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Population Genetics
Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.
Dec 11, 2018   The Lancet. Respiratory Medicine
Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L,   . . . . . .   , Morrell NW, Wilkins MR, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium
Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.
Dec 11, 2018
The Lancet. Respiratory Medicine
Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L, Germain M, Pauciulo MW, Hadinnapola C, Aman J, Girerd B, Arora A, Knight J, Hanscombe KB, Karnes JH, Kaakinen M, Gall H, Ulrich A, Harbaum L, Cebola I, Ferrer J, Lutz K, Swietlik EM, Ahmad F, Amouyel P, Archer SL, Argula R, Austin ED, Badesch D, Bakshi S, Barnett C, Benza R, Bhatt N, Bogaard HJ, Burger CD, Chakinala M, Church C, Coghlan JG, Condliffe R, Corris PA, Danesino C, Debette S, Elliott CG, Elwing J, Eyries M, Fortin T, Franke A, Frantz RP, Frost A, Garcia JGN, Ghio S, Ghofrani HA, Gibbs JSR, Harley J, He H, Hill NS, Hirsch R, Houweling AC, Howard LS, Ivy D, Kiely DG, Klinger J, Kovacs G, Lahm T, Laudes M, Machado RD, Ross RVM, Marsolo K, Martin LJ, Moledina S, Montani D, Nathan SD, Newnham M, Olschewski A, Olschewski H, Oudiz RJ, Ouwehand WH, Peacock AJ, Pepke-Zaba J, Rehman Z, Robbins I, Roden DM, Rosenzweig EB, Saydain G, Scelsi L, Schilz R, Seeger W, Shaffer CM, Simms RW, Simon M, Sitbon O, Suntharalingam J, Tang H, Tchourbanov AY, Thenappan T, Torres F, Toshner MR, Treacy CM, Noordegraaf AV, Waisfisz Q, Walsworth AK, Walter RE, Wharton J, White RJ, Wilt J, Wort SJ, Yung D, Lawrie A, Humbert M, Soubrier F, Trégouët DA, Prokopenko I, Kittles R, Gräf S, Nichols WC, Trembath RC, Desai AA, Morrell NW, Wilkins MR, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium
BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.
Sequencing Analysis of Genetic Loci for Resistance for Late Leaf Spot and Rust in Peanut (Arachis hypogaea L.).
Dec 11, 2018   Frontiers In Plant Science
Shirasawa K, Bhat RS, Khedikar YP, Sujay V, Kolekar RM, Yeri SB, Sukruth M, Cholin S, Asha B, Pandey MK, Varshney RK, Gowda MVC
Sequencing Analysis of Genetic Loci for Resistance for Late Leaf Spot and Rust in Peanut (Arachis hypogaea L.).
Dec 11, 2018
Frontiers In Plant Science
The aim of this study was to identify candidate resistance genes for late leaf spot (LLS) and rust diseases in peanut (Arachis hypogaea L.). We used a double-digest restriction-site associated DNA sequencing (ddRAD-Seq) technique based on next-generation sequencing (NGS) for genotyping analysis across the recombinant inbred lines (RILs) derived from a cross between a susceptible line, TAG 24, and a resistant line, GPBD 4. A total of 171 SNPs from the ddRAD-Seq together with 282 markers published in the previous studies were mapped on a genetic map covering 1510.1 cM. Subsequent quantitative trait locus (QTL) analysis revealed major genetic loci for LLS and rust resistance on chromosomes A02 and A03, respectively. Heterogeneous inbred family-derived near isogenic lines and the pedigree of the resistant gene donor, A. cardenasii Krapov. & W.C. Greg., including the resistant derivatives of ICGV 86855 and VG 9514 as well as GPBD 4, were employed for whole-genome resequencing analysis. The results indicated the QTL candidates for LLS and rust resistance were located in 1.4- and 2.7-Mb genome regions on A02 and A03, respectively. In these regions, four and six resistance-related genes with deleterious mutations were selected as candidates for LLS and rust resistance, respectively. These delimited genomic regions may be beneficial in breeding programs aimed at improving disease resistance and enhancing peanut productivity.
A quantitative trait locus, qSE3, promotes seed germination and seedling establishment under salinity stress in rice.
Dec 11, 2018   The Plant Journal : For Cell And Molecular Biology
He Y, Yang B, He Y, Zhan C, Cheng Y, Zhang J, Zhang H, Cheng J, Wang Z
A quantitative trait locus, qSE3, promotes seed germination and seedling establishment under salinity stress in rice.
