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Population Genetics
Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations
May 12, 2017   PLoS Genetics
Liang J, Le TH, Edwards DRV, Tayo BO, Gaulton KJ,   . . . . . .   , Rotimi C, Levy D, Chakravarti A, Zhu X, Franceschini N
Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations
May 12, 2017
PLoS Genetics
Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
May 15, 2017   Nature Genetics Add nature.com free-link Cancel
Weiner DJ, Wigdor EM, Ripke S, Walters RK, Kosmicki JA,   . . . . . .   , Mortensen PB, Børglum AD, Smith GD, Daly MJ, Robinson EB
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
May 15, 2017
Nature Genetics
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
Do environmental fluoride exposure and ESRα genetic variation modulate methylation modification on bone changes in Chinese farmers?
May 15, 2017   Chemical Research In Toxicology
Zhang Y, Huang H, Gong B, Duan L, Sun L, He T, Cheng X, Li Z, Cui L, Ba Y
Do environmental fluoride exposure and ESRα genetic variation modulate methylation modification on bone changes in Chinese farmers?
May 15, 2017
Chemical Research In Toxicology
Although increasing evidences suggest that estrogen receptor α (ESRα) genetic variation could modify bone damages caused by environmental fluoride exposure, little is known about epigenetic mechanisms in relation to bone changes. A case-control study was conducted among farmers aged 18-55 years in Henan Province, China. X-ray was used to detect bone changes. Methylation status was determined by methylation-specific PCR. Genotypes were identified by Taqman probe and Real-Time PCR. In this study, we found that methylation status in the promoter region of the ESRα gene was lower in bone change cases than that in controls, which was only observed in male farmers after stratification by gender. Furthermore, methylation level was negatively associated with the urinary fluoride concentration in male farmers. No significant association was found between the distribution of ESRα rs2941740 genotypes and the risk of bone changes. Multivariate logistic regression analysis showed that after adjusting for age and gender, increased serum calcium and methylation status were protective factors for bone changes. No interaction effect was observed between fluoride exposure and ESRα rs2941740 polymorphism on bone changes. In conclusion, the current work suggests that bone changes are associated with methylation status, which might be modulated by fluoride exposure in male farmers. Methylation status and bone changes were not modified by ESRα gene rs2941740 polymorphism in the promoter region.
Protein Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease
May 16, 2017   Circulation Research
Nomura A, Won HH, Khera AV, Takeuchi F, Ito K,   . . . . . .   , Kubo M, Kato N, Chen YI, Dewey F, Kathiresan S
Protein Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease
May 16, 2017
Circulation Research
Rationale: Therapies which inhibit cholesteryl ester transfer protein (CETP) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human deoxyribonucleic acid sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. Objective: To test whether protein truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results: We sequenced the exons of the CETP gene in 58,469 participants from 12 case-control studies (18,817 CHD cases, 39,652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift frame. We also genotyped one Japanese-specific PTV in 27,561 participants from three case-control studies (14,286 CHD cases, 13,275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58,469 participants with CETP gene sequencing data available, average age was 51.5 years and 43% were female; 1 in 975 participants carried a PTV at the CETP gene. Compared to non-carriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (HDL-C; effect size, 22.6 mg/dL; 95% confidence interval [CI], 18 to 27; P < 1.0x10-4), lower low-density lipoprotein cholesterol (LDL-C; -12.2 mg/dL; 95% CI, -23 to -0.98; P = 0.033), and lower triglycerides (-6.3%; 95% CI, -12 to -0.22, P = 0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% CI, 0.54 to 0.90; P = 5.1x10-3). Conclusions: Compared with non-carriers, carriers of PTV at CETP displayed higher HDL-C, lower LDL-C, lower triglycerides, and lower risk for CHD.
