002/t242-MRSA-IV/V, and putative animal-associated clones, including CC130-t12399-MRSA-XI, ST8-t064-MRSA-IVa, ST398-t011-MRSA-IVa, and CC6-t701-MRSA-V, were also identified. In total, 53.3% and 47.8% of isolates harbored genes for resistance to two or more classes of antimicrobial agents and two or more mobile genetic element-encoded virulence-associated factors, respectively. Effective ongoing surveillance of sporadic nosocomial MRSA is warranted for early detection of emerging clones and reservoirs of virulence, resistance, and SCCmec genes. PMID:24395241

Kinnevey, Peter M.; Shore, Anna C.; Brennan, Grainne I.; Sullivan, Derek J.; Ehricht, Ralf; Monecke, Stefan

2014-01-01

291

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

PubMed Central

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

Andreas, Jonathan; Patel, Shashank J.; Zhang, Suiyuan; Chines, Peter; Elkahloun, Abdel; Chandrasekharappa, Settara; Gutkind, J. Silvio; Molinolo, Alfredo A.; Crawford, Nigel P. S.

2014-01-01

292

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

ERIC Educational Resources Information Center

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

Howlin, Patricia; Karpf, Janne

2004-01-01

293

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

294

The Stability of Genetic Determination from Age 2 to Age 9: A Longitudinal Twin Study.  

ERIC Educational Resources Information Center

A longitudinal investigation of the social and cognitive development of male twins was conducted when twins were 2.5 years of age, and again when they were 8- to 10-years-old. This study was designed to re-examine the heritability of the traits studied at the earlier age and, thus, to address the question of the stability of genetic determination.…

Lytton, Hugh; And Others

295

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

296

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

PubMed

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

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

2014-11-13

297

The genetic and metabolic determinants of cardiovascular complications in type 2 diabetes: recent insights from animal models and clinical investigations.  

PubMed

Cardiovascular complications (CVC) are the most common causes of death in patients with type 2 diabetes (T2D). However the pathophysiological determinants and molecular mechanisms involved in the progression of CVC in T2D are poorly understood. We have undertaken the challenging task of identifying some of the genetic and clinical determinants of CVC through a unique multidisciplinary approach involving Canadian and Finnish investigators. We are studying novel animal models combining atherosclerosis, diet-induced obesity and T2D to understand the molecular basis of CVC in obesity-linked T2D. We are also conducting clinical studies to identify key determinants of CVC in T2D patients and to determine whether a lifestyle modification program targeting loss of visceral adipose tissue/ectopic fat could be associated with clinical benefits in these patients. Together, we strongly believe that we can fill some gaps in our understanding of the CVC pathogenesis in T2D and identify novel therapeutic targets and hope that this new knowledge may be translated into the design of effective clinical interventions to optimally reduce cardiovascular risk in T2D subjects. PMID:24500564

Kohen Avramoglu, Rita; Laplante, Marc-André; Le Quang, Khai; Deshaies, Yves; Després, Jean-Pierre; Larose, Eric; Mathieu, Patrick; Poirier, Paul; Pérusse, Louis; Vohl, Marie-Claude; Sweeney, Gary; Ylä-Herttuala, Seppo; Laakso, Markku; Uusitupa, Matti; Marette, André

2013-10-01

298

Determination of best-fit potential parameters for a reactive force field using a genetic algorithm  

Microsoft Academic Search

The ReaxFF interatomic potential, used for organic materials, involves more than 600 adjustable parameters, the best-fit values\\u000a of which must be determined for different materials. A new method of determining the set of best-fit parameters for specific\\u000a molecules containing carbon, hydrogen, nitrogen and oxygen is presented, based on a parameter reduction technique followed\\u000a by genetic algorithm (GA) minimization. This work

Poonam Pahari; Shashank Chaturvedi

299

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

300

Genetic mapping identifies a major locus spanning P450 clusters associated with pyrethroid resistance in kdr-free Anopheles arabiensis from Chad.  

PubMed

Prevention of malaria transmission throughout much of Africa is dependent on bednets that are impregnated with pyrethroid insecticides. Anopheles arabiensis is the major malaria vector in Chad and efforts to control this vector are threatened by the emergence of pyrethroid resistance. WHO bioassays revealed that An. arabiensis from Ndjamena is resistant to pyrethroids and dichlorodiphenyltrichloroethane (DDT) but fully susceptible to carbamates and organophosphates. No 1014F or 1014S kdr alleles were detected in this population. To determine the mechanisms that are responsible for resistance, genetic crosses were established between the Ndja strain and an insecticide susceptible population from Mozambique. Resistance was inherited as an autosomal trait and quantitative trait locus (QTL) mapping identified a single major locus on chromosome 2R, which explained 24.4% of the variance in resistance. This QTL is enriched in P450 genes including 25 cytochrome P450s in total. One of these, Cyp6p4 is 22-fold upregulated in the Ndja strain compared with the susceptible. Piperonyl butoxide (PBO) synergist and biochemical assays further support a role for P450s in conferring pyrethroid resistance in this population. PMID:23299100

Witzig, C; Parry, M; Morgan, J C; Irving, H; Steven, A; Cuamba, N; Kerah-Hinzoumbé, C; Ranson, H; Wondji, C S

2013-04-01

301

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

Genetics. Although schizophrenia typically onsets during adolescence and early adulthood, many that environmental factors, such as malnutrition or infections during pregnancy, can contribute to the development the first and second trimester of pregnancy increase one's risk for schizophrenia," said study leader Dr

302

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

PubMed Central

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 damselfly Ischnuraelegans, which has been the target of many ecological and evolutionary studies. We addressed the following questions: (i) Is the population structure affected by longitudinal or latitudinal gradients?; (ii) Do geographic boundaries limit gene flow?; (iii) Does geographic distance affect connectivity and is there a signature of past bottlenecks?; (iv) Is there evidence of a recent range expansion and (vi) what is the effect of geography and climatic factors on population structure? We found low to moderate genetic sub-structuring between populations (mean FST?=?0.06, Dest?=?0.12), and an effect of longitude, but not latitude, on genetic diversity. No significant effects of geographic boundaries (e.g. water bodies) were found. FST-and Dest-values increased with geographic distance; however, there was no evidence for recent bottlenecks. Finally, we did not detect any molecular signatures of range expansions or an effect of geographic suitability, although local precipitation had a strong effect on genetic differentiation. The population structure of this small insect has probably been shaped by ecological factors that are correlated with longitudinal gradients, geographic distances, and local precipitation. The relatively weak global population structure and high degree of genetic variation within populations suggest that I. elegans has high dispersal ability, which is consistent with this species being an effective and early coloniser of new habitats. PMID:21655216

Wellenreuther, Maren; Sanchez-Guillen, Rosa A.; Cordero-Rivera, Adolfo; Svensson, Erik I.; Hansson, Bengt

2011-01-01

303

High-resolution analysis of intrahost genetic diversity in dengue virus serotype 1 infection identifies mixed infections.  

PubMed

Little is known about the rate at which genetic variation is generated within intrahost populations of dengue virus (DENV) and what implications this diversity has for dengue pathogenesis, disease severity, and host immunity. Previous studies of intrahost DENV variation have used a low frequency of sampling and/or experimental methods that do not fully account for errors generated through amplification and sequencing of viral RNAs. We investigated the extent and pattern of genetic diversity in sequence data in domain III (DIII) of the envelope (E) gene in serial plasma samples (n = 49) taken from 17 patients infected with DENV type 1 (DENV-1), totaling some 8,458 clones. Statistically rigorous approaches were employed to account for artifactual variants resulting from amplification and sequencing, which we suggest have played a major role in previous studies of intrahost genetic variation. Accordingly, nucleotide sequence diversities of viral populations were very low, with conservative estimates of the average levels of genetic diversity ranging from 0 to 0.0013. Despite such sequence conservation, we observed clear evidence for mixed infection, with the presence of multiple phylogenetically distinct lineages present within the same host, while the presence of stop codon mutations in some samples suggests the action of complementation. In contrast to some previous studies we observed no relationship between the extent and pattern of DENV-1 genetic diversity and disease severity, immune status, or level of viremia. PMID:22090119

Thai, Khoa T D; Henn, Matthew R; Zody, Michael C; Tricou, Vianney; Nguyet, Nguyen Minh; Charlebois, Patrick; Lennon, Niall J; Green, Lisa; de Vries, Peter J; Hien, Tran Tinh; Farrar, Jeremy; van Doorn, H Rogier; de Jong, Menno D; Birren, Bruce W; Holmes, Edward C; Simmons, Cameron P

2012-01-01

304

New insights into the pathogenesis of pseudoxanthoma elasticum and related soft tissue calcification disorders by identifying genetic interactions and modifiers.  

PubMed

Screening of the adenosine triphosphate binding cassette transporter protein subfamily C member 6 gene (ABCC6) in pseudoxanthoma elasticum (PXE) revealed a mutation detection rate of approximately 87%. Although 25% of the unidentified disease alleles underlie deletions/insertions, there remain several PXE patients with no clear genotype. The recent identification of PXE-related diseases and the high intra-familiar and inter-individual clinical variability of PXE led to the assumption that secondary genetic co-factors exist. Here, we summarize current knowledge of the genetics underlying PXE and PXE-related disorders based on human and animal studies. Furthermore, we discuss the role of genetic interactions and modifier genes in PXE and PXE-related diseases characterized by soft tissue calcification. PMID:23802012

Hendig, Doris; Knabbe, Cornelius; Götting, Christian

2013-01-01

305

Balancing genetic uniqueness and genetic variation in determining conservation and translocation strategies: a comprehensive case study of threatened dwarf galaxias, Galaxiella pusilla (Mack) (Pisces: Galaxiidae).  

PubMed

Genetic markers are widely used to define and manage populations of threatened species based on the notion that populations with unique lineages of mtDNA and well-differentiated nuclear marker frequencies should be treated separately. However, a danger of this approach is that genetic uniqueness might be emphasized at the cost of genetic diversity, which is essential for adaptation and is potentially boosted by mixing geographically separate populations. Here, we re-explore the issue of defining management units, focussing on a detailed study of Galaxiella pusilla, a small freshwater fish of national conservation significance in Australia. Using a combination of microsatellite and mitochondrial markers, 51 populations across the species range were surveyed for genetic structure and diversity. We found an inverse relationship between genetic differentiation and genetic diversity, highlighting a long-term risk of deliberate isolation of G. pusilla populations based on protection of unique lineages. Instead, we adopt a method for identifying genetic management units that takes into consideration both uniqueness and genetic variation. This produced a management framework to guide future translocation and re-introduction efforts for G. pusilla, which contrasted to the framework based on a more traditional approach that may overlook important genetic variation in populations. PMID:23432132

Coleman, R A; Weeks, A R; Hoffmann, A A

2013-04-01

306

A genetic determinant of the phenotypic variance of the molecular weight of low density lipoprotein.  

PubMed

The molecular weight of monodisperse human plasma low densitylipoprotein has been measured in 69 individuals and found to vary over the range of 2.4 to 3.9 X 10-6. By contrast, the molecular weight of low density lipoprotein measured on two separate occasions for specific individuals shows a mean difference of 0.07 X 10-6 and a standard deviation of 0.08 X 10-6; hence low density lipoprotein differing in molecular weight by greater than 0.2 X 10-6 may be considered different macomolecules. The distribution of the molecular weight of low density lipoprotein does not differ as a function of age or sex. Hyperlipemic subjects having monodisperse low density lipoprotein show similar molecular weight distribution to normal subjects, as do subjects with premature coronary artery disease. Family studies reveal a correlation coefficient of 0.82 between average molecular weights of parents and offspring, with significance at 0.01. In order to assess the influence of environment on molecular weight of low density lipoprotein, the correlation coefficient between the fathers' and mothers' low density lipoprotein was measured and no statistically significant correlation was found. These data are interpreted as strong evidence for a genetic determination of molecular weight of low density lipoprotein. A study of individuals in five families yields molecular weight data consistent with a single gene locus genetic mode of inheritance without dominance. The regression coefficient of the mean low denisty lipoprotein parental molecular weight on the offspring molecular weight is 0.30. If the variability of molecular weight is considered as an expression of phenotypic variance, then the regression analysis identified 30% of this phenotypic variance as arising from additive gene action presumably at a single locus. Segregation in the family data is consistent. Since the differences in molecular weight of low density lipoprotein arise from differences in the amount of lipid bound to the apoprotein, it is likely that an additional portion of the phenotypic variance of the molecular weight results from individual variations in the metabolism of low density lipoprotein, which yield differences in lipid content. The individual variation in molecular weight is only approximately 5%; hence those metabolic sequences that influence molecular weight of low density lipoproteins must be precisely controlled. PMID:166386

Fisher, W R; Hammond, M G; Mengel, M C; Warmke, G L

1975-06-01

307

Genetic determinants of atherosclerosis, obesity, and energy balance in consomic mice.  