Dec 11, 2018
The Plant Journal : For Cell And Molecular Biology
Seed germination is a complex trait determined by both quantitative trait loci (QTLs) and environmental factors and also their interactions. In this study, we mapped one major QTL qSE3 for seed germination and seedling establishment under salinity stress in rice. To understand the molecular basis of this QTL, we isolated qSE3 by map-based cloning and found that it encodes a K+ transporter gene, OsHAK21. The expression of qSE3 was significantly up-regulated by salinity stress in germinating seeds. Physiological analysis suggested that qSE3 significantly increased K+ and Na+ uptake in germinating seeds under salinity stress, resulting in increased abscisic acid (ABA) biosynthesis and activated ABA signaling responses. Furthermore, qSE3 significantly decreased the H2 O2 level in germinating seeds under salinity stress. All of these seed physiological changes modulated by qSE3 might contribute to seed germination and seedling establishment under salinity stress. Based on analysis of single-nucleotide polymorphism data of rice accessions, we identified a HAP3 haplotype of qSE3 that was positively correlated with seed germination under salinity stress. This study provides important insights into the roles of qSE3 in seed germination and seedling establishment under salinity stress and facilitates the practical use of qSE3 in rice breeding. This article is protected by copyright. All rights reserved.
Linear mixed models for association analysis of quantitative traits with next-generation sequencing data.
Dec 11, 2018   Genetic Epidemiology
Chiu CY, Yuan F, Zhang BS, Yuan A, Li X,   . . . . . .   , Cook RJ, McMahon FJ, Amos CI, Xiong M, Fan R
Linear mixed models for association analysis of quantitative traits with next-generation sequencing data.
Dec 11, 2018
Genetic Epidemiology
We develop linear mixed models (LMMs) and functional linear mixed models (FLMMs) for gene-based tests of association between a quantitative trait and genetic variants on pedigrees. The effects of a major gene are modeled as a fixed effect, the contributions of polygenes are modeled as a random effect, and the correlations of pedigree members are modeled via inbreeding/kinship coefficients. F -statistics and χ 2 likelihood ratio test (LRT) statistics based on the LMMs and FLMMs are constructed to test for association. We show empirically that the F -distributed statistics provide a good control of the type I error rate. The F -test statistics of the LMMs have similar or higher power than the FLMMs, kernel-based famSKAT (family-based sequence kernel association test), and burden test famBT (family-based burden test). The F -statistics of the FLMMs perform well when analyzing a combination of rare and common variants. For small samples, the LRT statistics of the FLMMs control the type I error rate well at the nominal levels α = 0.01 and 0.05 . For moderate/large samples, the LRT statistics of the FLMMs control the type I error rates well. The LRT statistics of the LMMs can lead to inflated type I error rates. The proposed models are useful in whole genome and whole exome association studies of complex traits.
Genome sequence characterization of canine parvoviruses prevalent in the Sichuan province of China.
Dec 11, 2018   Transboundary And Emerging Diseases
Zhuang QY, Qiu Y, Pan ZH, Wang SC, Wang B, Wu WK, Yu JM, Yi Y, Sun FL, Wang KC
Genome sequence characterization of canine parvoviruses prevalent in the Sichuan province of China.
Dec 11, 2018
Transboundary And Emerging Diseases
Canine parvovirus 2 (CPV-2) infection is responsible for large numbers of animal deaths worldwide and is one of the most dangerous infectious diseases in young puppies. Twenty-four rectal swabs were collected from dogs with clinical signs of vomiting and hemorrhagic diarrhea and were initially verified to be infected with CPV-2 using colloidal gold test strips. From the 24 CPV-positive samples, complete genome of 5050-5054 nucleotides was sequenced with a next-generation sequencing platform. Characteristics of the Open Reading Frames from different CPV-2 strains detected in this study were analyzed. Several VP2 point mutations were discovered, and demonstrated the co-circulation of new CPV-2a, new CPV-2b and CPV-2c in Sichuan province of China. The analysis results of the Chinese CPV-2 retrieved from the NCBI nucleotide, showed that new CPV-2a has become the predominant variant in some provinces of China. Phylogenetic analysis of global VP2 and NS1 nucleotide sequences revealed certain correlations among geographical regions, types and circulating time, which lays the foundation for further research concerning the epidemiology, genetic variation, vaccination and molecular evolutionary relationships of the CPV-2 identified at different times and from different regions. This article is protected by copyright. All rights reserved.