Allele-specific expression reveals interactions between genetic variation and environment
May 22, 2017   Nature Methods Add nature.com free-link Cancel
Knowles DA, Davis JR, Edgington H, Raj A, Favé MJ, Zhu X, Potash JB, Weissman MM, Shi J, Levinson DF, Awadalla P, Mostafavi S, Montgomery SB, Battle A
Allele-specific expression reveals interactions between genetic variation and environment
May 22, 2017
Nature Methods
Identifying interactions between genetics and the environment (GxE) remains challenging. We have developed EAGLE, a hierarchical Bayesian model for identifying GxE interactions based on associations between environmental variables and allele-specific expression. Combining whole-blood RNA-seq with extensive environmental annotations collected from 922 human individuals, we identified 35 GxE interactions, compared with only four using standard GxE interaction testing. EAGLE provides new opportunities for researchers to identify GxE interactions using functional genomic data.
A complete tool set for molecular QTL discovery and analysis
May 18, 2017   Nature Communications
Delaneau O, Ongen H, Brown AA, Fort A, Panousis NI, Dermitzakis ET
A complete tool set for molecular QTL discovery and analysis
May 18, 2017
Nature Communications
Population scale studies combining genetic information with molecular phenotypes (for example, gene expression) have become a standard to dissect the effects of genetic variants onto organismal phenotypes. These kinds of data sets require powerful, fast and versatile methods able to discover molecular Quantitative Trait Loci (molQTL). Here we propose such a solution, QTLtools, a modular framework that contains multiple new and well-established methods to prepare the data, to discover proximal and distal molQTLs and, finally, to integrate them with GWAS variants and functional annotations of the genome. We demonstrate its utility by performing a complete expression QTL study in a few easy-to-perform steps. QTLtools is open source and available at https://qtltools.github.io/qtltools/.
Genetic architecture of epigenetic and neuronal ageing rates in human brain regions
May 18, 2017   Nature Communications
Lu AT, Hannon E, Levine ME, Crimmins EM, Lunnon K, Mill J, Geschwind DH, Horvath S
Genetic architecture of epigenetic and neuronal ageing rates in human brain regions
May 18, 2017
Nature Communications
Identifying genes regulating the pace of epigenetic ageing represents a new frontier in genome-wide association studies (GWASs). Here using 1,796 brain samples from 1,163 individuals, we carry out a GWAS of two DNA methylation-based biomarkers of brain age: the epigenetic ageing rate and estimated proportion of neurons. Locus 17q11.2 is significantly associated (P=4.5 × 10-9) with the ageing rate across five brain regions and harbours a cis-expression quantitative trait locus for EFCAB5 (P=3.4 × 10-20). Locus 1p36.12 is significantly associated (P=2.2 × 10-8) with epigenetic ageing of the prefrontal cortex, independent of the proportion of neurons. Our GWAS of the proportion of neurons identified two genome-wide significant loci (10q26 and 12p13.31) and resulted in a gene set that overlaps significantly with sets found by GWAS of age-related macular degeneration (P=1.4 × 10-12), ulcerative colitis (P
Linkage disequilibrium matches forensic genetic records to disjoint genomic marker sets
May 16, 2017   Proceedings Of The National Academy Of Sciences Of The United States Of America
Edge MD, Algee-Hewitt BFB, Pemberton TJ, Li JZ, Rosenberg NA
Linkage disequilibrium matches forensic genetic records to disjoint genomic marker sets
May 16, 2017
Proceedings Of The National Academy Of Sciences Of The United States Of America
Combining genotypes across datasets is central in facilitating advances in genetics. Data aggregation efforts often face the challenge of record matching-the identification of dataset entries that represent the same individual. We show that records can be matched across genotype datasets that have no shared markers based on linkage disequilibrium between loci appearing in different datasets. Using two datasets for the same 872 people-one with 642,563 genome-wide SNPs and the other with 13 short tandem repeats (STRs) used in forensic applications-we find that 90-98% of forensic STR records can be connected to corresponding SNP records and vice versa. Accuracy increases to 99-100% when ∼30 STRs are used. Our method expands the potential of data aggregation, but it also suggests privacy risks intrinsic in maintenance of databases containing even small numbers of markers-including databases of forensic significance.