PubMed

Metabolic diseases such as obesity and atherosclerosis result from complex interactions between environmental factors and genetic variants. A panel of chromosome substitution strains (CSSs) was developed to characterize genetic and dietary factors contributing to metabolic diseases and other biological traits and biomedical conditions. Our goal here was to identify quantitative trait loci (QTLs) contributing to obesity, energy expenditure, and atherosclerosis. Parental strains C57BL/6 and A/J together with a panel of 21 CSSs derived from these progenitors were subjected to chronic feeding of rodent chow and atherosclerotic (females) or diabetogenic (males) test diets, and evaluated for a variety of metabolic phenotypes including several traits unique to this report, namely fat pad weights, energy balance, and atherosclerosis. A total of 297 QTLs across 35 traits were discovered, two of which provided significant protection from atherosclerosis, and several dozen QTLs modulated body weight, body composition, and circulating lipid levels in females and males. While several QTLs confirmed previous reports, most QTLs were novel. Finally, we applied the CSS quantitative genetic approach to energy balance, and identified three novel QTLs controlling energy expenditure and one QTL modulating food intake. Overall, we identified many new QTLs and phenotyped several novel traits in this mouse model of diet-induced metabolic diseases. PMID:25001233

Spiezio, Sabrina H; Amon, Lynn M; McMillen, Timothy S; Vick, Cynthia M; Houston, Barbara A; Caldwell, Mark; Ogimoto, Kayoko; Morton, Gregory J; Kirk, Elizabeth A; Schwartz, Michael W; Nadeau, Joseph H; LeBoeuf, Renée C

2014-12-01

308

Copyright 1999 by the Genetics Society of America Suppressors of the Arabidopsis lsd5 Cell Death Mutation Identify Genes  

E-print Network

Copyright © 1999 by the Genetics Society of America Suppressors of the Arabidopsis lsd5 Cell Death hypersensitive reaction (HR). Arabidopsis lsd mutants that spontaneously exhibit cell death reminiscent of the HR disease resistance, one of these mutants, lsd5, was used to isolate new mutations that suppress its cell

Dangl, Jeff

309

Microsatellites and SNPs linkage analysis in a Sardinian genetic isolate confirms several essential hypertension loci previously identified in different populations  

Microsoft Academic Search

BACKGROUND: A multiplicity of study designs such as gene candidate analysis, genome wide search (GWS) and, recently, whole genome association studies have been employed for the identification of the genetic components of essential hypertension (EH). Several genome-wide linkage studies of EH and blood pressure-related phenotypes demonstrate that there is no single locus with a major effect while several genomic regions

Evelina Mocci; Maria P Concas; Manuela Fanciulli; Nicola Pirastu; Mauro Adamo; Valentina Cabras; Cristina Fraumene; Ivana Persico; Alessandro Sassu; Andrea Picciau; Dionigio A Prodi; Donatella Serra; Ginevra Biino; Mario Pirastu; Andrea Angius

2009-01-01

310

A Genome-wide Association Study of Host Genetic Determinants of the Antibody Response to Anthrax Vaccine Adsorbed  

PubMed Central

Several lines of evidence have supported a host genetic contribution to vaccine response, but genome-wide assessments for specific determinants have been sparse. Here we describe a genome-wide association study (GWAS) of protective antigen-specific antibody (AbPA) responses among 726 European-Americans who received Anthrax Vaccine Adsorbed (AVA) as part of a clinical trial. After quality control, 736,996 SNPs were tested for association with the AbPA response to 3 or 4 AVA vaccinations given over a 6-month period. No SNP achieved the threshold of genome-wide significance (p=5x10?8), but suggestive associations (p<1x10?5) were observed for SNPs in or near the class II region of the major histocompatibility complex (MHC), in the promoter region of SPSB1, and adjacent to MEX3C. Multivariable regression modeling suggested that much of the association signal within the MHC corresponded to previously identified HLA DR-DQ haplotypes involving component HLA-DRB1 alleles of *15:01, *01:01, or *01:02. We estimated the proportion of additive genetic variance explained by common SNP variation for the AbPA response after the 6 month vaccination. This analysis indicated a significant, albeit imprecisely estimated, contribution of variation tagged by common polymorphisms (p=0.032). Future studies will be required to replicate these findings in European Americans and to further elucidate the host genetic factors underlying variable immune response to AVA. PMID:22658931

Pajewski, Nicholas M.; Shrestha, Sadeep; Quinn, Conrad P.; Parker, Scott D.; Wiener, Howard; Aissani, Brahim; McKinney, Brett A.; Poland, Gregory A.; Edberg, Jeffrey C.; Kimberly, Robert P.; Tang, Jianming; Kaslow, Richard A.

2012-01-01

311

Genetic screen identifies insulin-like growth factor binding protein 5 as a modulator of tamoxifen resistance in breast cancer.  

PubMed

Tamoxifen resistance is one of the overarching challenges in the treatment of patients with estrogen receptor (ER)-positive breast cancer. Through a genome-wide RNA interference screen to discover genes responsible for tamoxifen resistance in vitro, we identified insulin-like growth factor binding protein 5 (IGFBP5) as a determinant of drug sensitivity. Specific knockdown of IGFBP5 by retroviral infection with short hairpin RNA-expressing cassette in MCF7 human breast cancer cells (pRS-shIGFBP5) conferred tamoxifen resistance in vitro due to concomitant loss of ERalpha expression and signaling. IGFBP5 expression was also reduced in MCF7 cells selected for tamoxifen resistance in culture (TAMR). Both tamoxifen-resistant MCF7-TAMR and MCF7-pRS-shIGFBP5 cells could be resensitized to drug by treatment with exogenous recombinant IGFBP5 (rIGFBP5) protein. Treatment with rIGFBP5 protein in mouse tumor xenografts reversed the in vivo tamoxifen resistance of MCF7-pRS-shIGFBP5 cell-derived tumors by reducing tumor cell proliferation. IGFBP5 immunohistochemical staining in a cohort of 153 breast cancer patients showed that low IGFBP5 expression was associated with shorter overall survival after tamoxifen therapy. Thus, IGFBP5 warrants investigation as an agent to reverse tamoxifen resistance. PMID:20354179

Ahn, Bo Young; Elwi, Adam N; Lee, Byoungchun; Trinh, Diane L N; Klimowicz, Alexander C; Yau, Annie; Chan, Jennifer A; Magliocco, Anthony; Kim, Sung-Woo

2010-04-15

312

Genetics  

NSDL National Science Digital Library

This activity helps students to understand basic principles of genetics, including relationships of genotype to phenotype, concepts of recessive and dominant alleles, and how understanding meiosis and fertilization provides the basis for understanding inheritance, as summarized in Punnett squares. The Student Handout includes an analysis of the inheritance of albinism that teaches all of these concepts, a Coin Toss Genetics activity that helps students understand the probabilistic nature of Punnett square predictions, and an analysis of the inheritance of sickle cell anemia that reinforces the basic concepts and introduces some of the complexities of genetics. The Genetics Supplement includes two additional activities, an analysis of student data on the sex makeup of sibships and pedigree analyses of recessive and dominant alleles with challenge questions that introduce the role of mutations and an evaluation of Punnett squares and pedigrees as models of inheritance.

Doherty, Jennifer; Waldron, Ingrid; Poethig, Scott

313

Application of Novel Polymorphic Microsatellite Loci Identified in the Korean Pacific Abalone (Haliotis diversicolor supertexta (Haliotidae)) in the Genetic Characterization of Wild and Released Populations  

PubMed Central

The small abalone, Haliotis diversicolor supertexta, of the family Haliotidae, is one of the most important species of marine shellfish in eastern Asia. Over the past few decades, this species has drastically declined in Korea. Thus, hatchery-bred seeds have been released into natural coastal areas to compensate for the reduced fishery resources. However, information on the genetic background of the small abalone is scarce. In this study, 20 polymorphic microsatellite DNA markers were identified using next-generation sequencing techniques and used to compare allelic variation between wild and released abalone populations in Korea. Using high-throughput genomic sequencing, a total of 1516 (2.26%; average length of 385 bp) reads containing simple sequence repeats were obtained from 86,011 raw reads. Among the 99 loci screened, 28 amplified successfully, and 20 were polymorphic. When comparing allelic variation between wild and released abalone populations, a total of 243 different alleles were observed, with 18.7 alleles per locus. High genetic diversity (mean heterozygosity = 0.81; mean allelic number = 15.5) was observed in both populations. A statistical analysis of the fixation index (FST) and analysis of molecular variance (AMOVA) indicated limited genetic differences between the two populations (FST = 0.002, p > 0.05). Although no significant reductions in the genetic diversity were found in the released population compared with the wild population (p > 0.05), the genetic diversity parameters revealed that the seeds released for stock abundance had a different genetic composition. These differences are likely a result of hatchery selection and inbreeding. Additionally, all the primer pair sets were effectively amplified in another congeneric species, H. diversicolor diversicolor, indicating that these primers are useful for both abalone species. These microsatellite loci may be valuable for future aquaculture and population genetic studies aimed at developing conservation and management plans for these two abalone species. PMID:23109820

An, Hye Suck; Lee, Jang Wook; Hong, Seong Wan

2012-01-01

314

Exploration of genetically determined resistance against hepatitis C infection in high-risk injecting drug users.  

PubMed

Genetic resistance to specific infections is well recognized. In hepatitis C virus (HCV) infection, genetic polymorphisms in IL-28B and the killer cell immunoglobulin-like receptors (KIR) and their HLA class I ligands have been shown to affect clearance of the virus following infection. There are limited data regarding resistance to established HCV infection. Reliable quantification of repeated exposure in high-risk populations, such as injecting drug users (IDU), is a key limitation of previous studies of resistance. Behavioural data and DNA from IDU (n = 210) in the Hepatitis C Incidence and Transmission Study in prisons (HITS-p) cohort were genotyped for polymorphisms in: IL-28B, peptidyl-prolyl isomerase A (PPIA), HLA-C and KIR2. To quantify risk, a composite risk index based on factors predictive of incident HCV infection was derived. Logistic regression analysis revealed the risk index was strongly associated with incident HCV infection (P < 0.0001). The upper tertile of the uninfected individuals had risk indices comparable to the incident cases, but remained uninfected. There were no significant differences in the frequencies of IL-28B or PPIA polymorphisms between these exposed-uninfected cases, or in the frequencies of KIR2-DL3, HLA-C1, or their combination. A framework for the investigation of genetic determinants of resistance to HCV infection has been developed. Several candidate gene associations were investigated and excluded. Further investigation of genetic determinants of resistance to HCV infection is warranted. PMID:24612442

Sugden, P B; Cameron, B; Luciani, F; Lloyd, A R

2014-08-01

315

Allelic variation in the Tyk2 and EGF genes as potential genetic determinants of CNS repair.  

PubMed

The potential for endogenous remyelination and axonal protection can be an important factor in determining disease outcome in demyelinating diseases like multiple sclerosis. In many multiple sclerosis (MS) patients CNS repair fails or is incomplete whereas in others the disease is accompanied by extensive repair of demyelinated lesions. We have described significant differences in the ability of two strains of mice to repair CNS damage following Theiler's virus-induced demyelination: FVB/NJ (FVB) mice repair damaged myelin spontaneously and completely, whereas B10.D1-H2(q)/SgJ (B10.Q) mice are deficient in the repair process. A QTL analysis was performed to identify genetic loci that differentially regulate CNS repair following chronic demyelination in these strains and two QTL were detected: one on chromosome 3 with a LOD score of 9.3 and a second on chromosome 9 with a LOD score of 14.0. The mouse genes for epidermal growth factor (EGF) and Tyk2 are encoded within the QTL on chromosomes 3 and 9, respectively. Sequence polymorphisms between the FVB and B10.Q strains at both the EGF and Tyk2 loci define functional variations consistent with roles for these genes in regulating myelin repair. EGF is a key regulator of cell growth and development and we show a sevenfold increase in EGF expression in FVB compared to B10.Q mice. Tyk2 is a Janus kinase that plays a central role in controlling the T(H)1 immune response and we show that attenuation of Tyk2 function correlates with enhanced CNS repair. PMID:20080754

Bieber, Allan J; Suwansrinon, Kanitta; Kerkvliet, Jason; Zhang, Weidong; Pease, Larry R; Rodriguez, Moses

2010-01-12

316

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution  

Microsoft Academic Search

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an

Iris M Heid; Anne U Jackson; Joshua C Randall; Thomas W Winkler; Lu Qi; Valgerdur Steinthorsdottir; Gudmar Thorleifsson; M Carola Zillikens; Elizabeth K Speliotes; Reedik Magi; Tsegaselassie Workalemahu; Charles C White; Nabila Bouatia-Naji; Tamara B Harris; Sonja I Berndt; Erik Ingelsson; Cristen J Willer; Michael N Weedon; Jian'an Luan; Sailaja Vedantam; Tonu Esko; Tuomas O Kilpelainen; Zoltan Kutalik; Shengxu Li; Keri L Monda; Anna L Dixon; Christopher C Holmes; Lee M Kaplan; Liming Liang; Josine L Min; Miriam F Moffatt; Cliona Molony; George Nicholson; Eric E Schadt; Krina T Zondervan; Mary F Feitosa; Teresa Ferreira; Hana Lango Allen; Robert J Weyant; Eleanor Wheeler; Andrew R Wood; Karol Estrada; Michael E Goddard; Guillaume Lettre; Massimo Mangino; Dale R Nyholt; Shaun Purcell; Albert Vernon Smith; Peter M Visscher; Jian Yang; Steven A McCarroll; James Nemesh; Benjamin F Voight; Devin Absher; Najaf Amin; Thor Aspelund; Lachlan Coin; Nicole L Glazer; Caroline Hayward; Nancy L Heard-Costa; Jouke-Jan Hottenga; Asa Johansson; Toby Johnson; Marika Kaakinen; Karen Kapur; Shamika Ketkar; Joshua W Knowles; Peter Kraft; Aldi T Kraja; Claudia Lamina; Michael F Leitzmann; Barbara McKnight; Andrew P Morris; Ken K Ong; John R B Perry; Marjolein J Peters; Ozren Polasek; Inga Prokopenko; Nigel W Rayner; Samuli Ripatti; Fernando Rivadeneira; Neil R Robertson; Serena Sanna; Ulla Sovio; Ida Surakka; Alexander Teumer; Sophie van Wingerden; Veronique Vitart; Jing Hua Zhao; Christine Cavalcanti-Proenca; Peter S Chines; Eva Fisher; Jennifer R Kulzer; Cecile Lecoeur; Narisu Narisu; Camilla Sandholt; Laura J Scott; Kaisa Silander; Klaus Stark; Mari-Liis Tammesoo; Tanya M Teslovich; Nicholas John Timpson; Richard M Watanabe; Ryan Welch; Daniel I Chasman; Matthew N Cooper; John-Olov Jansson; Johannes Kettunen; Robert W Lawrence; Niina Pellikka; Markus Perola; Liesbeth Vandenput; Helene Alavere; Peter Almgren; Larry D Atwood; Amanda J Bennett; Reiner Biffar; Lori L Bonnycastle; Stefan R Bornstein; Thomas A Buchanan; Harry Campbell; Ian N M Day; Mariano Dei; Marcus Dorr; Paul Elliott; Michael R Erdos; Johan G Eriksson; Nelson B Freimer; Mao Fu; Stefan Gaget; Eco J C Geus; Anette P Gjesing; Harald Grallert; Jurgen Graszler; Christopher J Groves; Candace Guiducci; Anna-Liisa Hartikainen; Neelam Hassanali; Aki S Havulinna; Karl-Heinz Herzig; Andrew A Hicks; Jennie Hui; Wilmar Igl; Pekka Jousilahti; Antti Jula; Eero Kajantie; Leena Kinnunen; Ivana Kolcic; Seppo Koskinen; Peter Kovacs; Heyo K Kroemer; Vjekoslav Krzelj; Johanna Kuusisto; Kirsti Kvaloy; Jaana Laitinen; Olivier Lantieri; G Mark Lathrop; Marja-Liisa Lokki; Robert N Luben; Barbara Ludwig; Wendy L McArdle; Anne McCarthy; Mario A Morken; Mari Nelis; Matt J Neville; Guillaume Pare; Alex N Parker; John F Peden; Irene Pichler; Kirsi H Pietilainen; Carl G P Platou; Anneli Pouta; Martin Ridderstrale; Nilesh J Samani; Jouko Saramies; Juha Sinisalo; Jan H Smit; Rona J Strawbridge; Heather M Stringham; Amy J Swift; Maris Teder-Laving; Brian Thomson; Gianluca Usala; Joyce B J van Meurs; Gert-Jan van Ommen; Vincent Vatin; Claudia B Volpato; Henri Wallaschofski; G Bragi Walters; Elisabeth Widen; Sarah H Wild; Gonneke Willemsen; Daniel R Witte; Lina Zgaga; Paavo Zitting; John P Beilby; Alan L James; Mika Kahonen; Terho Lehtimaki; Markku S Nieminen; Claes Ohlsson; Lyle J Palmer; Olli Raitakari; Paul M Ridker; Michael Stumvoll; Anke Tonjes; Jorma Viikari; Beverley Balkau; Yoav Ben-Shlomo; Richard N Bergman; Heiner Boeing; George Davey Smith; Shah Ebrahim; Philippe Froguel; Torben Hansen; Christian Hengstenberg; Kristian Hveem; Bo Isomaa; Torben Jorgensen; Fredrik Karpe; Kay-Tee Khaw; Markku Laakso; Debbie A Lawlor; Michel Marre; Thomas Meitinger; Andres Metspalu; Kristian Midthjell; Oluf Pedersen; Veikko Salomaa; Peter E H Schwarz; Tiinamaija Tuomi; Jaakko Tuomilehto; Timo T Valle; Nicholas J Wareham; Alice M Arnold; Jacques S Beckmann; Sven Bergmann; Eric Boerwinkle; Dorret I Boomsma; Mark J Caulfield; Francis S Collins; Gudny Eiriksdottir; Vilmundur Gudnason; Ulf Gyllensten; Anders Hamsten; Andrew T Hattersley; Albert Hofman; Frank B Hu; Thomas Illig; Carlos Iribarren; Marjo-Riitta Jarvelin; W H Linda Kao; Jaakko Kaprio; Lenore J Launer; Patricia B Munroe; Ben Oostra; Brenda W Penninx; Peter P Pramstaller; Bruce M Psaty; Thomas Quertermous; Aila Rissanen; Igor Rudan; Alan R Shuldiner; Nicole Soranzo; Timothy D Spector; Ann-Christine Syvanen; Manuela Uda; Andre Uitterlinden; Henry Volzke; Peter Vollenweider; James F Wilson; Jacqueline C Witteman; Alan F Wright; Goncalo R Abecasis; Michael Boehnke; Ingrid B Borecki; Panos Deloukas