A dissection model for mapping complex traits.
Dec 11, 2018   The Plant Journal : For Cell And Molecular Biology
Sang M, Shi H, Wei K, Ye M, Jiang L, Sun L, Wu R
A dissection model for mapping complex traits.
Dec 11, 2018
The Plant Journal : For Cell And Molecular Biology
Many quantitative traits are composites of other traits that contribute differentially to genetic variation. QTL mapping of these composite traits can benefit by incorporating the mechanistic process of how their formation is mediated by the underlying components. We propose a dissection model by which to map these interconnected components traits under a joint likelihood setting. The model can test how a composite trait is determined by pleiotropic QTLs for its component traits or jointly by different sets of QTLs each responsible for a different component. The model can visualize the pattern of time-varying genetic effects for individual components and their impacts on composite traits. The dissection model was used to map two composite traits, stemwood volume growth decomposed into its stem height, stem diameter and stem form components for Euramerican poplar adult trees, and total lateral root length constituted by its average lateral root length and lateral root number components for Euphrates poplar seedlings. We found the pattern of how QTLs for different components contribute to phenotypic variation in composite traits. The detailed understanding of the genetic machineries of composite traits will not only help in the design of molecular breeding in plants and animals, but also shed light on the evolutionary processes of quantitative traits under natural selection. This article is protected by copyright. All rights reserved.
Functional mapping of N deficiency-induced response in wheat yield-component traits by implementing high-throughput phenotyping.
Dec 11, 2018   The Plant Journal : For Cell And Molecular Biology
Jiang L, Sun L, Ye M, Wang J, Wang Y, Bogard M, Lacaze X, Fournier A, Beauchêne K, Gouache D, Wu R
Functional mapping of N deficiency-induced response in wheat yield-component traits by implementing high-throughput phenotyping.
Dec 11, 2018
The Plant Journal : For Cell And Molecular Biology
As overfertilization leads to environmental concerns and the cost of N-fertilizer increases, the issue of how to select crop cultivars that can produce high yield on N-deficient lands has become crucially important. However, little is known about the genetic mechanisms by which crops respond to environmental changes induced by N signaling. Here, we dissected the genetic architecture of N-induced phenotypic plasticity in bread wheat (Triticum aestivum L.) by integrating functional mapping and semi-automatic high-throughput phenotyping data of yield-related canopy architecture. We identified a set of quantitative trait loci (QTLs) that determined the pattern and magnitude of how wheat cultivars responded to low N stress from normal N supply throughout wheat life cycle. This analysis highlighted the phenological landscape of genetic effects exerted by individual QTLs, as well as their interactions with N-induced signals and with canopy measurement angles. This information may shed light on our mechanistic understanding of plant adaptation and provide valuable information for the breeding of N-deficiency tolerant wheat varieties. This article is protected by copyright. All rights reserved.
PopViz: a webserver for visualizing minor allele frequencies and damage prediction scores of human genetic variations.
Dec 11, 2018   Bioinformatics (Oxford, England)
Zhang P, Bigio B, Rapaport F, Zhang SY, Casanova JL, Abel L, Boisson B, Itan Y
PopViz: a webserver for visualizing minor allele frequencies and damage prediction scores of human genetic variations.
Dec 11, 2018
Bioinformatics (Oxford, England)
Summary: Next-generation sequencing (NGS) generates large amounts of genomic data and reveals about 20 000 genetic coding variants per individual studied. Several mutation damage prediction scores are available to prioritize variants, but there is currently no application to help investigators to determine the relevance of the candidate genes and variants quickly and visually from population genetics data and deleteriousness scores. Here, we present PopViz, a user-friendly, rapid, interactive, mobile-compatible webserver providing a gene-centric visualization of the variants of any human gene, with (i) population-specific minor allele frequencies from the gnomAD population genetic database; (ii) mutation damage prediction scores from CADD, EIGEN and LINSIGHT and (iii) amino-acid positions and protein domains. This application will be particularly useful in investigations of NGS data for new disease-causing genes and variants, by reinforcing or rejecting the plausibility of the candidate genes, and by selecting and prioritizing, the candidate variants for experimental testing. Availability and implementation: PopViz webserver is freely accessible from http://shiva.rockefeller.edu/PopViz/. Supplementary information: Supplementary data are available at Bioinformatics online.
Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation.