Evolutionary forces affecting synonymous variations in plant genomes
May 22, 2017   PLoS Genetics
Clément Y, Sarah G, Holtz Y, Homa F, Pointet S,   . . . . . .   , Santoni S, Labouisse JP, Pham JL, David J, Glémin S
Evolutionary forces affecting synonymous variations in plant genomes
May 22, 2017
PLoS Genetics
Base composition is highly variable among and within plant genomes, especially at third codon positions, ranging from GC-poor and homogeneous species to GC-rich and highly heterogeneous ones (particularly Monocots). Consequently, synonymous codon usage is biased in most species, even when base composition is relatively homogeneous. The causes of these variations are still under debate, with three main forces being possibly involved: mutational bias, selection and GC-biased gene conversion (gBGC). So far, both selection and gBGC have been detected in some species but how their relative strength varies among and within species remains unclear. Population genetics approaches allow to jointly estimating the intensity of selection, gBGC and mutational bias. We extended a recently developed method and applied it to a large population genomic dataset based on transcriptome sequencing of 11 angiosperm species spread across the phylogeny. We found that at synonymous positions, base composition is far from mutation-drift equilibrium in most genomes and that gBGC is a widespread and stronger process than selection. gBGC could strongly contribute to base composition variation among plant species, implying that it should be taken into account in plant genome analyses, especially for GC-rich ones.
An independent component analysis confounding factor correction framework for identifying broad impact expression quantitative trait loci
May 15, 2017   PLoS Computational Biology
Ju JH, Shenoy SA, Crystal RG, Mezey JG
An independent component analysis confounding factor correction framework for identifying broad impact expression quantitative trait loci
May 15, 2017
PLoS Computational Biology
Genome-wide expression Quantitative Trait Loci (eQTL) studies in humans have provided numerous insights into the genetics of both gene expression and complex diseases. While the majority of eQTL identified in genome-wide analyses impact a single gene, eQTL that impact many genes are particularly valuable for network modeling and disease analysis. To enable the identification of such broad impact eQTL, we introduce CONFETI: Confounding Factor Estimation Through Independent component analysis. CONFETI is designed to address two conflicting issues when searching for broad impact eQTL: the need to account for non-genetic confounding factors that can lower the power of the analysis or produce broad impact eQTL false positives, and the tendency of methods that account for confounding factors to model broad impact eQTL as non-genetic variation. The key advance of the CONFETI framework is the use of Independent Component Analysis (ICA) to identify variation likely caused by broad impact eQTL when constructing the sample covariance matrix used for the random effect in a mixed model. We show that CONFETI has better performance than other mixed model confounding factor methods when considering broad impact eQTL recovery from synthetic data. We also used the CONFETI framework and these same confounding factor methods to identify eQTL that replicate between matched twin pair datasets in the Multiple Tissue Human Expression Resource (MuTHER), the Depression Genes Networks study (DGN), the Netherlands Study of Depression and Anxiety (NESDA), and multiple tissue types in the Genotype-Tissue Expression (GTEx) consortium. These analyses identified both cis-eQTL and trans-eQTL impacting individual genes, and CONFETI had better or comparable performance to other mixed model confounding factor analysis methods when identifying such eQTL. In these analyses, we were able to identify and replicate a few broad impact eQTL although the overall number was small even when applying CONFETI. In light of these results, we discuss the broad impact eQTL that have been previously reported from the analysis of human data and suggest that considerable caution should be exercised when making biological inferences based on these reported eQTL.
Global clues to the nature of genomic mutations in humans
May 17, 2017   ELife
Scally A
Global clues to the nature of genomic mutations in humans
May 17, 2017
ELife
An analysis of worldwide human genetic variation reveals the footprints of ancient changes in genomic mutation processes.