2010-01-01

317

Robust Flight Path Determination for Mars Precision Landing Using Genetic Algorithms  

NASA Technical Reports Server (NTRS)

This paper documents the application of genetic algorithms (GAs) to the problem of robust flight path determination for Mars precision landing. The robust flight path problem is defined here as the determination of the flight path which delivers a low-lift open-loop controlled vehicle to its desired final landing location while minimizing the effect of perturbations due to uncertainty in the atmospheric model and entry conditions. The genetic algorithm was capable of finding solutions which reduced the landing error from 111 km RMS radial (open-loop optimal) to 43 km RMS radial (optimized with respect to perturbations) using 200 hours of computation on an Ultra-SPARC workstation. Further reduction in the landing error is possible by going to closed-loop control which can utilize the GA optimized paths as nominal trajectories for linearization.

Bayard, David S.; Kohen, Hamid

1997-01-01

318

Ecology, not the genetics of sex determination, determines who helps in eusocial populations.  

PubMed

In eusocial species, the sex ratio of helpers varies from female only, in taxa such as the social Hymenoptera (ants, bees, and wasps) [1], to an unbiased mixture of males and females, as in most termites [2]. Hamilton suggested that this difference owes to the haplodiploid genetics of the Hymenoptera leading to females being relatively more related to their siblings [3]. However, it has been argued that Hamilton's hypothesis does not work [4-9] and that the sex of helpers could instead be explained by variation in the ecological factors that favor eusociality [10]. Here we test these two competing hypotheses, which focus on the possible importance of different terms in Hamilton's rule [2, 11], with a comparative study across all sexual eusocial taxa. We find that the sex ratio of helpers (1) shows no significant correlation with whether species are haplodiploid or diploid and (2) shows a strong correlation with the ecological factor that had favored eusociality. Specifically, when the role of helpers is to defend the nest, both males and females help, whereas when the role of helpers is to provide brood care, then helpers are the sex or sexes that provided parental care ancestrally. More generally, our results confirm the ability of kin selection theory to explain the biology of eusocial species, independently of ploidy, and add support to the idea that haplodiploidy has been more important for shaping conflicts within eusocial societies than for explaining its origins [6, 12-19]. PMID:24268409

Ross, Laura; Gardner, Andy; Hardy, Nate; West, Stuart A

2013-12-01

319

Mapping the genetic determinants of human immunodeficiency virus type 2 for cell tropism and replication efficiency  

Microsoft Academic Search

Summary.  ?Two distinct infectious molecular clones of human immunodeficiency type 2 (HIV-2) were analyzed for their biological properties\\u000a in six cell lines. Fourteen chimeric and ten mutant viruses were constructed from these two viral genomes to localize the\\u000a genetic determinants responsible for the phenotypes. Growth property of the viruses in the cell lines, together with the biochemical\\u000a data, showed that a

M. Kawamura; R. Shimano; T. Ogasawara; R. Inubushi; K. Amano; H. Akari; A. Adachi

1998-01-01

320

Genetics  

NSDL National Science Digital Library

What affects how physical characteristics are transmitted from parent to offspring? This is a question that can be answered at many levels. Molecular biologists examine the pattern of nucleotides in deoxyribonucleic acid (DNA) and the effect of mutations on the proteins produced. Classical geneticists explore the patterns by which traits are transmitted through families. Medical geneticists attempt to describe and develop treatments for diseases that have a genetic component. Genetic engineers analyze how traits can be altered in organisms through modern technology. These are only a few of the strategies that scientists employ to explain the nature of heredity. Explore historical perspectives on the study of genetics and investigate how cutting-edge technology is being used to expand our understanding of heredity.

National Science Teachers Association (NSTA)

2005-04-01

321

The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation  

PubMed Central

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection. PMID:21051598

Pereyra, Florencia; Jia, Xiaoming; McLaren, Paul J.; Telenti, Amalio; de Bakker, Paul I.W.; Walker, Bruce D.; Jia, Xiaoming; McLaren, Paul J.; Ripke, Stephan; Brumme, Chanson J.; Pulit, Sara L.; Telenti, Amalio; Carrington, Mary; Kadie, Carl M.; Carlson, Jonathan M.; Heckerman, David; de Bakker, Paul I.W.; Pereyra, Florencia; de Bakker, Paul I.W.; Graham, Robert R.; Plenge, Robert M.; Deeks, Steven G.; Walker, Bruce D.; Gianniny, Lauren; Crawford, Gabriel; Sullivan, Jordan; Gonzalez, Elena; Davies, Leela; Camargo, Amy; Moore, Jamie M.; Beattie, Nicole; Gupta, Supriya; Crenshaw, Andrew; Burtt, Noel P.; Guiducci, Candace; Gupta, Namrata; Carrington, Mary; Gao, Xiaojiang; Qi, Ying; Yuki, Yuko; Pereyra, Florencia; Piechocka-Trocha, Alicja; Cutrell, Emily; Rosenberg, Rachel; Moss, Kristin L.; Lemay, Paul; O'Leary, Jessica; Schaefer, Todd; Verma, Pranshu; Toth, Ildiko; Block, Brian; Baker, Brett; Rothchild, Alissa; Lian, Jeffrey; Proudfoot, Jacqueline; Alvino, Donna Marie L.; Vine, Seanna; Addo, Marylyn M.; Allen, Todd M.; Altfeld, Marcus; Henn, Matthew R.; Le Gall, Sylvie; Streeck, Hendrik; Walker, Bruce D.; Haas, David W.; Kuritzkes, Daniel R.; Robbins, Gregory K.; Shafer, Robert W.; Gulick, Roy M.; Shikuma, Cecilia M.; Haubrich, Richard; Riddler, Sharon; Sax, Paul E.; Daar, Eric S.; Ribaudo, Heather J.; Agan, Brian; Agarwal, Shanu; Ahern, Richard L.; Allen, Brady L.; Altidor, Sherly; Altschuler, Eric L.; Ambardar, Sujata; Anastos, Kathryn; Anderson, Ben; Anderson, Val; Andrady, Ushan; Antoniskis, Diana; Bangsberg, David; Barbaro, Daniel; Barrie, William; Bartczak, J.; Barton, Simon; Basden, Patricia; Basgoz, Nesli; Bazner, Suzane; Bellos, Nicholaos C.; Benson, Anne M.; Berger, Judith; Bernard, Nicole F.; Bernard, Annette M.; Birch, Christopher; Bodner, Stanley J.; Bolan, Robert K.; Boudreaux, Emilie T.; Bradley, Meg; Braun, James F.; Brndjar, Jon E.; Brown, Stephen J.; Brown, Katherine; Brown, Sheldon T.; Burack, Jedidiah; Bush, Larry M.; Cafaro, Virginia; Campbell, Omobolaji; Campbell, John; Carlson, Robert H.; Carmichael, J. Kevin; Casey, Kathleen K.; Cavacuiti, Chris; Celestin, Gregory; Chambers, Steven T.; Chez, Nancy; Chirch, Lisa M.; Cimoch, Paul J.; Cohen, Daniel; Cohn, Lillian E.; Conway, Brian; Cooper, David A.; Cornelson, Brian; Cox, David T.; Cristofano, Michael V.; Cuchural, George; Czartoski, Julie L.; Dahman, Joseph M.; Daly, Jennifer S.; Davis, Benjamin T.; Davis, Kristine; Davod, Sheila M.; Deeks, Steven G.; DeJesus, Edwin; Dietz, Craig A.; Dunham, Eleanor; Dunn, Michael E.; Ellerin, Todd B.; Eron, Joseph J.; Fangman, John J.W.; Farel, Claire E.; Ferlazzo, Helen; Fidler, Sarah; Fleenor-Ford, Anita; Frankel, Renee; Freedberg, Kenneth A.; French, Neel K.; Fuchs, Jonathan D.; Fuller, Jon D.; Gaberman, Jonna; Gallant, Joel E.; Gandhi, Rajesh T.; Garcia, Efrain; Garmon, Donald; Gathe, Joseph C.; Gaultier, Cyril R.; Gebre, Wondwoosen; Gilman, Frank D.; Gilson, Ian; Goepfert, Paul A.; Gottlieb, Michael S.; Goulston, Claudia; Groger, Richard K.; Gurley, T. Douglas; Haber, Stuart; Hardwicke, Robin; Hardy, W. David; Harrigan, P. Richard; Hawkins, Trevor N.; Heath, Sonya; Hecht, Frederick M.; Henry, W. Keith; Hladek, Melissa; Hoffman, Robert P.; Horton, James M.; Hsu, Ricky K.; Huhn, Gregory D.; Hunt, Peter; Hupert, Mark J.; Illeman, Mark L.; Jaeger, Hans; Jellinger, Robert M.; John, Mina; Johnson, Jennifer A.; Johnson, Kristin L.; Johnson, Heather; Johnson, Kay; Joly, Jennifer; Jordan, Wilbert C.; Kauffman, Carol A.; Khanlou, Homayoon; Killian, Robert K.; Kim, Arthur Y.; Kim, David D.; Kinder, Clifford A.; Kirchner, Jeffrey T.; Kogelman, Laura; Kojic, Erna Milunka; Korthuis, P. Todd; Kurisu, Wayne; Kwon, Douglas S.; LaMar, Melissa; Lampiris, Harry; Lanzafame, Massimiliano; Lederman, Michael M.; Lee, David M.; Lee, Jean M.L.; Lee, Marah J.; Lee, Edward T.Y.; Lemoine, Janice; Levy, Jay A.; Llibre, Josep M.; Liguori, Michael A.; Little, Susan J.; Liu, Anne Y.; Lopez, Alvaro J.; Loutfy, Mono R.; Loy, Dawn; Mohammed, Debbie Y.; Man, Alan; Mansour, Michael K.; Marconi, Vincent C.; Markowitz, Martin; Marques, Rui; Martin, Jeffrey N.; Martin, Harold L.; Mayer, Kenneth Hugh; McElrath, M. Juliana; McGhee, Theresa A.; McGovern, Barbara H.; McGowan, Katherine; McIntyre, Dawn; Mcleod, Gavin X.; Menezes, Prema; Mesa, Greg; Metroka, Craig E.; Meyer-Olson, Dirk; Miller, Andy O.; Montgomery, Kate; Mounzer, Karam C.; Nagami, Ellen H.; Nagin, Iris; Nahass, Ronald G.; Nelson, Margret O.; Nielsen, Craig; Norene, David L.; O'Connor, David H.; Ojikutu, Bisola O.; Okulicz, Jason; Oladehin, Olakunle O.; Oldfield, Edward C.; Olender, Susan A.

2011-01-01

322

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.  