Dec 13, 2018   JAMA
Choi SH, Weng LC, Roselli C, Lin H, Haggerty CM,   . . . . . .   , Murray MF, Lunetta KL, Lubitz SA, Ellinor PT, DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation.
Dec 13, 2018
JAMA
Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants). Exposures: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. Main Outcomes and Measures: Early-onset AF (defined as AF onset in persons
atSNP Search: a web resource for statistically evaluating influence of human genetic variation on transcription factor binding.
Dec 11, 2018   Bioinformatics (Oxford, England)
Shin S, Hudson R, Harrison C, Craven M, Keles S
atSNP Search: a web resource for statistically evaluating influence of human genetic variation on transcription factor binding.
Dec 11, 2018
Bioinformatics (Oxford, England)
Summary: Understanding the regulatory roles of non-coding genetic variants has become a central goal for interpreting results of genome-wide association studies. The regulatory significance of the variants may be interrogated by assessing their influence on transcription factor binding. We have developed atSNP Search, a comprehensive web database for evaluating motif matches to the human genome with both reference and variant alleles and assessing the overall significance of the variant alterations on the motif matches. Convenient search features, comprehensive search outputs, and a useful help menu are key components of atSNP Search. atSNP Search enables convenient interpretation of regulatory variants by statistical significance testing and composite logo plots, which are graphical representations of motif matches with the reference and variant alleles. Existing motif-based regulatory variant discovery tools only consider a limited pool of variants due to storage or other limitations. In contrast, atSNP Search users can test more than 37 billion variant-motif pairs with marginal significance in motif matches or match alteration. Computational evidence from atSNP Search, when combined with experimental validation, may help with the discovery of underlying disease mechanisms. Availability: atSNP Search is freely available at http://atsnp.biostat.wisc.edu. Supplementary Information: Supplementary data are available at Bioinformatics online.
A naturally occurring variation in the BrMAM-3 gene is associated with aliphatic glucosinolate accumulation in Brassica rapa leaves.
Dec 11, 2018   Horticulture Research
Zhang J, Wang H, Liu Z, Liang J, Wu J, Cheng F, Mei S, Wang X
A naturally occurring variation in the BrMAM-3 gene is associated with aliphatic glucosinolate accumulation in Brassica rapa leaves.
Dec 11, 2018
Horticulture Research
Glucosinolate profiles significantly vary among Brassica rapa genotypes. However, the molecular basis of these variations is largely unknown. In this study, we investigated a major quantitative trait locus (QTL) controlling aliphatic glucosinolate accumulation in B. rapa leaves. The QTL, which encompasses three tandem MAM genes and two MYB genes, was detected in two BC2DH populations. Among the five-candidate genes, only the expression level of BrMAM-3 (Bra013007) was significantly correlated with the accumulation of aliphatic glucosinolates in B. rapa leaves. We identified a naturally occurring insertion within exon 1 of BrMAM-3, which is predicted to be a loss-of-function mutation, as confirmed by qRT-PCR. We determined that the loss of function was associated with the low glucosinolate content in B. rapa accessions. Furthermore, overexpressing the BrMAM-3 gene resulted in an increase in total aliphatic glucosinolates in Arabidopsis transgenic lines. Our study provides insights into the molecular mechanism underlying the accumulation of aliphatic glucosinolates in B. rapa leaves, thereby facilitating in the manipulation of total aliphatic glucosinolate content in Brassica crops.
Dissecting the Genomic Architecture of Resistance to Eimeria maxima Parasitism in the Chicken.
Dec 11, 2018   Frontiers In Genetics
Boulton K, Nolan MJ, Wu Z, Riggio V, Matika O,   . . . . . .   , Tomley FM, Hume DA, Smith AL, Blake DP, Psifidi A
Dissecting the Genomic Architecture of Resistance to Eimeria maxima Parasitism in the Chicken.