Droplet Barcode Sequencing for targeted linked-read haplotyping of single DNA molecules
May 19, 2017   Nucleic Acids Research
Redin D, Borgström E, He M, Aghelpasand H, Käller M, Ahmadian A
Droplet Barcode Sequencing for targeted linked-read haplotyping of single DNA molecules
May 19, 2017
Nucleic Acids Research
Data produced with short-read sequencing technologies result in ambiguous haplotyping and a limited capacity to investigate the full repertoire of biologically relevant forms of genetic variation. The notion of haplotype-resolved sequencing data has recently gained traction to reduce this unwanted ambiguity and enable exploration of other forms of genetic variation; beyond studies of just nucleotide polymorphisms, such as compound heterozygosity and structural variations. Here we describe Droplet Barcode Sequencing, a novel approach for creating linked-read sequencing libraries by uniquely barcoding the information within single DNA molecules in emulsion droplets, without the aid of specialty reagents or microfluidic devices. Barcode generation and template amplification is performed simultaneously in a single enzymatic reaction, greatly simplifying the workflow and minimizing assay costs compared to alternative approaches. The method has been applied to phase multiple loci targeting all exons of the highly variable Human Leukocyte Antigen A (HLA-A) gene, with DNA from eight individuals present in the same assay. Barcode-based clustering of sequencing reads confirmed analysis of over 2000 independently assayed template molecules, with an average of 753 reads in support of called polymorphisms. Our results show unequivocal characterization of all alleles present, validated by correspondence against confirmed HLA database entries and haplotyping results from previous studies. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
Crosstalk between vertical and horizontal gene transfer: plasmid replication control by a conjugative relaxase
May 19, 2017   Nucleic Acids Research
Lorenzo-Díaz F, Fernández-López C, Lurz R, Bravo A, Espinosa M
Crosstalk between vertical and horizontal gene transfer: plasmid replication control by a conjugative relaxase
May 19, 2017
Nucleic Acids Research
Horizontal gene transfer is a key process in the evolution of bacteria and also represents a source of genetic variation in eukaryotes. Among elements participating in gene transfer, thousands of small (
DEOGEN2: prediction and interactive visualization of single amino acid variant deleteriousness in human proteins
May 12, 2017   Nucleic Acids Research
Raimondi D, Tanyalcin I, Ferté J, Gazzo A, Orlando G, Lenaerts T, Rooman M, Vranken W
DEOGEN2: prediction and interactive visualization of single amino acid variant deleteriousness in human proteins
May 12, 2017
Nucleic Acids Research
High-throughput sequencing methods are generating enormous amounts of genomic data, giving unprecedented insights into human genetic variation and its relation to disease. An individual human genome contains millions of Single Nucleotide Variants: to discriminate the deleterious from the benign ones, a variety of methods have been developed that predict whether a protein-coding variant likely affects the carrier individual's health. We present such a method, DEOGEN2, which incorporates heterogeneous information about the molecular effects of the variants, the domains involved, the relevance of the gene and the interactions in which it participates. This extensive contextual information is non-linearly mapped into one single deleteriousness score for each variant. Since for the non-expert user it is sometimes still difficult to assess what this score means, how it relates to the encoded protein, and where it originates from, we developed an interactive online framework (http://deogen2.mutaframe.com/) to better present the DEOGEN2 deleteriousness predictions of all possible variants in all human proteins. The prediction is visualized so both expert and non-expert users can gain insights into the meaning, protein context and origins of each prediction. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
Pleiotropic Effects of Trait-Associated Genetic Variation on DNA Methylation: Utility for Refining GWAS Loci
May 22, 2017   American Journal Of Human Genetics
Hannon E, Weedon M, Bray N, O'Donovan M, Mill J
Pleiotropic Effects of Trait-Associated Genetic Variation on DNA Methylation: Utility for Refining GWAS Loci
May 22, 2017
American Journal Of Human Genetics