PubMed

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection. PMID:21051598

Pereyra, Florencia; Jia, Xiaoming; McLaren, Paul J; Telenti, Amalio; de Bakker, Paul I W; Walker, Bruce D; Ripke, Stephan; Brumme, Chanson J; Pulit, Sara L; Carrington, Mary; Kadie, Carl M; Carlson, Jonathan M; Heckerman, David; Graham, Robert R; Plenge, Robert M; Deeks, Steven G; Gianniny, Lauren; Crawford, Gabriel; Sullivan, Jordan; Gonzalez, Elena; Davies, Leela; Camargo, Amy; Moore, Jamie M; Beattie, Nicole; Gupta, Supriya; Crenshaw, Andrew; Burtt, Noël P; Guiducci, Candace; Gupta, Namrata; Gao, Xiaojiang; Qi, Ying; Yuki, Yuko; Piechocka-Trocha, Alicja; Cutrell, Emily; Rosenberg, Rachel; Moss, Kristin L; Lemay, Paul; O'Leary, Jessica; Schaefer, Todd; Verma, Pranshu; Toth, Ildiko; Block, Brian; Baker, Brett; Rothchild, Alissa; Lian, Jeffrey; Proudfoot, Jacqueline; Alvino, Donna Marie L; Vine, Seanna; Addo, Marylyn M; Allen, Todd M; Altfeld, Marcus; Henn, Matthew R; Le Gall, Sylvie; Streeck, Hendrik; Haas, David W; Kuritzkes, Daniel R; Robbins, Gregory K; Shafer, Robert W; Gulick, Roy M; Shikuma, Cecilia M; Haubrich, Richard; Riddler, Sharon; Sax, Paul E; Daar, Eric S; Ribaudo, Heather J; Agan, Brian; Agarwal, Shanu; Ahern, Richard L; Allen, Brady L; Altidor, Sherly; Altschuler, Eric L; Ambardar, Sujata; Anastos, Kathryn; Anderson, Ben; Anderson, Val; Andrady, Ushan; Antoniskis, Diana; Bangsberg, David; Barbaro, Daniel; Barrie, William; Bartczak, J; Barton, Simon; Basden, Patricia; Basgoz, Nesli; Bazner, Suzane; Bellos, Nicholaos C; Benson, Anne M; Berger, Judith; Bernard, Nicole F; Bernard, Annette M; Birch, Christopher; Bodner, Stanley J; Bolan, Robert K; Boudreaux, Emilie T; Bradley, Meg; Braun, James F; Brndjar, Jon E; Brown, Stephen J; Brown, Katherine; Brown, Sheldon T; Burack, Jedidiah; Bush, Larry M; Cafaro, Virginia; Campbell, Omobolaji; Campbell, John; Carlson, Robert H; Carmichael, J Kevin; Casey, Kathleen K; Cavacuiti, Chris; Celestin, Gregory; Chambers, Steven T; Chez, Nancy; Chirch, Lisa M; Cimoch, Paul J; Cohen, Daniel; Cohn, Lillian E; Conway, Brian; Cooper, David A; Cornelson, Brian; Cox, David T; Cristofano, Michael V; Cuchural, George; Czartoski, Julie L; Dahman, Joseph M; Daly, Jennifer S; Davis, Benjamin T; Davis, Kristine; Davod, Sheila M; DeJesus, Edwin; Dietz, Craig A; Dunham, Eleanor; Dunn, Michael E; Ellerin, Todd B; Eron, Joseph J; Fangman, John J W; Farel, Claire E; Ferlazzo, Helen; Fidler, Sarah; Fleenor-Ford, Anita; Frankel, Renee; Freedberg, Kenneth A; French, Neel K; Fuchs, Jonathan D; Fuller, Jon D; Gaberman, Jonna; Gallant, Joel E; Gandhi, Rajesh T; Garcia, Efrain; Garmon, Donald; Gathe, Joseph C; Gaultier, Cyril R; Gebre, Wondwoosen; Gilman, Frank D; Gilson, Ian; Goepfert, Paul A; Gottlieb, Michael S; Goulston, Claudia; Groger, Richard K; Gurley, T Douglas; Haber, Stuart; Hardwicke, Robin; Hardy, W David; Harrigan, P Richard; Hawkins, Trevor N; Heath, Sonya; Hecht, Frederick M; Henry, W Keith; Hladek, Melissa; Hoffman, Robert P; Horton, James M; Hsu, Ricky K; Huhn, Gregory D; Hunt, Peter; Hupert, Mark J; Illeman, Mark L; Jaeger, Hans; Jellinger, Robert M; John, Mina; Johnson, Jennifer A; Johnson, Kristin L; Johnson, Heather; Johnson, Kay; Joly, Jennifer; Jordan, Wilbert C; Kauffman, Carol A; Khanlou, Homayoon; Killian, Robert K; Kim, Arthur Y; Kim, David D; Kinder, Clifford A; Kirchner, Jeffrey T; Kogelman, Laura; Kojic, Erna Milunka; Korthuis, P Todd; Kurisu, Wayne; Kwon, Douglas S; LaMar, Melissa; Lampiris, Harry; Lanzafame, Massimiliano; Lederman, Michael M; Lee, David M; Lee, Jean M L; Lee, Marah J; Lee, Edward T Y; Lemoine, Janice; Levy, Jay A; Llibre, Josep M; Liguori, Michael A; Little, Susan J; Liu, Anne Y; Lopez, Alvaro J; Loutfy, Mono R; Loy, Dawn; Mohammed, Debbie Y; Man, Alan; Mansour, Michael K; Marconi, Vincent C; Markowitz, Martin; Marques, Rui; Martin, Jeffrey N; Martin, Harold L; Mayer, Kenneth Hugh; McElrath, M Juliana; McGhee, Theresa A; McGovern, Barbara H; McGowan, Katherine; McIntyre, Dawn; Mcleod, Gavin X; Menezes, Prema; Mesa, Greg; Metroka, Craig E; Meyer-Olson, Dirk; Miller, Andy O; Montgomery, Kate; Mounzer, Karam C; Nagami, Ellen H; Nagin, Iris; Nahass, Ronald G; Nelson, Margret O; Nielsen, Craig; Norene, David L; O'Connor, David H; Ojikutu, Bisola O; Okulicz, Jason; Oladehin, Olakunle O; Oldfield, Edward C; Olender, Susan A; Ostrowski, Mario; Owen, William F; Pae, Eunice; Parsonnet, Jeffrey; Pavlatos, Andrew M; Perlmutter, Aaron M; Pierce, Michael N; Pincus, Jonathan M; Pisani, Leandro; Price, Lawrence Jay; Proia, Laurie; Prokesch, Richard C; Pujet, Heather Calderon; Ramgopal, Moti; Rathod, Almas; Rausch, Michael; Ravishankar, J; Rhame, Frank S

2010-12-10

323

Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.  

PubMed

Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10), OR = 0.84) and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8), OR = 0.85)-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered. PMID:21738487

Do, Chuong B; Tung, Joyce Y; Dorfman, Elizabeth; Kiefer, Amy K; Drabant, Emily M; Francke, Uta; Mountain, Joanna L; Goldman, Samuel M; Tanner, Caroline M; Langston, J William; Wojcicki, Anne; Eriksson, Nicholas

2011-06-01

324

Genetic, nongenetic and epigenetic risk determinants in developmental programming of type 2 diabetes.  

PubMed

Low birthweight (LBW) individuals and offspring of women with gestational diabetes mellitus (GDM) exhibit increased risk of developing type 2 diabetes (T2D) and associated cardiometabolic traits in adulthood, which for both groups may be mediated by adverse events and developmental changes in fetal life. T2D is a multifactorial disease occurring as a result of complicated interplay between genetic and both prenatal and postnatal nongenetic factors, and it remains unknown to what extent the increased risk of T2D associated with LBW or GDM in the mother may be due to, or confounded by, genetic factors. Indeed, it has been shown that genetic changes influencing risk of diabetes may also be associated with reduced fetal growth as a result of reduced insulin secretion and/or action. Similarly, increased risk of T2D among offspring could be explained by T2D susceptibility genes shared between the mother and her offspring. Epigenetic mechanisms may explain the link between factors operating in fetal life and later risk of developing T2D, but so far convincing evidence is lacking for epigenetic changes as a prime and direct cause of T2D. This review addresses recent literature on the early origins of adult disease hypothesis, with a special emphasis on the role of genetic compared with nongenetic and epigenetic risk determinants and disease mechanisms. PMID:25179736

Vaag, Allan; Brøns, Charlotte; Gillberg, Linn; Hansen, Ninna S; Hjort, Line; Arora, Geeti P; Thomas, Nihal; Broholm, Christa; Ribel-Madsen, Rasmus; Grunnet, Louise G

2014-11-01

325

Genetic diversity in natural populations of Jacaranda decurrens Cham. determined using RAPD and AFLP markers  

PubMed Central

Jacaranda decurrens (Bignoniaceae) is an endemic species of the Cerrado with validated antitumoral activity. The genetic diversity of six populations of J. decurrens located in the State of São Paulo was determined in this study by using molecular markers for randomly amplified polymorphic DNA (RAPD) and amplified fragment length polymorphism (AFLP). Following optimization of the amplification reaction, 10 selected primers generated 78 reproducible RAPD fragments that were mostly (69.2%) polymorphic. Two hundred and five reproducible AFLP fragments were generated by using four selected primer combinations; 46.3% of these fragments were polymorphic, indicating a considerable level of genetic diversity. Analysis of molecular variance (AMOVA) using these two groups of markers indicated that variability was strongly structured amongst populations. The unweighted pair group method with arithmatic mean (UPGMA) and Pearson's correlation coefficient (RAPD -0.16, p = 0.2082; AFLP 0.37, p = 0.1006) between genetic matrices and geographic distances suggested that the population structure followed an island model in which a single population of infinite size gave rise to the current populations of J. decurrens, independently of their spatial position. The results of this study indicate that RAPD and AFLP markers were similarly efficient in measuring the genetic variability amongst natural populations of J. decurrens. These data may be useful for developing strategies for the preservation of this medicinal species in the Cerrado. PMID:21637428

2010-01-01

326

Genetic determinants of pediatric HIV-1 infection: vertical transmission and disease progression among children.  

PubMed Central

It is very likely that perinatal human immunodeficiency virus type 1 (HIV-1) infection is influenced by a combination of virologic and host factors. A greater understanding of the role played by various risk factors for HIV-1 infection is crucial for the design of new preventive and therapeutic strategies. In recent years, a number of studies have suggested that host genetic factors are important determinants of both the susceptibility to perinatal HIV-1 infection and the subsequent pathogenesis of acquired immunodeficiency syndrome (AIDS). Control of HIV-1 infection involves the processing of specific viral peptides and their presentation to cells of the immune system by highly polymorphic human leukocyte antigen (HLA) alleles. The contribution of multiple HLA class I and II alleles in modulating pediatric HIV/AIDS outcomes has now been confirmed by several independent groups. Penetration of HIV-1 into cells is mediated by interaction between CD4 and chemokine receptors that serve as entry coreceptors. Genetic polymorphisms in chemokine ligand and chemokine receptor genes have recently been associated both with mother-to-child HIV-1 transmission and disease progression in children. These observations suggest a key role for genetic factors in pediatric HIV-1 infection. This article describes the current state of knowledge regarding host genetic influences on pediatric HIV-1 infection and discusses the role of these genes in HIV/AIDS pathogenesis. PMID:11778647

Matt, C.; Roger, M.

2001-01-01

327

Genetic determinants of pediatric HIV-1 infection: vertical transmission and disease progression among children.  

PubMed

It is very likely that perinatal human immunodeficiency virus type 1 (HIV-1) infection is influenced by a combination of virologic and host factors. A greater understanding of the role played by various risk factors for HIV-1 infection is crucial for the design of new preventive and therapeutic strategies. In recent years, a number of studies have suggested that host genetic factors are important determinants of both the susceptibility to perinatal HIV-1 infection and the subsequent pathogenesis of acquired immunodeficiency syndrome (AIDS). Control of HIV-1 infection involves the processing of specific viral peptides and their presentation to cells of the immune system by highly polymorphic human leukocyte antigen (HLA) alleles. The contribution of multiple HLA class I and II alleles in modulating pediatric HIV/AIDS outcomes has now been confirmed by several independent groups. Penetration of HIV-1 into cells is mediated by interaction between CD4 and chemokine receptors that serve as entry coreceptors. Genetic polymorphisms in chemokine ligand and chemokine receptor genes have recently been associated both with mother-to-child HIV-1 transmission and disease progression in children. These observations suggest a key role for genetic factors in pediatric HIV-1 infection. This article describes the current state of knowledge regarding host genetic influences on pediatric HIV-1 infection and discusses the role of these genes in HIV/AIDS pathogenesis. PMID:11778647

Matt, C; Roger, M

2001-09-01

328

Determinants of Success in National Programs to Eliminate Lymphatic Filariasis: A Perspective Identifying Essential Elements and Research Needs  

Microsoft Academic Search

The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000. To understand why some national programs have been more successful than others, a panel of individuals with expertise in LF elimination efforts met to assess available data from programs in 8 countries. The goal was to identify: 1) the factors determining success for national LF elimination programs (defined

Dominique Kyelem; Gautam Biswas; Moses J. Bockarie; Mark H. Bradley; Maged El-Setouhy; Peter U. Fischer; Ralph H. Henderson; James W. Kazura; Patrick J. Lammie; Sammy M. Njenga; Eric A. Ottesen; Kapa D. Ramaiah; Frank O. Richards; Gary J. Weil; Steven A. Williams

329

The Birds and the Bees and the Flowers and the Trees: Lessons from Genetic Mapping of Sex Determination in Plants and Animals  

PubMed Central

The ability to identify genetic markers in nonmodel systems has allowed geneticists to construct linkage maps for a diversity of species, and the sex-determining locus is often among the first to be mapped. Sex determination is an important area of study in developmental and evolutionary biology, as well as ecology. Its importance for organisms might suggest that sex determination is highly conserved. However, genetic studies have shown that sex determination mechanisms, and the genes involved, are surprisingly labile. We review studies using genetic mapping and phylogenetic inferences, which can help reveal evolutionary pattern within this lability and potentially identify the changes that have occurred among different sex determination systems. We define some of the terminology, particularly where confusion arises in writing about such a diverse range of organisms, and highlight some major differences between plants and animals, and some important similarities. We stress the importance of studying taxa suitable for testing hypotheses, and the need for phylogenetic studies directed to taxa where the patterns of changes can be most reliably inferred, if the ultimate goal of testing hypotheses regarding the selective forces that have led to changes in such an essential trait is to become feasible. PMID:20855574

Charlesworth, Deborah; Mank, Judith E.

2010-01-01

330

Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.  

PubMed

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2 × 10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. PMID:24520335

Okada, Yukinori; Diogo, Dorothee; Greenberg, Jeffrey D; Mouassess, Faten; Achkar, Walid A L; Fulton, Robert S; Denny, Joshua C; Gupta, Namrata; Mirel, Daniel; Gabriel, Stacy; Li, Gang; Kremer, Joel M; Pappas, Dimitrios A; Carroll, Robert J; Eyler, Anne E; Trynka, Gosia; Stahl, Eli A; Cui, Jing; Saxena, Richa; Coenen, Marieke J H; Guchelaar, Henk-Jan; Huizinga, Tom W J; Dieudé, Philippe; Mariette, Xavier; Barton, Anne; Canhão, Helena; Fonseca, João E; de Vries, Niek; Tak, Paul P; Moreland, Larry W; Bridges, S Louis; Miceli-Richard, Corinne; Choi, Hyon K; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Raj, Towfique; De Jager, Philip L; Raychaudhuri, Soumya; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Siminovitch, Katherine A; Gregersen, Peter K; Mardis, Elaine R; Arayssi, Thurayya; Kazkaz, Layla A; Plenge, Robert M

2014-01-01

331

genetics  

NSDL National Science Digital Library

learning about our genetic make up We've been learning about DNA. Go to each web site, read and follow the instructions of the activities provided. On a piece of paper write your answers to the following questions and submit your work. Put the site for each of the questions you are answering. The first site is, ...