Dec 11, 2018
Frontiers In Genetics
Coccidiosis in poultry, caused by protozoan parasites of the genus Eimeria, is an intestinal disease with substantial economic impact. With the use of anticoccidial drugs under public and political pressure, and the comparatively higher cost of live-attenuated vaccines, an attractive complementary strategy for control is to breed chickens with increased resistance to Eimeria parasitism. Prior infection with Eimeria maxima leads to complete immunity against challenge with homologous strains, but only partial resistance to challenge with antigenically diverse heterologous strains. We investigate the genetic architecture of avian resistance to E. maxima primary infection and heterologous strain secondary challenge using White Leghorn populations of derived inbred lines, C.B12 and 15I, known to differ in susceptibility to the parasite. An intercross population was infected with E. maxima Houghton (H) strain, followed 3 weeks later by E. maxima Weybridge (W) strain challenge, while a backcross population received a single E. maxima W infection. The phenotypes measured were parasite replication (counting fecal oocyst output or qPCR for parasite numbers in intestinal tissue), intestinal lesion score (gross pathology, scale 0-4), and for the backcross only, serum interleukin-10 (IL-10) levels. Birds were genotyped using a high density genome-wide DNA array (600K, Affymetrix). Genome-wide association study located associations on chromosomes 1, 2, 3, and 5 following primary infection in the backcross population, and a suggestive association on chromosome 1 following heterologous E. maxima W challenge in the intercross population. This mapped several megabases away from the quantitative trait locus (QTL) linked to the backcross primary W strain infection, suggesting different underlying mechanisms for the primary- and heterologous secondary- responses. Underlying pathways for those genes located in the respective QTL for resistance to primary infection and protection against heterologous challenge were related mainly to immune response, with IL-10 signaling in the backcross primary infection being the most significant. Additionally, the identified markers associated with IL-10 levels exhibited significant additive genetic variance. We suggest this is a phenotype of interest to the outcome of challenge, being scalable in live birds and negating the requirement for single-bird cages, fecal oocyst counts, or slaughter for sampling (qPCR).
Draft Genome Sequence of an Erwinia tracheiphila Isolate from an Infected Muskmelon (Cucumis melo).
Dec 11, 2018   Microbiology Resource Announcements
Shapiro LR, Andrade A, Scully ED, Rocha J, Paulson JN, Kolter R
Draft Genome Sequence of an Erwinia tracheiphila Isolate from an Infected Muskmelon (Cucumis melo).
Dec 11, 2018
Microbiology Resource Announcements
Erwinia tracheiphila is a bacterial plant pathogen emerging in eastern North America. To aid in understanding genetic variation within E. tracheiphila, here we sequence the first reference genome of an infected muskmelon (Cucumis melo). The genome assembles into a single chromosomal contig, three plasmid contigs, and one bacteriophage contig.
The Muskox Lost a Substantial Part of Its Genetic Diversity on Its Long Road to Greenland.
Dec 11, 2018   Current Biology : CB
Hansen CCR, Hvilsom C, Schmidt NM, Aastrup P, Van Coeverden de Groot PJ, Siegismund HR, Heller R
The Muskox Lost a Substantial Part of Its Genetic Diversity on Its Long Road to Greenland.
Dec 11, 2018
Current Biology : CB
The muskox (Ovibos moschatus) is the largest terrestrial herbivore in the Arctic and plays a vital role in the tundra ecosystem [1-4]. Its range, abundance, and genetic diversity have declined dramatically over the past 30,000 years [5]. Two subspecies are recognized, but little is known about the genetic structure and how this relates to the species history. One unresolved question is how and when the species dispersed into its present range, notably the present strongholds in the Canadian archipelago and Greenland. We used genotyping by sequencing (GBS) data from 116 muskox individuals and genotype likelihood-based methods to infer the genetic diversity and distribution of genetic variation in the species. We identified a basal split separating the two recognized subspecies, in agreement with isolation of the muskox into several refugia in the Nearctic around 21,000 years ago [6], near the last glacial maximum (LGM). In addition, we found evidence of strong, successive founder effects inflicting a progressive loss of genetic diversity as the muskox colonized the insular High Arctic from an unknown Nearctic origin. These have resulted in exceptionally low genetic diversity in the Greenlandic populations, as well as extremely high genetic differentiation among regional populations. Our results highlight the need for further investigations of genetic erosion in Nearctic terrestrial mammals, of which several show similar colonization histories in the High Artic.
Sex-specific dominance reversal of genetic variation for fitness.
Dec 11, 2018   PLoS Biology
Grieshop K, Arnqvist G
Sex-specific dominance reversal of genetic variation for fitness.