Most genetic variants identified in genome-wide association studies (GWASs) of complex traits are thought to act by affecting gene regulation rather than directly altering the protein product. As a consequence, the actual genes involved in disease are not necessarily the most proximal to the associated variants. By integrating data from GWAS analyses with those from genetic studies of regulatory variation, it is possible to identify variants pleiotropically associated with both a complex trait and measures of gene regulation. In this study, we used summary-data-based Mendelian randomization (SMR), a method developed to identify variants pleiotropically associated with both complex traits and gene expression, to identify variants associated with complex traits and DNA methylation. We used large DNA methylation quantitative trait locus (mQTL) datasets generated from two different tissues (blood and fetal brain) to prioritize genes for >40 complex traits with robust GWAS data and found considerable overlap with the results of SMR analyses performed with expression QTL (eQTL) data. We identified multiple examples of variable DNA methylation associated with GWAS variants for a range of complex traits, demonstrating the utility of this approach for refining genetic association signals. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Antigenic and Biological Characterization of ORF2-6 Variants at Early Times Following PRRSV Infection
May 16, 2017   Viruses
Evans AB, Loyd H, Dunkelberger JR, van Tol S, Bolton MJ, Dorman KS, Dekkers JCM, Carpenter S
Antigenic and Biological Characterization of ORF2-6 Variants at Early Times Following PRRSV Infection
May 16, 2017
Viruses
Genetic diversity of porcine reproductive and respiratory syndrome virus (PRRSV) challenges efforts to develop effective and broadly acting vaccines. Although genetic variation in PRRSV has been extensively documented, the effects of this variation on virus phenotype are less well understood. In the present study, PRRSV open reading frame (ORF)2-6 variants predominant during the first six weeks following experimental infection were characterized for antigenic and replication phenotype. There was limited genetic variation during these early times after infection; however, distinct ORF2-6 haplotypes that differed from the NVSL97-7895 inoculum were identified in each of the five pigs examined. Chimeric viruses containing all or part of predominant ORF2-6 haplotypes were constructed and tested in virus neutralization and in vitro replication assays. In two pigs, genetic variation in ORF2-6 resulted in increased resistance to neutralization by autologous sera. Mapping studies indicated that variation in either ORF2-4 or ORF5-6 could confer increased neutralization resistance, but there was no single amino acid substitution that was predictive of neutralization phenotype. Detailed analyses of the early steps in PRRSV replication in the presence and absence of neutralizing antibody revealed both significant inhibition of virion attachment and, independently, a significant delay in the appearance of newly synthesized viral RNA. In all pigs, genetic variation in ORF2-6 also resulted in significant reduction in infectivity on MARC-145 cells, suggesting variation in ORF2-6 may also be important for virus replication in vivo. Together, these data reveal that variation appearing early after infection, though limited, alters important virus phenotypes and contributes to antigenic and biologic diversity of PRRSV.
Association study of genetic variation in DNA repair pathway genes and risk of basal cell carcinoma
May 16, 2017   International Journal Of Cancer
Lin Y, Chahal HS, Wu W, Cho HG, Ransohoff KJ, Song F, Tang JY, Sarin KY, Han J
Association study of genetic variation in DNA repair pathway genes and risk of basal cell carcinoma
May 16, 2017
International Journal Of Cancer
DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair-related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single-nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified three SNPs (rs2805831 upstream of XPA: OR = 0.93, P = 1.35 × 10-6 ; rs659857 in exon of MUS81: OR = 1.06, P = 3.09 × 10-6 ; and rs57343616 in 3' UTR of NABP2: OR = 1.11, P = 6.47 × 10-6 ) as significantly associated with BCC risk in meta-analysis, and all of them were nominally significant in both data sets. Furthermore, rs659857 [T] was significantly associated with decreased expression of MUS81 mRNA in the expression quantitative trait locus (eQTL) analysis. Our findings suggest that the inherited common variation in three DNA repair genes- XPA, MUS81 and NABP2- may be involved in the development of BCC. To our knowledge, our study is the first report thoroughly examining the effects of SNPs across DNA repair pathway genes on BCC risk based on a genome-wide association meta-analysis. This article is protected by copyright. All rights reserved. © 2017 UICC.