Curran, Carolyn

2011-12-05

332

Direct calorimetry identifies deficiencies in respirometry for the determination of resting metabolic rate in C57Bl/6 and FVB mice.  

PubMed

Substantial research efforts have been aimed at identifying novel targets to increase resting metabolic rate (RMR) as an adjunct approach to the treatment of obesity. Respirometry (one form of "indirect calorimetry") is unquestionably the dominant technique used in the obesity research field to assess RMR in vivo, although this method relies upon a lengthy list of assumptions that are likely to be violated in pharmacologically or genetically manipulated animals. A "total" calorimeter, including a gradient layer direct calorimeter coupled to a conventional respirometer, was used to test the accuracy of respirometric-based estimations of RMR in laboratory mice (Mus musculus Linnaeus) of the C57Bl/6 and FVB background strains. Using this combined calorimeter, we determined that respirometry underestimates RMR of untreated 9- to 12-wk-old male mice by ?10-12%. Quantitative and qualitative differences resulted between methods for untreated C57Bl/6 and FVB mice, C57Bl/6 mice treated with ketamine-xylazine anesthesia, and FVB mice with genetic deletion of the angiotensin II type 2 receptor. We conclude that respirometric methods underestimate RMR in mice in a magnitude that is similar to or greater than the desired RMR effects of novel therapeutics. Sole reliance upon respirometry to assess RMR in mice may lead to false quantitative and qualitative conclusions regarding the effects of novel interventions. Increased use of direct calorimetry for the assessment of RMR and confirmation of respirometry results and the reexamination of previously discarded potential obesity therapeutics are warranted. PMID:23964071

Burnett, Colin M L; Grobe, Justin L

2013-10-01

333

Direct calorimetry identifies deficiencies in respirometry for the determination of resting metabolic rate in C57Bl/6 and FVB mice  

PubMed Central

Substantial research efforts have been aimed at identifying novel targets to increase resting metabolic rate (RMR) as an adjunct approach to the treatment of obesity. Respirometry (one form of “indirect calorimetry”) is unquestionably the dominant technique used in the obesity research field to assess RMR in vivo, although this method relies upon a lengthy list of assumptions that are likely to be violated in pharmacologically or genetically manipulated animals. A “total” calorimeter, including a gradient layer direct calorimeter coupled to a conventional respirometer, was used to test the accuracy of respirometric-based estimations of RMR in laboratory mice (Mus musculus Linnaeus) of the C57Bl/6 and FVB background strains. Using this combined calorimeter, we determined that respirometry underestimates RMR of untreated 9- to 12-wk-old male mice by ?10–12%. Quantitative and qualitative differences resulted between methods for untreated C57Bl/6 and FVB mice, C57Bl/6 mice treated with ketamine-xylazine anesthesia, and FVB mice with genetic deletion of the angiotensin II type 2 receptor. We conclude that respirometric methods underestimate RMR in mice in a magnitude that is similar to or greater than the desired RMR effects of novel therapeutics. Sole reliance upon respirometry to assess RMR in mice may lead to false quantitative and qualitative conclusions regarding the effects of novel interventions. Increased use of direct calorimetry for the assessment of RMR and confirmation of respirometry results and the reexamination of previously discarded potential obesity therapeutics are warranted. PMID:23964071

Burnett, Colin M. L.

2013-01-01

334

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance  

PubMed Central

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction, but contributed little to our understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways may be uncovered by accounting for differences in body mass index (BMI) and potential interaction between BMI and genetic variants. We applied a novel joint meta-analytical approach to test associations with fasting insulin (FI) and glucose (FG) on a genome-wide scale. We present six previously unknown FI loci at P<5×10?8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496non-diabetic individuals. Risk variants were associated with higher triglyceride and lower HDL cholesterol levels, suggestive of a role for these FI loci in insulin resistance pathways. The localization of these additional loci will aid further characterization of the role of insulin resistance in T2D pathophysiology. PMID:22581228

Manning, Alisa K.; Hivert, Marie-France; Scott, Robert A.; Grimsby, Jonna L.; Bouatia-Naji, Nabila; Chen, Han; Rybin, Denis; Liu, Ching-Ti; Bielak, Lawrence F.; Prokopenko, Inga; Amin, Najaf; Barnes, Daniel; Cadby, Gemma; Hottenga, Jouke-Jan; Ingelsson, Erik; Jackson, Anne U.; Johnson, Toby; Kanoni, Stavroula; Ladenvall, Claes; Lagou, Vasiliki; Lahti, Jari; Lecoeur, Cecile; Liu, Yongmei; Martinez-Larrad, Maria Teresa; Montasser, May E.; Navarro, Pau; Perry, John R. B.; Rasmussen-Torvik, Laura J.; Salo, Perttu; Sattar, Naveed; Shungin, Dmitry; Strawbridge, Rona J.; Tanaka, Toshiko; van Duijn, Cornelia M.; An, Ping; de Andrade, Mariza; Andrews, Jeanette S.; Aspelund, Thor; Atalay, Mustafa; Aulchenko, Yurii; Balkau, Beverley; Bandinelli, Stefania; Beckmann, Jacques S.; Beilby, John P.; Bellis, Claire; Bergman, Richard N.; Blangero, John; Boban, Mladen; Boehnke, Michael; Boerwinkle, Eric; Bonnycastle, Lori L.; Boomsma, Dorret I.; Borecki, Ingrid B.; Bottcher, Yvonne; Bouchard, Claude; Brunner, Eric; Budimir, Danijela; Campbell, Harry; Carlson, Olga; Chines, Peter S.; Clarke, Robert; Collins, Francis S.; Corbaton-Anchuelo, Arturo; Couper, David; de Faire, Ulf; Dedoussis, George V; Deloukas, Panos; Dimitriou, Maria; Egan, Josephine M; Eiriksdottir, Gudny; Erdos, Michael R.; Eriksson, Johan G.; Eury, Elodie; Ferrucci, Luigi; Ford, Ian; Forouhi, Nita G.; Fox, Caroline S; Franzosi, Maria Grazia; Franks, Paul W; Frayling, Timothy M; Froguel, Philippe; Galan, Pilar; de Geus, Eco; Gigante, Bruna; Glazer, Nicole L.; Goel, Anuj; Groop, Leif; Gudnason, Vilmundur; Hallmans, Goran; Hamsten, Anders; Hansson, Ola; Harris, Tamara B.; Hayward, Caroline; Heath, Simon; Hercberg, Serge; Hicks, Andrew A.; Hingorani, Aroon; Hofman, Albert; Hui, Jennie; Hung, Joseph; Jarvelin, Marjo Riitta; Jhun, Min A.; Johnson, Paul C.D.; Jukema, J Wouter; Jula, Antti; Kao, W.H.; Kaprio, Jaakko; Kardia, Sharon L. R.; Keinanen-Kiukaanniemi, Sirkka; Kivimaki, Mika; Kolcic, Ivana; Kovacs, Peter; Kumari, Meena; Kuusisto, Johanna; Kyvik, Kirsten Ohm; Laakso, Markku; Lakka, Timo; Lannfelt, Lars; Lathrop, G Mark; Launer, Lenore J.; Leander, Karin; Li, Guo; Lind, Lars; Lindstrom, Jaana; Lobbens, Stephane; Loos, Ruth J. F.; Luan, Jian'an; Lyssenko, Valeriya; Magi, Reedik; Magnusson, Patrik K. E.; Marmot, Michael; Meneton, Pierre; Mohlke, Karen L.; Mooser, Vincent; Morken, Mario A.; Miljkovic, Iva; Narisu, Narisu; O'Connell, Jeff; Ong, Ken K.; Oostra, Ben A.; Palmer, Lyle J.; Palotie, Aarno; Pankow, James S.; Peden, John F.; Pedersen, Nancy L.; Pehlic, Marina; Peltonen, Leena; Penninx, Brenda; Pericic, Marijana; Perola, Markus; Perusse, Louis; Peyser, Patricia A; Polasek, Ozren; Pramstaller, Peter P.; Province, Michael A.; Raikkonen, Katri; Rauramaa, Rainer; Rehnberg, Emil; Rice, Ken; Rotter, Jerome I.; Rudan, Igor; Ruokonen, Aimo; Saaristo, Timo; Sabater-Lleal, Maria; Salomaa, Veikko; Savage, David B.; Saxena, Richa; Schwarz, Peter; Seedorf, Udo; Sennblad, Bengt; Serrano-Rios, Manuel; Shuldiner, Alan R.; Sijbrands, Eric J.G.; Siscovick, David S.; Smit, Johannes H.; Small, Kerrin S.; Smith, Nicholas L.; Smith, Albert Vernon; Stancakova, Alena; Stirrups, Kathleen; Stumvoll, Michael; Sun, Yan V.; Swift, Amy J.; Tonjes, Anke; Tuomilehto, Jaakko; Trompet, Stella; Uitterlinden, Andre G.; Uusitupa, Matti; Vikstrom, Max; Vitart, Veronique; Vohl, Marie-Claude; Voight, Benjamin F.; Vollenweider, Peter; Waeber, Gerard; Waterworth, Dawn M; Watkins, Hugh; Wheeler, Eleanor; Widen, Elisabeth; Wild, Sarah H.; Willems, Sara M.; Willemsen, Gonneke; Wilson, James F.; Witteman, Jacqueline C.M.; Wright, Alan F.; Yaghootkar, Hanieh; Zelenika, Diana; Zemunik, Tatijana; Zgaga, Lina; Wareham, Nicholas J.; McCarthy, Mark I.; Barroso, Ines; Watanabe, Richard M.; Florez, Jose C.; Dupuis, Josee; Meigs, James B.; Langenberg, Claudia

2013-01-01

335

3D finite compartment modeling of formation and healing of bruises may identify methods for age determination of bruises  

PubMed Central

Simulating the spatial and temporal behavior of bruises may identify methods that allow accurate age determination of bruises to assess child abuse. We developed a numerical 3D model to simulate the spatial kinetics of hemoglobin and bilirubin during the formation and healing of bruises. Using this model, we studied how skin thickness, bruise diameter and diffusivities affect the formation and healing of circular symmetric bruises and compared a simulated bruise with a natural inhomogeneous bruise. Healing is faster for smaller bruises in thinner and less dense skin. The simulated and natural bruises showed similar spatial and temporal dynamics. The different spatio-temporal dynamics of hemoglobin and bilirubin allows age determination of model bruises. Combining our model predictions with individual natural bruises may allow optimizing our model parameters. It may particularly identify methods for more accurate age determination than currently possible to aid the assessment of child abuse. PMID:20556661

van Gemert, Martin J. C.; van Leeuwen, Ton G.; Aalders, Maurice C. G.

2010-01-01

336

Use of diverse electronic medical record systems to identify genetic risk for type 2 diabetes within a genome-wide association study  

PubMed Central

Objective Genome-wide association studies (GWAS) require high specificity and large numbers of subjects to identify genotype–phenotype correlations accurately. The aim of this study was to identify type 2 diabetes (T2D) cases and controls for a GWAS, using data captured through routine clinical care across five institutions using different electronic medical record (EMR) systems. Materials and Methods An algorithm was developed to identify T2D cases and controls based on a combination of diagnoses, medications, and laboratory results. The performance of the algorithm was validated at three of the five participating institutions compared against clinician review. A GWAS was subsequently performed using cases and controls identified by the algorithm, with samples pooled across all five institutions. Results The algorithm achieved 98% and 100% positive predictive values for the identification of diabetic cases and controls, respectively, as compared against clinician review. By standardizing and applying the algorithm across institutions, 3353 cases and 3352 controls were identified. Subsequent GWAS using data from five institutions replicated the TCF7L2 gene variant (rs7903146) previously associated with T2D. Discussion By applying stringent criteria to EMR data collected through routine clinical care, cases and controls for a GWAS were identified that subsequently replicated a known genetic variant. The use of standard terminologies to define data elements enabled pooling of subjects and data across five different institutions to achieve the robust numbers required for GWAS. Conclusions An algorithm using commonly available data from five different EMR can accurately identify T2D cases and controls for genetic study across multiple institutions. PMID:22101970

Hayes, M Geoffrey; Rasmussen-Torvik, Laura; Pacheco, Jennifer A; Thompson, William K; Armstrong, Loren L; Denny, Joshua C; Peissig, Peggy L; Miller, Aaron W; Wei, Wei-Qi; Bielinski, Suzette J; Chute, Christopher G; Leibson, Cynthia L; Jarvik, Gail P; Crosslin, David R; Carlson, Christopher S; Newton, Katherine M; Wolf, Wendy A; Chisholm, Rex L; Lowe, William L

2011-01-01

337

Visual Tuning Properties of Genetically Identified Layer 2/3 Neuronal Types in the Primary Visual Cortex of Cre-Transgenic Mice  

PubMed Central

The putative excitatory and inhibitory cell classes within the mouse primary visual cortex V1 have different functional properties as studied using recording microelectrode. Excitatory neurons show high selectivity for the orientation angle of moving gratings while the putative inhibitory neurons show poor selectivity. However, the study of selectivity of the genetically identified interneurons and their subtypes remain controversial. Here we use novel Cre-driver and reporter mice to identify genetic subpopulations in vivo for two-photon calcium dye imaging: Wfs1(+)/Gad1(?) mice that labels layer 2/3 excitatory cell population and Pvalb(+)/Gad1(+) mice that labels a genetic subpopulation of inhibitory neurons. The cells in both mice were identically labeled with a tdTomato protein, visible in vivo, using a Cre-reporter line. We found that the Wfs1(+) cells exhibited visual tuning properties comparable to the excitatory population, i.e., high selectivity and tuning to the angle, direction, and spatial frequency of oriented moving gratings. The functional tuning of Pvalb(+) neurons was consistent with previously reported narrow-spiking interneurons in microelectrode studies, exhibiting poorer selectivity than the excitatory neurons. This study demonstrates the utility of Cre-transgenic mouse technology in selective targeting of subpopulations of neurons and makes them amenable to structural, functional, and connectivity studies. PMID:21283555

Zariwala, Hatim A.; Madisen, Linda; Ahrens, Kurt F.; Bernard, Amy; Lein, Edward S.; Jones, Allan R.; Zeng, Hongkui

2011-01-01

338

Genetic architecture of sex determination in fish: applications to sex ratio control in aquaculture  

PubMed Central

Controlling the sex ratio is essential in finfish farming. A balanced sex ratio is usually good for broodstock management, since it enables to develop appropriate breeding schemes. However, in some species the production of monosex populations is desirable because the existence of sexual dimorphism, primarily in growth or first time of sexual maturation, but also in color or shape, can render one sex more valuable. The knowledge of the genetic architecture of sex determination (SD) is convenient for controlling sex ratio and for the implementation of breeding programs. Unlike mammals and birds, which show highly conserved master genes that control a conserved genetic network responsible for gonad differentiation (GD), a huge diversity of SD mechanisms has been reported in fish. Despite theory predictions, more than one gene is in many cases involved in fish SD and genetic differences have been observed in the GD network. Environmental factors also play a relevant role and epigenetic mechanisms are becoming increasingly recognized for the establishment and maintenance of the GD pathways. Although major genetic factors are frequently involved in fish SD, these observations strongly suggest that SD in this group resembles a complex trait. Accordingly, the application of quantitative genetics combined with genomic tools is desirable to address its study and in fact, when applied, it has frequently demonstrated a multigene trait interacting with environmental factors in model and cultured fish species. This scenario has notable implications for aquaculture and, depending upon the species, from chromosome manipulation or environmental control techniques up to classical selection or marker assisted selection programs, are being applied. In this review, we selected four relevant species or fish groups to illustrate this diversity and hence the technologies that can be used by the industry for the control of sex ratio: turbot and European sea bass, two reference species of the European aquaculture, and salmonids and tilapia, representing the fish for which there are well established breeding programs.