Dec 11, 2018
PLoS Biology
The maintenance of genetic variance in fitness represents one of the most longstanding enigmas in evolutionary biology. Sexually antagonistic (SA) selection may contribute substantially to maintaining genetic variance in fitness by maintaining alternative alleles with opposite fitness effects in the two sexes. This is especially likely if such SA loci exhibit sex-specific dominance reversal (SSDR)-wherein the allele that benefits a given sex is also dominant in that sex-which would generate balancing selection and maintain stable SA polymorphisms for fitness. However, direct empirical tests of SSDR for fitness are currently lacking. Here, we performed a full diallel cross among isogenic strains derived from a natural population of the seed beetle Callosobruchus maculatus that is known to exhibit SA genetic variance in fitness. We measured sex-specific competitive lifetime reproductive success (i.e., fitness) in >500 sex-by-genotype F1 combinations and found that segregating genetic variation in fitness exhibited pronounced contributions from dominance variance and sex-specific dominance variance. A closer inspection of the nature of dominance variance revealed that the fixed allelic variation captured within each strain tended to be dominant in one sex but recessive in the other, revealing genome-wide SSDR for SA polymorphisms underlying fitness. Our findings suggest that SA balancing selection could play an underappreciated role in maintaining fitness variance in natural populations.
Genetic diversity of the enteroviruses detected from cerebrospinal fluid (CSF) samples of patients with suspected aseptic meningitis in northern West Bank, Palestine in 2017.
Dec 11, 2018   PloS One
Dumaidi K, Al-Jawabreh A, Samarah F, Zraiqi A, Yaseen D
Genetic diversity of the enteroviruses detected from cerebrospinal fluid (CSF) samples of patients with suspected aseptic meningitis in northern West Bank, Palestine in 2017.
Dec 11, 2018
PloS One
BACKGROUND: Human enterovirus genus showed a wide range of genetic diversity. OBJECTIVES: To investigate the genetic diversity of the enteroviruses isolated in 2017 in northern West Bank, Palestine. STUDY DESIGN: 249 CSF samples from aseptic meningitis cases were investigated for HEV using two RT-PCR protocols targeting the 5' NCR and the VP1 region of the HEV genome. The phylogenetic characterization of the sequenced VP1 region of Echovirus18 (E18) and Coxsackievirus B5 (CVB5) isolated in Palestine along with 27 E18 and 27 CVB5 sequences available from the Genbank were described. RESULTS: E18 and CVB5 account for 50% and 35% of the successfully HEV types, respectively. Phylogenetic tree of E18 and CVB5 showed three main clusters, with all Palestinian isolates uniquely clustering together with those from China and from different countries, respectively. Cluster I of E18, with 13 Palestinian and 6 Chinese isolates, showed the lowest haplotype-to-sequence ratio (0.6:1), haplotype diversity (Hd), nucleotide diversity (π), and number of segregating sites (S) compared to clusters II and III. Furthermore, cluster I showed negative Tajima's D and Fu-Li'sF tests with statistically significant departure from neutrality (P
Modeling genome-wide enzyme evolution predicts strong epistasis underlying catalytic turnover rates.
Dec 12, 2018   Nature Communications
Heckmann D, Zielinski DC, Palsson BO
Modeling genome-wide enzyme evolution predicts strong epistasis underlying catalytic turnover rates.
Dec 12, 2018
Nature Communications
Systems biology describes cellular phenotypes as properties that emerge from the complex interactions of individual system components. Little is known about how these interactions have affected the evolution of metabolic enzymes. Here, we combine genome-scale metabolic modeling with population genetics models to simulate the evolution of enzyme turnover numbers (kcats) from a theoretical ancestor with inefficient enzymes. This systems view of biochemical evolution reveals strong epistatic interactions between metabolic genes that shape evolutionary trajectories and influence the magnitude of evolved kcats. Diminishing returns epistasis prevents enzymes from developing higher kcats in all reactions and keeps the organism far from the potential fitness optimum. Multifunctional enzymes cause synergistic epistasis that slows down adaptation. The resulting fitness landscape allows kcat evolution to be convergent. Predicted kcat parameters show a significant correlation with experimental data, validating our modeling approach. Our analysis reveals how evolutionary forces shape modern kcats and the whole of metabolism.
GWAS identifies 14 loci for device-measured physical activity and sleep duration.
Dec 13, 2018   Nature Communications
Doherty A, Smith-Byrne K, Ferreira T, Holmes MV, Holmes C, Pulit SL, Lindgren CM
GWAS identifies 14 loci for device-measured physical activity and sleep duration.