Trends in DNA Methylation with Age Replicate Across Diverse Human Populations
May 23, 2017   Genetics
Gopalan S, Carja O, Fagny M, Patin E, Myrick JW, McEwen LM, Mah SM, Kobor MS, Froment A, Feldman MW, Quintana-Murci L, Henn BM
Trends in DNA Methylation with Age Replicate Across Diverse Human Populations
May 23, 2017
Genetics
Aging is associated with widespread changes in genome-wide patterns of DNA methylation. Thousands of CpG sites whose tissue-specific methylation levels are strongly correlated with chronological age have been previously identified. However, the majority of these studies have focused primarily on cosmopolitan populations living in the developed world; it is not known if age-related patterns of DNA methylation at these loci are similar across a broad range of human genetic and ecological diversity. We investigated genome-wide methylation patterns using saliva- and whole blood-derived DNA from two traditionally hunting and gathering African populations: the Baka of the western Central African rainforest and the ≠Khomani San of the South African Kalahari Desert. We identified hundreds of CpG sites whose methylation levels are significantly associated with age, thousands that are significant in a meta-analysis, and replicate trends previously reported in populations of non-African descent. We confirmed that an age-associated site in the promoter of the gene ELOVL2 shows a remarkably congruent relationship with aging in humans, despite extensive genetic and environmental variation across populations. We also demonstrate that genotype state at methylation quantitative trait loci (meQTLs) can affect methylation trends at some age-associated CpG sites. Our study explores the relationship between CpG methylation and chronological age in populations of African hunter-gatherers, who rely on different diets across diverse ecologies. While many age-related CpG sites replicate across populations, we show that considering common genetic variation at meQTLs further improves our ability to detect previously identified age associations. Copyright © 2017, The Genetics Society of America.
Resolving the Complex Genetic Basis of Phenotypic Variation and Variability of Cellular Growth
May 12, 2017   Genetics
Ziv N, Shuster BM, Siegal ML, Gresham D
Resolving the Complex Genetic Basis of Phenotypic Variation and Variability of Cellular Growth
May 12, 2017
Genetics
In all organisms, many traits vary continuously between individuals. Explaining the genetic basis of quantitative trait variation requires comprehensively accounting for genetic and non-genetic factors as well as their interactions. The growth of microbial cells can be characterized by a lag duration, an exponential growth phase and a stationary phase. Parameters that characterize these growth phases can vary among genotypes (phenotypic variation), environmental conditions (phenotypic plasticity) and among isogenic cells in a given environment (phenotypic variability). We used a high-throughput microscopy assay to map genetic loci determining variation in lag duration and exponential growth rate in growth rate limiting and non-limiting glucose concentrations, using segregants from a cross of two natural isolates of the budding yeast, Saccharomyces cerevisiae We find that some quantitative trait loci (QTL) are common between traits and environments whereas some are unique, exhibiting gene by environment interactions. Furthermore, whereas variation in the central tendency of growth rate or lag duration is explained by many additive loci, differences in phenotypic variability are primarily the result of genetic interactions. We used bulk segregant mapping to increase QTL resolution by performing whole genome sequencing of complex mixtures of an advanced intercross mapping population under selection in glucose-limited chemostats. We find that sequence variation in the high affinity glucose transporter HXT7 contributes to variation in growth rate and lag duration. Allele replacements of the entire locus as well as of a single amino acid reveal that the effect of variation in HXT7 depends on genetic, and allelic, background. Amplifications of HXT7 are frequently selected in experimental evolution in glucose-limited environments, but we find that HXT7 amplifications result in antagonistic pleiotropy that is absent in naturally occurring variants of HXT7 Our study highlights the complex nature of the genotype to phenotype map within and between environments. Copyright © 2017, The Genetics Society of America.
Inferring the Joint Demographic History of Multiple Populations: Beyond the Diffusion Approximation
May 12, 2017   Genetics
Jouganous J, Long W, Ragsdale AP, Gravel S
Inferring the Joint Demographic History of Multiple Populations: Beyond the Diffusion Approximation
May 12, 2017
Genetics
Understanding variation in allele frequencies across populations is a central goal of population genetics. Classical models for the distribution of allele frequencies, using forward simulation, coalescent theory, or the diffusion approximation, have been applied extensively for demographic inference, medical study design, and evolutionary studies. Here we propose a tractable model of ordinary differential equations for the evolution of allele frequencies that is closely related to the diffusion approximation but avoids many of its limitations and approximations. We show that the approach is typically faster, more numerically stable, and more easily generalizable than the state-of-the-art software implementation of the diffusion approximation. We present a number of applications to human sequence data, including demographic inference with a five-population joint frequency spectrum and a discussion of the robustness of Out-of-Africa model inference to the choice of modern population. Copyright © 2017, The Genetics Society of America.