Martinez, Paulino; Vinas, Ana M.; Sanchez, Laura; Diaz, Noelia; Ribas, Laia; Piferrer, Francesc

2014-01-01

339

Genetic architecture of sex determination in fish: applications to sex ratio control in aquaculture.  

PubMed

Controlling the sex ratio is essential in finfish farming. A balanced sex ratio is usually good for broodstock management, since it enables to develop appropriate breeding schemes. However, in some species the production of monosex populations is desirable because the existence of sexual dimorphism, primarily in growth or first time of sexual maturation, but also in color or shape, can render one sex more valuable. The knowledge of the genetic architecture of sex determination (SD) is convenient for controlling sex ratio and for the implementation of breeding programs. Unlike mammals and birds, which show highly conserved master genes that control a conserved genetic network responsible for gonad differentiation (GD), a huge diversity of SD mechanisms has been reported in fish. Despite theory predictions, more than one gene is in many cases involved in fish SD and genetic differences have been observed in the GD network. Environmental factors also play a relevant role and epigenetic mechanisms are becoming increasingly recognized for the establishment and maintenance of the GD pathways. Although major genetic factors are frequently involved in fish SD, these observations strongly suggest that SD in this group resembles a complex trait. Accordingly, the application of quantitative genetics combined with genomic tools is desirable to address its study and in fact, when applied, it has frequently demonstrated a multigene trait interacting with environmental factors in model and cultured fish species. This scenario has notable implications for aquaculture and, depending upon the species, from chromosome manipulation or environmental control techniques up to classical selection or marker assisted selection programs, are being applied. In this review, we selected four relevant species or fish groups to illustrate this diversity and hence the technologies that can be used by the industry for the control of sex ratio: turbot and European sea bass, two reference species of the European aquaculture, and salmonids and tilapia, representing the fish for which there are well established breeding programs. PMID:25324858

Martínez, Paulino; Viñas, Ana M; Sánchez, Laura; Díaz, Noelia; Ribas, Laia; Piferrer, Francesc

2014-01-01

340

A multiplexed immunofluorescence method identifies Phakopsora pachyrhizi Urediniospores and determines their viability.  

PubMed

Soybean rust, caused by Phakopsora pachyrhizi, occurs concomitantly wherever soybean is grown in the tropical and subtropical regions of the world. After reports of its first occurrence in Brazil in 2001 and the continental United States in 2004, research on the disease and its pathogen has greatly increased. One area of research has focused on capturing urediniospores, primarily by rain collection or wind traps, and detecting them either by microscopic observations or by immunological or molecular techniques. This system of detection has been touted for use as a potential warning system to recommend early applications of fungicides. One shortcoming of the method has been an inability to determine whether the spores are viable. Our study developed a method to detect viable P. pachyrhizi urediniospores using an immunofluorescence assay combined with propidium iodide (PI) staining. Antibodies reacted to P. pachyrhizi and other Phakopsora spp. but did not react with other common soybean pathogens or most other rust fungi tested, based on an indirect immunofluorescence assay using fluorescein isothiocyanate-labeled secondary antibodies. Two vital staining techniques were used to assess viability of P. pachyrhizi urediniospores: one combined carboxy fluorescein diacetate (CFDA) and PI, and the other utilized (2-chloro-4-[2,3-dihydro-3-methyl-(benzo-1,3-thiazol-2-yl)-methylidene]-1-phenylquinolinium iodide] (FUN 1). Using the CFDA-PI method, viable spores stained green with CFDA and nonviable spores counterstained red with PI. Using the FUN 1 method, cylindrical intravacuolar structures were induced to form within metabolically active urediniospores, causing them to fluoresce bright red to reddish-orange, whereas dead spores, with no metabolic activity, had an extremely diffused, faint fluorescence. An immunofluorescence technique in combination with PI counterstaining was developed to specifically detect viable P. pachyrhizi urediniospores. The method is rapid and reliable, with a potential for application in forecasting soybean rust based on the detection of viable urediniospores. PMID:22894915

Vittal, R; Haudenshield, J S; Hartman, G L

2012-12-01

341

Population stochasticity, random determination of handedness, and the genetic basis of antisymmetry.  

PubMed

Conspicuous lateral asymmetries of organisms are classified into two major categories: antisymmetry (AS), characterized by almost equal frequencies of dextral and sinistral morphs, and directional asymmetry (DA), in which one morph dominates. I compared and characterized two types of genes, both with existing examples, in their roles in the evolutionary transitions between AS and DA for the first time. Handedness genes (HGs) determine the chirality in a strict sense, while randomization genes (RGs) randomize the chirality. A theory predicts that, in an AS population maintained by HGs under negative frequency-dependent selection, RGs harness fluctuation of the morph frequencies as their driving force and thus increase their frequency until half of the population flips the phenotype. These predictions were confirmed by simulations. Consequently, RGs mask the genetic effects of HGs, which provides a possible explanation for the apparent lack of a genetic basis for AS in empirical AS studies. PMID:21888921

Kamimura, Yoshitaka

2011-12-01

342

Determining the causes and consequences of nicotine dependence: emerging genetic research methods.  

PubMed

Tobacco use remains the leading cause of preventable death worldwide. Establishing the genetic aetiology of tobacco use and dependence is an important first step in understanding the neurobiological mechanisms of tobacco use, and in turn the development of effective treatments. In addition, whilst the effects of tobacco use on a broad range of physical illnesses (e.g. lung cancer, respiratory disease, cardiovascular disease) are now well-established, the causal effects of tobacco use on a number of other outcomes remains to be established. Determining the causes and consequences of tobacco use therefore continues to be both a scientific and a public health priority. Here we review emerging methods in genetic research that allow stronger causal inferences to be drawn from observational data. PMID:25135777

Ware, Jennifer J; Munafò, Marcus R

2014-10-01

343

Combination of pharmacophore hypothesis, genetic function approximation model, and molecular docking to identify novel inhibitors of S6K1.  

PubMed

S6K1 has emerged as a potential target for the treatment for obesity, type II diabetes and cancer diseases. Discovery of S6K1 inhibitors has thus attracted much attention in recent years. In this investigation, a hybrid virtual screening method that involves pharmacophore hypothesis, genetic function approximation (GFA) model, and molecular docking technology has been used to discover S6K1 inhibitors especially with novel scaffolds. The common feature pharmacophore hypothesis and GFA regression model of S6K1 inhibitors were first developed and applied in a virtual screen of the Specs database for retrieving S6K1 inhibitors. Then, the molecular docking method was carried out to re-filter these screened compounds. Finally, 60 compounds with promising S6K1 inhibitory activity were carefully selected and have been handed over to the other group to complete the follow-up compound synthesis (or purchase) and activity test. PMID:23982212

Zhang, Hui; Xiang, Ming-Li; Liang, Jun-Yu; Zeng, Tao; Zhang, Xiao-Nuo; Zhang, Ji; Yang, Sheng-Yong

2013-11-01

344

Am. J. Hum. Genet. 76:934949, 2005 Joint Modeling of Linkage and Association: Identifying SNPs Responsible  

E-print Network

unaffected family members. Introduction Positional cloning is widely used for identification of genes involved in human diseases. To date, hundreds of disease genes have been identified solely on the basis. 2002). The first step in a traditional positional-cloning approach involves a genomewide linkage

Abecasis, Goncalo

345

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

E-print Network

Identify HLA-G as an Asthma Susceptibility Gene on Chromosome 6p21 Dan Nicolae,1 Nancy J. Cox,2,3 Lucille A and Departments of 8 Pediatrics and 9 Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; 10

Das, Soma

346

Identifying significant genetic regulatory networks in the prostate cancer from microarray data based on transcription factor analysis and conditional independency  

Microsoft Academic Search

BACKGROUND: Prostate cancer is a world wide leading cancer and it is characterized by its aggressive metastasis. According to the clinical heterogeneity, prostate cancer displays different stages and grades related to the aggressive metastasis disease. Although numerous studies used microarray analysis and traditional clustering method to identify the individual genes during the disease processes, the important gene regulations remain unclear.

Hsiang-Yuan Yeh; Shih-Wu Cheng; Yu-Chun Lin; Cheng-Yu Yeh; Shih-Fang Lin; Von-Wun Soo

2009-01-01

347

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

E-print Network

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...

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

2014-05-04

348

Infection, Genetics and Evolution 3 (2003) 271279 The use of specific and generic primers to identify trypanosome  

E-print Network

to identify trypanosome infections of wild tsetse flies in Tanzania by PCR Imna Malelea,b, Lisa Craskec with the fly's saliva when it bites. Tsetse also trans- mit some trypanosome species in their faeces, Wendy Gibsonc, a Tsetse & Trypanosomiasis Research Institute, P.O. Box 1026, Tanga, Tanzania b School

Tyler, Charles

349

Full Genome Sequencing and Genetic Characterization of Eubenangee Viruses Identify Pata Virus as a Distinct Species within the Genus Orbivirus  

Microsoft Academic Search

Eubenangee virus has previously been identified as the cause of Tammar sudden death syndrome (TSDS). Eubenangee virus (EUBV), Tilligery virus (TILV), Pata virus (PATAV) and Ngoupe virus (NGOV) are currently all classified within the Eubenangee virus species of the genus Orbivirus, family Reoviridae. Full genome sequencing confirmed that EUBV and TILV (both of which are from Australia) show high levels

Manjunatha N. Belaganahalli; Sushila Maan; Narender S. Maan; Kyriaki Nomikou; Ian Pritchard; Ross Lunt; Peter D. Kirkland; Houssam Attoui; Joe Brownlie; Peter P. C. Mertens

2012-01-01

350

Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors  

PubMed Central

The spindle checkpoint is essential to ensure proper chromosome segregation and thereby maintain genomic stability. Mitotic arrest deficiency 2 (Mad2), a critical component of the spindle checkpoint, is overexpressed in many cancer cells. Thus, we hypothesized that Mad2 overexpression could specifically make cancer cells susceptible to death by inducing a synthetic dosage lethality defect. Because the spindle checkpoint pathway is highly conserved between yeast and humans, we performed a synthetic genetic array analysis in yeast, which revealed that Mad2 overexpression induced lethality in 13 gene deletions. Among the human homologs of candidate genes, knockdown of PPP2R1A, a gene encoding a constant regulatory subunit of protein phosphatase 2, significantly inhibited the growth of Mad2-overexpressing tumor cells. PPP2R1A inhibition induced Mad2 phosphorylation and suppressed Mad2 protein levels. Depletion of PPP2R1A inhibited colony formation of Mad2-overexpressing HeLa cells but not of unphosphorylated Mad2 mutant-overexpressing cells, suggesting that the lethality induced by PP2A depletion in Mad2-overexpressing cells is dependent on Mad2 phosphorylation. Also, the PP2A inhibitor cantharidin induced Mad2 phosphorylation and inhibited the growth of Mad2-overexpressing cancer cells. Aurora B knockdown inhibited Mad2 phosphorylation in mitosis, resulting in the blocking of PPP2R1A inhibition–induced cell death. Taken together, our results strongly suggest that PP2A is a good therapeutic target in Mad2-overexpressing tumors. PMID:24425774

Bian, Yang; Kitagawa, Risa; Bansal, Parmil K.; Fujii, Yo; Stepanov, Alexander; Kitagawa, Katsumi

2014-01-01

351

Identifying clusters as low-lying mimina--efficiency of stochastic and genetic algorithms using inexpensive electronic structure levels.  

PubMed

Molecular candidates possessing unconventional chemical bonding paradigms (e.g., boron wheels, molecular stars, and multicenter bonding) have attracted a great deal of attention by the computational community. The viability of such systems is necessarily assessed through the identification of the lowest lying energy forms of a given chemical composition on the potential energy surface (PES). Although dozens of search algorithms have been developed, only a few are general and simple enough to become standard everyday procedures for this purpose. The simple random search and genetic algorithm (GA) are among these: but how do these approaches perform on typical isomeric searches? The performance of three specific variants for the ab initio exploration of the PES of prototype planar tetracoordinated and hypercoordinated carbon-containing systems C(2) Al(4) and CB(6) (2-) are compared. The advantages of preoptimizing with a low-cost semiempirical method (e.g., PM6) together with the most cost-efficient GA-based variant are discussed, and the trends verified by the isomer search of the larger Si(5) Li(7) (+) clusters. PMID:22162002

Avaltroni, Fabrice; Corminboeuf, Clemence

2012-02-15

352

Five cryptic species in the amazonian catfish Centromochlus existimatus identified based on biogeographic predictions and genetic data.  