Dec 13, 2018
Nature Communications
Physical activity and sleep duration are established risk factors for many diseases, but their aetiology is poorly understood, partly due to relying on self-reported evidence. Here we report a genome-wide association study (GWAS) of device-measured physical activity and sleep duration in 91,105 UK Biobank participants, finding 14 significant loci (7 novel). These loci account for 0.06% of activity and 0.39% of sleep duration variation. Genome-wide estimates of ~ 15% phenotypic variation indicate high polygenicity. Heritability is higher in women than men for overall activity (23 vs. 20%, p = 1.5 × 10-4) and sedentary behaviours (18 vs. 15%, p = 9.7 × 10-4). Heritability partitioning, enrichment and pathway analyses indicate the central nervous system plays a role in activity behaviours. Two-sample Mendelian randomisation suggests that increased activity might causally lower diastolic blood pressure (beta mmHg/SD: -0.91, SE = 0.18, p = 8.2 × 10-7), and odds of hypertension (Odds ratio/SD: 0.84, SE = 0.03, p = 4.9 × 10-8). Our results advocate the value of physical activity for reducing blood pressure.
A map of constrained coding regions in the human genome.
Dec 11, 2018   Nature Genetics Add nature.com free-link Cancel
Havrilla JM, Pedersen BS, Layer RM, Quinlan AR
A map of constrained coding regions in the human genome.
Dec 11, 2018
Nature Genetics
Deep catalogs of genetic variation from thousands of humans enable the detection of intraspecies constraint by identifying coding regions with a scarcity of variation. While existing techniques summarize constraint for entire genes, single gene-wide metrics conceal regional constraint variability within each gene. Therefore, we have created a detailed map of constrained coding regions (CCRs) by leveraging variation observed among 123,136 humans from the Genome Aggregation Database. The most constrained CCRs are enriched for pathogenic variants in ClinVar and mutations underlying developmental disorders. CCRs highlight protein domain families under high constraint and suggest unannotated or incomplete protein domains. The highest-percentile CCRs complement existing variant prioritization methods when evaluating de novo mutations in studies of autosomal dominant disease. Finally, we identify highly constrained CCRs within genes lacking known disease associations. This observation suggests that CCRs may identify regions under strong purifying selection that, when mutated, cause severe developmental phenotypes or embryonic lethality.
Widespread cis-regulation of RNA-editing in a large mammal.
Dec 11, 2018   RNA (New York, N.Y.)
Lopdell TJ, Hawkins V, Couldrey C, Tiplady K, Davis SR, Snell RG, Harris BL, Littlejohn MD
Widespread cis-regulation of RNA-editing in a large mammal.
Dec 11, 2018
RNA (New York, N.Y.)
Post-transcriptional RNA editing may regulate transcript expression and diversity in cells, with potential impacts on various aspects of physiology and environmental adaptation. A small number of recent genome-wide studies in Drosophila, mouse, and human have shown that RNA editing can be genetically modulated, highlighting loci that quantitatively impact editing of transcripts. The potential gene expression and physiological consequences of these RNA editing quantitative trait loci (edQTL), however, are almost entirely unknown. Here, we present analyses of RNA editing in a large domestic mammal (Bos taurus), where we use whole genome and high depth RNA sequencing to discover, characterise, and conduct genetic mapping studies of novel transcript edits. Using a discovery population of nine deeply-sequenced cows, we identify 2,413 edit sites in the mammary transcriptome, the majority of which are adenosine to inosine edits (98.6%). Most sites are predicted to reside in double-stranded secondary structures (85.1%), and quantification of the rates of editing in an additional 355 cows reveals editing is negatively correlated with gene expression in the majority of cases. Genetic analyses of RNA editing and gene expression highlight 152 cis-regulated edQTL, of which fifteen appear to co-segregate with expression QTL effects. Trait association analyses in a separate population of 9,989 lactating cows also shows twelve of the cis-edQTL coincide with at least one co-segregating lactation QTL. Together, these results enhance our understanding of RNA editing dynamics in mammals, and suggest mechanistic links by which loci may impact phenotype through RNA-editing mediated processes.
Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice.
Dec 11, 2018   Proceedings Of The National Academy Of Sciences Of The United States Of America
Ron-Harel N, Notarangelo G, Ghergurovich JM, Paulo JA, Sage PT, Santos D, Satterstrom FK, Gygi SP, Rabinowitz JD, Sharpe AH, Haigis MC
Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice.
Dec 11, 2018
Proceedings Of The National Academy Of Sciences Of The United States Of America
T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation. We observed a decrease in the number and activation of naïve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity. Using quantitative proteomics, we defined the aged T cell proteome and discovered a specific deficit in the induction of enzymes of one-carbon metabolism. The activation of aged naïve T cells was enhanced by addition of products of one-carbon metabolism (formate and glycine). These studies define mechanisms of skewed metabolic remodeling in aged T cells and provide evidence that modulation of metabolism has the potential to promote immune function in aged individuals.