Cross-Tissue Exploration of Genetic and Epigenetic Effects on Brain Gray Matter in Schizophrenia
May 18, 2017   Schizophrenia Bulletin
Lin D, Chen J, Ehrlich S, Bustillo JR, Perrone-Bizzozero N, Walton E, Clark VP, Wang YP, Sui J, Du Y, Ho BC, Schulz CS, Calhoun VD, Liu J
Cross-Tissue Exploration of Genetic and Epigenetic Effects on Brain Gray Matter in Schizophrenia
May 18, 2017
Schizophrenia Bulletin
Closely linking genetics and environment factors, epigenetics has been of increasing interest in psychiatric disease studies. In this work, we integrated single nucleotide polymorphisms (SNPs), DNA methylation of blood and saliva, and brain gray matter (GM) measures to explore the role of genetic and epigenetic variation to the brain structure changes in schizophrenia (SZ). By focusing on the reported SZ genetic risk regions, we applied a multi-stage multivariate analysis to a discovery dataset (92 SZ patients and 110 controls, blood) and an independent replication dataset (93 SZ patients and 99 controls, saliva). Two pairs of SNP-methylation components were significantly correlated (r = .48 and .35) in blood DNA, and replicated (r = .46 and .29) in saliva DNA, reflecting cross-tissue SNP cis-effects. In the discovery data, both SNP-related methylation components were also associated with one GM component primarily located in cerebellum, caudate, and thalamus. Additionally, another methylation component in NOSIP gene with significant SZ patient differences (P = .009), was associated with 8 GM components (7 with patient differences) including superior, middle, and inferior frontal gyri, superior, middle, and inferior temporal gyri, cerebellum, insula, cuneus, and lingual gyrus. Of these, 5 methylation-GM associations were replicated (P < .05). In contrast, no pairwise significant associations were observed between SNP and GM components. This study strongly supports that compared to genetic variation, epigenetics show broader and more significant associations with brain structure as well as diagnosis, which can be cross-tissue, and the potential in explaining the mechanism of genetic risks in SZ. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
ASD restricted and repetitive behaviors associated at 17q21.33: genes prioritized by expression in fetal brains
May 23, 2017   Molecular Psychiatry
Cantor RM, Navarro L, Won H, Walker RL, Lowe JK, Geschwind DH
ASD restricted and repetitive behaviors associated at 17q21.33: genes prioritized by expression in fetal brains
May 23, 2017
Molecular Psychiatry
Autism spectrum disorder (ASD) is a behaviorally defined condition that manifests in infancy or early childhood as deficits in communication skills and social interactions. Often, restricted and repetitive behaviors (RRBs) accompany this disorder. ASD is polygenic and genetically complex, so we hypothesized that focusing analyses on intermediate core component phenotypes, such as RRBs, can reduce genetic heterogeneity and improve statistical power. Applying this approach, we mined Caucasian genome-wide association studies (GWAS) data from two of the largest ASD family cohorts, the Autism Genetics Resource Exchange and Autism Genome Project (AGP). Of the 12 RRBs measured by the Autism Diagnostic Interview-Revised, seven were found to be significantly familial and substantially variable, and hence, were tested for genome-wide association in 3104 ASD-affected children from 2045 families. Using a stringent significance threshold (P
A new formulation of random genetic drift and its application to the evolution of cell populations
May 19, 2017   Molecular Biology And Evolution
Chen Y, Tong D, Wu CI
A new formulation of random genetic drift and its application to the evolution of cell populations
May 19, 2017
Molecular Biology And Evolution