PubMed

Accurately quantifying biodiversity is fundamental for both evolutionary theory and conservation strategies. DNA-based studies are exposing high cryptic diversity irrespective of taxonomic group or environmental setting, and increasing the ever-growing estimates of global biodiversity. This has severe implications for under-sampled and species-rich tropical regions, such as the Amazon Basin. We used biogeographic predictions derived from geomorphological history and contemporary hydrochemical and genetic data to examine cryptic diversity in the Amazonian driftwood catfish Centromochlus existimatus. Using both nuclear and mitochondrial DNA markers, five deeply divergent cryptic lineages are reported, for which at least three are sympatric in distribution. These lineages appear relatively old, with divergence times dating back to middle Miocene. Diversification events appear to be chronologically associated with the formation of the modern Amazon River system, and perhaps influenced by hydrochemical gradients between tributaries. The cause of apparent morphological stasis in the C. existimatus species complex is speculated within the context of hydrochemistry and non-visual mating cues and a full taxonomic revision is recommended. Our findings suggest that the diversity of Amazonian ichthyofauna is vastly underestimated and highlight the relevance of biogeographic predictions to guide sampling efforts in ecologically complex and under-studied ecosystems. PMID:23144977

Cooke, Georgina M; Chao, Ning L; Beheregaray, Luciano B

2012-01-01

353

Genetic analysis of the bone morphogenetic protein-related gene, gbb, identifies multiple requirements during Drosophila development.  

PubMed Central

We have isolated mutations in the Drosophila melanogaster gene glass bottom boat (gbb), which encodes a TGF-beta signaling molecule (formerly referred to as 60A) with highest sequence similarity to members of the bone morphogenetic protein (BMP) subgroup including vertebrate BMPs 5-8. Genetic analysis of both null and hypomorphic gbb alleles indicates that the gene is required in many developmental processes, including embryonic midgut morphogenesis, patterning of the larval cuticle, fat body morphology, and development and patterning of the imaginal discs. In the embryonic midgut, we show that gbb is required for the formation of the anterior constriction and for maintenance of the homeotic gene Antennapedia in the visceral mesoderm. In addition, we show a requirement for gbb in the anterior and posterior cells of the underlying endoderm and in the formation and extension of the gastric caecae. gbb is required in all the imaginal discs for proper disc growth and for specification of veins in the wing and of macrochaete in the notum. Significantly, some of these tissues have been shown to also require the Drosophila BMP2/4 homolog decapentaplegic (dpp), while others do not. These results indicate that signaling by both gbb and dpp may contribute to the development of some tissues, while in others, gbb may signal independently of dpp. PMID:10353905

Wharton, K A; Cook, J M; Torres-Schumann, S; de Castro, K; Borod, E; Phillips, D A

1999-01-01

354

Genetic Variation Is the Major Determinant of Individual Differences in Leukocyte Endothelial Adhesion  

PubMed Central

Objective To determine the genetic contribution to leukocyte endothelial adhesion. Methods Leukocyte endothelial adhesion was assessed through a novel cell-based assay using human lymphoblastoid cell lines. A high-throughput screening method was developed to evaluate the inter-individual variability in leukocyte endothelial adhesion using lymphoblastoid cell lines derived from different donors. To assess heritability, ninety-two lymphoblastoid cell lines derived from twenty-three monozygotic twin pairs and twenty-three sibling pairs were compared. These lymphoblastoid cell lines were plated with the endothelial cell line EA.hy926 and labeled with Calcein AM dye. Fluorescence was assessed to determine endothelial cell adhesion to each lymphoblastoid cell line. Intra-pair similarity was determined for monozygotic twins and siblings using Pearson pairwise correlation coefficients. Results A leukocyte endothelial adhesion assay for lymphoblastoid cell lines was developed and optimized (CV?=?8.68, Z?-factor?=?0.67, SNR?=?18.41). A higher adhesion correlation was found between the twins than that between the siblings. Intra-pair similarity for leukocyte endothelial adhesion in monozygotic twins was 0.60 compared to 0.25 in the siblings. The extent to which these differences are attributable to underlying genetic factors was quantified and the heritability of leukocyte endothelial adhesion was calculated to be 69.66% (p-value<0.0001). Conclusions There is a heritable component to leukocyte endothelial adhesion. Underlying genetic predisposition plays a significant role in inter-individual variability of leukocyte endothelial adhesion. PMID:24520339

Grassi, Michael A.; Rao, Vidhya; Winkler, Kathryn P.; Zhang, Wei; Bogaard, Joseph D.; Chen, Siquan; LaCroix, Bonnie; Lenkala, Divya; Rehman, Jalees; Malik, Asrar B.; Cox, Nancy J.; Huang, R. Stephanie

2014-01-01

355

Unique Regulatory Properties of Mesangial Cells Are Genetically Determined in the Rat  

PubMed Central

Mesangial cells are glomerular cells of stromal origin. During immune complex mediated crescentic glomerulonephritis (Crgn), infiltrating and proliferating pro-inflammatory macrophages lead to crescent formation. Here we have hypothesised that mesangial cells, given their mesenchymal stromal origin, show similar immunomodulatory properties as mesenchymal stem cells (MSCs), by regulating macrophage function associated with glomerular crescent formation. We show that rat mesangial cells suppress conA-stimulated splenocyte proliferation in vitro, as previously shown for MSCs. We then investigated mesangial cell-macrophage interaction by using mesangial cells isolated from nephrotoxic nephritis (NTN)-susceptible Wistar Kyoto (WKY) and NTN-resistant Lewis (LEW) rats. We first determined the mesangial cell transcriptome in WKY and LEW rats and showed that this is under marked genetic control. Supernatant transfer results show that WKY mesangial cells shift bone marrow derived macrophage (BMDM) phenotype to M1 or M2 according to the genetic background (WKY or LEW) of the BMDMs. Interestingly, these effects were different when compared to those of MSCs suggesting that mesangial cells can have unique immunomodulatory effects in the kidney. These results demonstrate the importance of the genetic background in the immunosuppressive effects of cells of stromal origin and specifically of mesangial cell-macrophage interactions in the pathophysiology of crescentic glomerulonephritis. PMID:25343449

Lai, Ping-Chin; Chiu, Ling-Yin; Srivastava, Prashant; Trento, Cristina; Dazzi, Francesco; Petretto, Enrico; Cook, H. Terence; Behmoaras, Jacques

2014-01-01

356

[Genetic singularity coefficients of common vetch Vicia sativa L. accessions determined with molecular markers].  

PubMed

Organization and practical application of ex situ collections require estimation of genetic differences between numerous accessions of local cultivars and field weed forms collected from the same ecological and geographical region and similar in their morphophysiological characteristics. A mathematical algorithm for estimating the degree of genetic singularity of a specimen in the system of local gene pool determined with the help of molecular markers is described. The utility of this algorithm is demonstrated by the example of classification of 677 common vetch accessions from the collection of the Vavilov Institute of Plant Industry from 11 ecological-geographic regions of Russia analyzed using AFLP. The proposed classification of accessions is the result of processing the AFLP data by weighting the marker traits based on their frequency in particular regions. This allowed each accession to be characterized according to the ratio of rare and frequent alleles as a genetic singularity coefficient. The proposed method is appropriate for any types of molecular markers. A practical result of its application is the classification of accessions using a five-point score scale, which can be added to descriptors of certificate databases and used for optimization of the work with collections. PMID:19137734

Potokina, E K; Aleksandrova, T G

2008-11-01

357

76 FR 37767 - Pioneer Hi-Bred International, Inc.; Determination of Nonregulated Status for Corn Genetically...  

Federal Register 2010, 2011, 2012, 2013

...DP-32138-1, which has been genetically engineered to produce...opposition to GE crops and genetically modified organisms but did not...the whole ecosystem; food and feed safety; and...introduction of certain genetically engineered...

2011-06-28

358

A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy  

PubMed Central

Candidate antibacterials are usually identified on the basis of their in vitro activity. However, the apparent inhibitory activity of new leads can be misleading because most culture media do not reproduce an environment relevant to infection in vivo. In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism can affect antimicrobial activity. Novel pyrimidine–imidazoles (PIs) were identified in a whole-cell screen against Mycobacterium tuberculosis. Lead optimization generated in vitro potent derivatives with desirable pharmacokinetic properties, yet without in vivo efficacy. Mechanism of action studies linked the PI activity to glycerol metabolism, which is not relevant for M. tuberculosis during infection. PIs induced self-poisoning of M. tuberculosis by promoting the accumulation of glycerol phosphate and rapid ATP depletion. This study underlines the importance of understanding central bacterial metabolism in vivo and of developing predictive in vitro culture conditions as a prerequisite for the rational discovery of new antibiotics. PMID:20975714

Pethe, Kevin; Sequeira, Patricia C.; Agarwalla, Sanjay; Rhee, Kyu; Kuhen, Kelli; Phong, Wai Yee; Patel, Viral; Beer, David; Walker, John R.; Duraiswamy, Jeyaraj; Jiricek, Jan; Keller, Thomas H.; Chatterjee, Arnab; Tan, Mai Ping; Ujjini, Manjunatha; Rao, Srinivasa P.S.; Camacho, Luis; Bifani, Pablo; Mak, Puiying A.; Ma, Ida; Barnes, S. Whitney; Chen, Zhong; Plouffe, David; Thayalan, Pamela; Ng, Seow Hwee; Au, Melvin; Lee, Boon Heng; Tan, Bee Huat; Ravindran, Sindhu; Nanjundappa, Mahesh; Lin, Xiuhua; Goh, Anne; Lakshminarayana, Suresh B.; Shoen, Carolyn; Cynamon, Michael; Kreiswirth, Barry; Dartois, Veronique; Peters, Eric C.; Glynne, Richard; Brenner, Sydney; Dick, Thomas

2010-01-01

359

Population genetics of sex determination in Mytilus mussels: reanalyses and a model.  

PubMed

Large variations in offspring sex ratio have been reported in Mytilus mussels, which show doubly uniparental inheritance of mitochondria (DUI). Here, we reanalyzed the published sex ratio data, using simple population genetics concepts and logistic regression. Contrary to previous studies that detected only maternal effects, we found both paternal and maternal effects on the offspring sex ratio. We propose that sex in Mytilus is controlled by a pair of nuclear sex ratio alleles expressed in the mother and by minor sex-determining genes inherited from the father and also possibly from the mother. PMID:23505313

Yusa, Yoichi; Breton, Sophie; Hoeh, Walter R

2013-01-01

360

The human language faculty: genetically determined? An approach to testable hypotheses.  

PubMed

A kind of generation gap seems to divide researchers interested in the evolutionary status of the human language capacity. There is still opposition to the theory of a genetically determined universal or primal grammar. But although not well acquainted with the transformational-generative linguistic methodology that led to the hypothesis, an increasing number of linguists base their work with a "new grammar" on the acceptance of innateness of the human language faculty. It is proposed that dyslexia offers a hypothesis testable with the new advanced gene mapping, and that Creole Languages and Sign Languages of the Deaf may come to offer possibilities of similarly testable hypotheses. PMID:8206785

Hansen, O

1994-01-01

361

Evaluation of SNP Data from the Malus Infinium Array Identifies Challenges for Genetic Analysis of Complex Genomes of Polyploid Origin  

PubMed Central

High throughput arrays for the simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) have made the rapid genetic characterisation of plant genomes and the development of saturated linkage maps a realistic prospect for many plant species of agronomic importance. However, the correct calling of SNP genotypes in divergent polyploid genomes using array technology can be problematic due to paralogy, and to divergence in probe sequences causing changes in probe binding efficiencies. An Illumina Infinium II whole-genome genotyping array was recently developed for the cultivated apple and used to develop a molecular linkage map for an apple rootstock progeny (M432), but a large proportion of segregating SNPs were not mapped in the progeny, due to unexpected genotype clustering patterns. To investigate the causes of this unexpected clustering we performed BLAST analysis of all probe sequences against the ‘Golden Delicious’ genome sequence and discovered evidence for paralogous annealing sites and probe sequence divergence for a high proportion of probes contained on the array. Following visual re-evaluation of the genotyping data generated for 8,788 SNPs for the M432 progeny using the array, we manually re-scored genotypes at 818 loci and mapped a further 797 markers to the M432 linkage map. The newly mapped markers included the majority of those that could not be mapped previously, as well as loci that were previously scored as monomorphic, but which segregated due to divergence leading to heterozygosity in probe annealing sites. An evaluation of the 8,788 probes in a diverse collection of Malus germplasm showed that more than half the probes returned genotype clustering patterns that were difficult or impossible to interpret reliably, highlighting implications for the use of the array in genome-wide association studies. PMID:23826289

Troggio, Michela; Surbanovski, Nada; Bianco, Luca; Moretto, Marco; Giongo, Lara; Banchi, Elisa; Viola, Roberto; Fernandez, Felicdad Fernandez; Costa, Fabrizio; Velasco, Riccardo; Cestaro, Alessandro; Sargent, Daniel James

2013-01-01

362

Genome-wide Association Study Identifies Genetic Variation in Neurocan as a Susceptibility Factor for Bipolar Disorder  

PubMed Central

We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10?8; odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10?4; odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10?9 (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies. PMID:21353194

Cichon, Sven; Muhleisen, Thomas W.; Degenhardt, Franziska A.; Mattheisen, Manuel; Miro, Xavier; Strohmaier, Jana; Steffens, Michael; Meesters, Christian; Herms, Stefan; Weingarten, Moritz; Priebe, Lutz; Haenisch, Britta; Alexander, Michael; Vollmer, Jennifer; Breuer, Rene; Schmal, Christine; Tessmann, Peter; Moebus, Susanne; Wichmann, H.-Erich; Schreiber, Stefan; Muller-Myhsok, Bertram; Lucae, Susanne; Jamain, Stephane; Leboyer, Marion; Bellivier, Frank; Etain, Bruno; Henry, Chantal; Kahn, Jean-Pierre; Heath, Simon; Hamshere, Marian; O'Donovan, Michael C.; Owen, Michael J.; Craddock, Nick; Schwarz, Markus; Vedder, Helmut; Kammerer-Ciernioch, Jutta; Reif, Andreas; Sasse, Johanna; Bauer, Michael; Hautzinger, Martin; Wright, Adam; Mitchell, Philip B.; Schofield, Peter R.; Montgomery, Grant W.; Medland, Sarah E.; Gordon, Scott D.; Martin, Nicholas G.; Gustafsson, Omar; Andreassen, Ole; Djurovic, Srdjan; Sigurdsson, Engilbert; Steinberg, Stacy; Stefansson, Hreinn; Stefansson, Kari; Kapur-Pojskic, Lejla; Oruc, Liliana; Rivas, Fabio; Mayoral, Fermin; Chuchalin, Alexander; Babadjanova, Gulja; Tiganov, Alexander S.; Pantelejeva, Galina; Abramova, Lilia I.; Grigoroiu-Serbanescu, Maria; Diaconu, Carmen C.; Czerski, Piotr M.; Hauser, Joanna; Zimmer, Andreas; Lathrop, Mark; Schulze, Thomas G.; Wienker, Thomas F.; Schumacher, Johannes; Maier, Wolfgang; Propping, Peter; Rietschel, Marcella; Nothen, Markus M.