Random genetic drift, or stochastic change in gene frequency, is a fundamental evolutionary force that is usually defined within the ideal Wright-Fisher (WF) population. However, as the theory is increasingly applied to populations that deviate strongly from the ideal model, a paradox of random drift has emerged. When drift is defined by the WF model, it becomes stronger as the population size, N, decreases. However, the intensity of competition decreases when N decreases and, hence, drift might become weaker. To resolve the paradox, we propose that random drift be defined by the variance of "individual output", V(k) [k being the progeny number of each individual with the mean of E(k)], rather than by the WF sampling. If the distribution of k is known for any population, its strength of drift relative to a WF population of the same size, N, can be calculated. Generally, E(k) and V(k) should be density dependent but their relationships are different with or without competition, leading to opposite predictions on the efficiency of random drift as N changes. We apply the "individual output" model to asexual cell populations that are either unregulated (such as tumors) or negatively density-dependent (e.g. bacteria). In such populations, the efficiency of drift could be as low as 
Global gene expression analysis provides insight into local adaptation to geothermal streams in tadpoles of the Andean toad Rhinella spinulosa
May 17, 2017   Scientific Reports
Pastenes L, Valdivieso C, Di Genova A, Travisany D, Hart A, Montecino M, Orellana A, Gonzalez M, Gutiérrez RA, Allende ML, Maass A, Méndez MA
Global gene expression analysis provides insight into local adaptation to geothermal streams in tadpoles of the Andean toad Rhinella spinulosa
May 17, 2017
Scientific Reports
The anuran Rhinella spinulosa is distributed along the Andes Range at altitudes that undergo wide daily and seasonal variation in temperature. One of the populations inhabits geothermal streams, a stable environment that influences life history traits such as the timing of metamorphosis. To investigate whether this population has undergone local adaptation to this unique habitat, we carried out transcriptome analyses in animals from two localities in two developmental stages (prometamorphic and metamorphic) and exposed them to two temperatures (20 and 25 °C). RNA-Seq, de novo assembly and annotation defined a transcriptome revealing 194,469 high quality SNPs, with 1,507 genes under positive selection. Comparisons among the experimental conditions yielded 1,593 differentially expressed genes. A bioinformatics search for candidates revealed a total of 70 genes that are highly likely to be implicated in the adaptive response of the population living in a stable environment, compared to those living in an environment with variable temperatures. Most importantly, the population inhabiting the geothermal environment showed decreased transcriptional plasticity and reduced genetic variation compared to its counterpart from the non-stable environment. This analysis will help to advance the understanding of the molecular mechanisms that account for the local adaptation to geothermal streams in anurans.
Population genetics of an alien whitefly in China: implications for its dispersal and invasion success
May 23, 2017   Scientific Reports
Li HR, Pan HP, Tao YL, Zhang YJ, Chu D
Population genetics of an alien whitefly in China: implications for its dispersal and invasion success
May 23, 2017
Scientific Reports
Invasive genotypes may be associated with their ability to access the invasion habitat. The whitefly, Bemisia tabaci Q, has been an important agricultural pest in China since 2008. In order to identify the invasion routes and to provide insight into its invasion success in China, we analyzed the composition, distribution, and genetic diversity of mitochondrial haplotypes of B. tabaci Q. Samples were obtained from 23 provincial level administrative units in 2011, and analyses conducted based on the mtCOI. Our results revealed five haplotypes (abbreviated as Q1H1-Q1H5) were present in the Q1 subclade based on 773-bp mtCOI fragment analysis. The diversity of haplotypes indicated the B. tabaci Q populations were derived from multiple invasion sources originating from the western Mediterranean region. Among the haplotypes, Q1H1 was dominant, followed by Q1H2. The whitefly populations were generally characterized by low levels of genetic diversity based on the 773-bp mtCOI fragment. Similar results were obtained when the 657-bp fragment was analyzed using the procedure in a previous report. Potential mechanisms contributing to the dominance of the Q1H1 in China are also discussed. These results will be helpful in revealing the mechanisms that enabled the successful invasion of B. tabaci Q into the country.

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