2011-01-01

363

A Screen for Genetic Suppressor Elements of Hepatitis C Virus Identifies a Supercharged Protein Inhibitor of Viral Replication  

PubMed Central

Genetic suppressor elements (GSEs) are biomolecules derived from a gene or genome of interest that act as transdominant inhibitors of biological functions presumably by disruption of critical biological interfaces. We exploited a cell death reporter cell line for hepatitis C virus (HCV) infection, n4mBid, to develop an iterative selection/enrichment strategy for the identification of anti-HCV GSEs. Using this approach, a library of fragments of an HCV genome was screened for sequences that suppress HCV infection. A 244 amino acid gene fragment, B1, was strongly enriched after 5 rounds of selection. B1 derives from a single-base frameshift of the enhanced green fluorescent protein (eGFP) which was used as a filler during fragment cloning. B1 has a very high net positive charge of 43 at neutral pH and a high charge-to-mass (kDa) ratio of 1.5. We show that B1 expression specifically inhibits HCV replication. In addition, five highly positively charged B1 fragments produced from progressive truncation at the C-terminus all retain the ability to inhibit HCV, suggesting that a high positive charge, rather than a particular motif in B1, likely accounts for B1’s anti-HCV activity. Another supercharged protein, +36GFP, was also found to strongly inhibit HCV replication when added to cells at the time of infection. This study reports a new methodology for HCV inhibitor screening and points to the anti-HCV potential of positively charged proteins/peptides. PMID:24391867

Simeon, Rudo L.; Chen, Zhilei

2013-01-01

364

Genetic association analysis of 300 genes identifies a risk haplotype in SLC18A2 for post-traumatic stress disorder in two independent samples.  

PubMed

The genetic architecture of post-traumatic stress disorder (PTSD) remains poorly understood with the vast majority of genetic association studies reporting on single candidate genes. We conducted a large genetic study in trauma-exposed European-American women (N=2538; 845 PTSD cases, 1693 controls) by testing 3742 SNPs across more than 300 genes and conducting polygenic analyses using results from the Psychiatric Genome-Wide Association Studies Consortium (PGC). We tested the association between each SNP and two measures of PTSD, a severity score and diagnosis. We found a significant association between PTSD (diagnosis) and SNPs (top SNP: rs363276, odds ratio (OR)=1.4, p=2.1E-05) in SLC18A2 (vesicular monoamine transporter 2). A haplotype analysis of 9 SNPs in SLC18A2, including rs363276, identified a risk haplotype (CGGCGGAAG, p=0.0046), and the same risk haplotype was associated with PTSD in an independent cohort of trauma-exposed African-Americans (p=0.049; N=748, men and women). SLC18A2 is involved in transporting monoamines to synaptic vesicles and has been implicated in a number of neuropsychiatric disorders including major depression. Eight genes previously associated with PTSD had SNPs with nominally significant associations (p<0.05). The polygenic analyses suggested that there are SNPs in common between PTSD severity and bipolar disorder. Our data are consistent with a genetic architecture for PTSD that is highly polygenic, influenced by numerous SNPs with weak effects, and may overlap with mood disorders. Genome-wide studies with very large samples sizes are needed to detect these types of effects. PMID:24525708

Solovieff, Nadia; Roberts, Andrea L; Ratanatharathorn, Andrew; Haloosim, Michelle; De Vivo, Immaculata; King, Anthony P; Liberzon, Israel; Aiello, Allison; Uddin, Monica; Wildman, Derek E; Galea, Sandro; Smoller, Jordan W; Purcell, Shaun M; Koenen, Karestan C

2014-07-01

365

Characterization of Genetic Determinants That Modulate Candida albicans Filamentation in the Presence of Bacteria  

PubMed Central

In the human body, fungi and bacteria share many niches where the close contact of these organisms maintains a balance among the microbial population. However, when this microbial balance is disrupted, as with antibiotic treatment, other bacteria or fungi can grow uninhibited. C. albicans is the most common opportunistic fungal pathogen affecting humans and can uniquely control its morphogenesis between yeast, pseudohyphal, and hyphal forms. Numerous studies have shown that C. albicans interactions with bacteria can impact its ability to undergo morphogenesis; however, the genetics that govern this morphological control via these bacterial interactions are still relatively unknown. To aid in the understanding of the cross-kingdom interactions of C. albicans with bacteria and the impact on morphology we utilized a haploinsufficiency based C. albicans mutant screen to test for the ability of C. albicans to produce hyphae in the presence of three bacterial species (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus). Of the 18,144 mutant strains tested, 295 mutants produced hyphae in the presence of all three bacterial species. The 295 mutants identified 132 points of insertion, which included identified/predicted genes, major repeat sequences, and a number of non-coding/unannotated transcripts. One gene, CDR4, displayed increased expression when co-cultured with S. aureus, but not E. coli or P. aeruginosa. Our data demonstrates the ability to use a large scale library screen to identify genes involved in Candida-bacterial interactions and provides the foundation for comprehending the genetic pathways relating to bacterial control of C. albicans morphogenesis. PMID:23951271

Fox, Sean J.; Shelton, Bryce T.; Kruppa, Michael D.

2013-01-01

366

Genetic identification and fisher identifiability analysis of the Doyle-Fuller-Newman model from experimental cycling of a LiFePO4 cell  

NASA Astrophysics Data System (ADS)

This article examines the problem of identifying the physical parameters of fundamental electrochemistry-based battery models from non-invasive voltage/current cycling tests. The article is particularly motivated by the problem of fitting the Doyle-Fuller-Newman (DFN) battery model to lithium-ion battery cycling data. Previous research in the literature identifies subsets of the DFN model's parameter experimentally. In contrast, this article makes the two unique contributions of: (i) identifying the full set of DFN model parameters from cycling data using a genetic algorithm (GA), and (ii) assessing the accuracy and identifiability of the resulting full parameter set using Fisher information. The specific battery used within this study has lithium iron phosphate cathode chemistry and is intended for high-power applications such as plug-in hybrid electric vehicles (PHEVs). We use seven experimental cycling data sets for model fitting and validation, six of them derived from PHEV drive cycles. This makes the identified parameter values appropriate for PHEV battery simulation and model-based design and control optimization.

Forman, Joel C.; Moura, Scott J.; Stein, Jeffrey L.; Fathy, Hosam K.

2012-07-01

367

Identifying hybridizing taxa within the Daphnia longispina species complex: a comparison of genetic methods and phenotypic approaches  

Microsoft Academic Search

Daphnia galeata Sars, D. longispina O. F. Müller and D. cucullata Sars (Crustacea: Cladocera) are closely related species which often produce interspecific hybrids in natural populations.\\u000a Several marker systems are available for taxon determination in this hybridizing complex, but their performance and reliability\\u000a has not been systematically assessed. We compared results from identifications by three molecular methods. More than 1,200\\u000a individuals

Štepánka Dlouhá; Anne Thielsch; Robert H. S. Kraus; Jaromír Seda; Klaus Schwenk; Adam Petrusek

2010-01-01

368

Genetic Determinants of Sindbis Virus Mosquito Infection Are Associated with a Highly Conserved Alphavirus and Flavivirus Envelope Sequence?  

PubMed Central

Wild-type Sindbis virus (SINV) strain MRE16 efficiently infects Aedes aegypti midgut epithelial cells (MEC), but laboratory-derived neurovirulent SINV strain TE/5?2J infects MEC poorly. SINV determinants for MEC infection have been localized to the E2 glycoprotein. The E2 amino acid sequences of MRE16 and TE/5?2J differ at 60 residue sites. To identify the genetic determinants of MEC infection of MRE16, the TE/5?2J virus genome was altered to contain either domain chimeras or more focused nucleotide substitutions of MRE16. The growth patterns of derived viruses in cell culture were determined, as were the midgut infection rates (MIR) in A. aegypti mosquitoes. The results showed that substitutions of MRE16 E2 aa 95 to 96 and 116 to 119 into the TE/5?2J virus increased MIR both independently and in combination with each other. In addition, a unique PPF/.GDS amino acid motif was located between these two sites that was found to be a highly conserved sequence among alphaviruses and flaviviruses but not other arboviruses. PMID:18160430

Pierro, Dennis J.; Powers, Erik L.; Olson, Ken E.

2008-01-01

369

Genome-Wide Mutagenesis of Xanthomonas axonopodis pv. citri Reveals Novel Genetic Determinants and Regulation Mechanisms of Biofilm Formation  

PubMed Central

Xanthomonas axonopodis pv. citri (Xac) causes citrus canker disease, a major threat to citrus production worldwide. Accumulating evidence suggests that the formation of biofilms on citrus leaves plays an important role in the epiphytic survival of this pathogen prior to the development of canker disease. However, the process of Xac biofilm formation is poorly understood. Here, we report a genome-scale study of Xac biofilm formation in which we identified 92 genes, including 33 novel genes involved in biofilm formation and 7 previously characterized genes, colR, fhaB, fliC, galU, gumD, wxacO, and rbfC, known to be important for Xac biofilm formation. In addition, 52 other genes with defined or putative functions in biofilm formation were identified, even though they had not previously reported been to be associated with biofilm formation. The 92 genes were isolated from 292 biofilm-defective mutants following a screen of a transposon insertion library containing 22,000 Xac strain 306 mutants. Further analyses indicated that 16 of the novel genes are involved in the production of extracellular polysaccharide (EPS) and/or lipopolysaccharide (LPS), 7 genes are involved in signaling and regulatory pathways, and 5 genes have unknown roles in biofilm formation. Furthermore, two novel genes, XAC0482, encoding a haloacid dehalogenase-like phosphatase, and XAC0494 (designated as rbfS), encoding a two-component sensor protein, were confirmed to be biofilm-related genes through complementation assays. Our data demonstrate that the formation of mature biofilm requires EPS, LPS, both flagellum-dependent and flagellum-independent cell motility, secreted proteins and extracellular DNA. Additionally, multiple signaling pathways are involved in Xac biofilm formation. This work is the first report on a genome-wide scale of the genetic processes of biofilm formation in plant pathogenic bacteria. The report provides significant new information about the genetic determinants and regulatory mechanism of biofilm formation. PMID:21750733

Li, Jinyun; Wang, Nian

2011-01-01

370

Evolving Attractive Faces Using Morphing Technology and a Genetic Algorithm: A New Approach to Determining Ideal Facial Aesthetics  

PubMed Central

Objectives The objectives of this study were to: 1) determine if a genetic algorithm in combination with morphing software can be used to evolve more attractive faces; and 2) evaluate whether this approach can be used as a tool to define or identify the attributes of the ideal attractive face. Study Design Basic research study incorporating focus group evaluations. Methods Digital images were acquired of 250 female volunteers (18–25 y). Randomly selected images were used to produce a parent generation (P) of 30 synthetic faces using morphing software. Then, a focus group of 17 trained volunteers (18–25 y) scored each face on an attractiveness scale ranging from 1 (unattractive) to 10 (attractive). A genetic algorithm was used to select 30 new pairs from the parent generation, and these were morphed using software to produce a new first generation (F1) of faces. The F1 faces were scored by the focus group, and the process was repeated for a total of four iterations of the algorithm. The algorithm mimics natural selection by using the attractiveness score as the selection pressure; the more attractive faces are more likely to morph. All five generations (P-F4) were then scored by three focus groups: a) surgeons (n = 12), b) cosmetology students (n = 44), and c) undergraduate students (n = 44). Morphometric measurements were made of 33 specific features on each of the 150 synthetic faces, and correlated with attractiveness scores using univariate and multivariate analysis. Results The average facial attractiveness scores increased with each generation and were 3.66 (+0.60), 4.59 (±0.73), 5.50 (±0.62), 6.23 (±0.31), and 6.39 (±0.24) for P and F1–F4 generations, respectively. Histograms of attractiveness score distributions show a significant shift in the skew of each curve toward more attractive faces with each generation. Univariate analysis identified nasal width, eyebrow arch height, and lip thickness as being significantly correlated with attractiveness scores. Multivariate analysis identified a similar collection of morphometric measures. No correlation with more commonly accepted measures such as the length facial thirds or fifths were identified. When images are examined as a montage (by generation), clear distinct trends are identified: oval shaped faces, distinct arched eyebrows, and full lips predominate. Faces evolve to approximate the guidelines suggested by classical canon. F3 and F4 generation faces look profoundly similar. The statistical and qualitative analysis indicates that the algorithm and methodology succeeds in generating successively more attractive faces. Conclusions The use of genetic algorithms in combination with a morphing software and traditional focus-group derived attractiveness scores can be used to evolve attractive synthetic faces. We have demonstrated that the evolution of attractive faces can be mimicked in software. Genetic algorithms and morphing provide a robust alternative to traditional approaches rooted in comparing attractiveness scores with a series of morphometric measurements in human subjects. PMID:18401273

Wong, Brian J. F.; Karmi, Koohyar; Devcic, Zlatko; McLaren, Christine E.; Chen, Wen-Pin

2013-01-01

371

The phytochemical and genetic survey of common and dwarf juniper (Juniperus communis and Juniperus nana) identifies chemical races and close taxonomic identity of the species.  

PubMed

Juniperus communis L. (= J. communis var. communis) and Juniperus nana Willd. (= J. communis var. SAXATILIS) are subspecies of juniper. J. communis grows widely in both hemispheres, primarily in lower elevations while J. nana is mainly observed in high mountains. Although they can be distinguished by morphological features, it is not known whether they are genetically and phytochemically distinct entities. We aimed to check whether it is possible to distinguish these two plants (i) by pharmaceutically important chemical traits and (ii) on the basis of intraspecifically highly polymorphic fragment of chloroplast DNA. We used GC with achiral as well as with enantioselective stationary phase columns to identify the main monoterpenes of the essential oil. Sequence analysis of the TRNL (UAA)- TRNF (GAA) intergenic spacer of the chloroplast genome was used as a genetic marker of taxonomic identity between these two subspecies. The chromatographic analysis showed the existence of three chemical races - the alpha-pinene type, the sabinene type and one with intermediate contents of these terpenes among both J. communis and J. nana. Surprisingly, sequence analysis of TRNL (UAA)- TRNF (GAA) revealed 100 % similarity between the common and the dwarf juniper. Thus, the monoterpene pattern is related to geographical origin, and not to the species identity. We suggest that the three chemical races identified in the present study should be considered as separate sources of pharmaceutical raw material. Our results demons