Rapid evolution of a skin-lightening allele in southern African KhoeSan.
Dec 11, 2018   Proceedings Of The National Academy Of Sciences Of The United States Of America
Lin M, Siford RL, Martin AR, Nakagome S, Möller M, Hoal EG, Bustamante CD, Gignoux CR, Henn BM
Rapid evolution of a skin-lightening allele in southern African KhoeSan.
Dec 11, 2018
Proceedings Of The National Academy Of Sciences Of The United States Of America
Skin pigmentation is under strong directional selection in northern European and Asian populations. The indigenous KhoeSan populations of far southern Africa have lighter skin than other sub-Saharan African populations, potentially reflecting local adaptation to a region of Africa with reduced UV radiation. Here, we demonstrate that a canonical Eurasian skin pigmentation gene, SLC24A5, was introduced to southern Africa via recent migration and experienced strong adaptive evolution in the KhoeSan. To reconstruct the evolution of skin pigmentation, we collected phenotypes from over 400 ≠Khomani San and Nama individuals and high-throughput sequenced candidate pigmentation genes. The derived causal allele in SLC24A5, p.Ala111Thr, significantly lightens basal skin pigmentation in the KhoeSan and explains 8 to 15% of phenotypic variance in these populations. The frequency of this allele (33 to 53%) is far greater than expected from colonial period European gene flow; however, the most common derived haplotype is identical among European, eastern African, and KhoeSan individuals. Using four-population demographic simulations with selection, we show that the allele was introduced into the KhoeSan only 2,000 y ago via a back-to-Africa migration and then experienced a selective sweep (s = 0.04 to 0.05 in ≠Khomani and Nama). The SLC24A5 locus is both a rare example of intense, ongoing adaptation in very recent human history, as well as an adaptive gene flow at a pigmentation locus in humans.
Fluctuating selection on migrant adaptive sodium transporter alleles in coastal Arabidopsis thaliana.
Dec 13, 2018   Proceedings Of The National Academy Of Sciences Of The United States Of America
Busoms S, Paajanen P, Marburger S, Bray S, Huang XY, Poschenrieder C, Yant L, Salt DE
Fluctuating selection on migrant adaptive sodium transporter alleles in coastal Arabidopsis thaliana.
Dec 13, 2018
Proceedings Of The National Academy Of Sciences Of The United States Of America
Stressors such as soil salinity and dehydration are major constraints on plant growth, causing worldwide crop losses. Compounding these insults, increasing climate volatility requires adaptation to fluctuating conditions. Salinity stress responses are relatively well understood in Arabidopsis thaliana, making this system suited for the rapid molecular dissection of evolutionary mechanisms. In a large-scale genomic analysis of Catalonian A. thaliana, we resequenced 77 individuals from multiple salinity gradients along the coast and integrated these data with 1,135 worldwide A. thaliana genomes for a detailed understanding of the demographic and evolutionary dynamics of naturally evolved salinity tolerance. This revealed that Catalonian varieties adapted to highly fluctuating soil salinity are not Iberian relicts but instead have immigrated to this region more recently. De novo genome assembly of three allelic variants of the high-affinity K+ transporter (HKT1;1) locus resolved structural variation between functionally distinct alleles undergoing fluctuating selection in response to seasonal changes in soil salinity. Plants harboring alleles responsible for low root expression of HKT1;1 and consequently high leaf sodium (HKT1;1 HLS ) were migrants that have moved specifically into areas where soil sodium levels fluctuate widely due to geography and rainfall variation. We demonstrate that the proportion of plants harboring HKT1;1 HLS alleles correlates with soil sodium level over time, HKT1;1 HLS -harboring plants are better adapted to intermediate levels of salinity, and the HKT1;1 HLS allele clusters with high-sodium accumulator accessions worldwide. Together, our evidence suggests that HKT1;1 is under fluctuating selection in response to climate volatility and is a worldwide determinant in adaptation to saline conditions.
Genetic variation in TLR pathway and the risk of pulmonary tuberculosis in a Moldavian population.
Dec 11, 2018   Infection, Genetics And Evolution : Journal Of Molecular Epidemiology And Evolutionary Genetics In Infectious Diseases
Varzari A, Deyneko IV, Vladei I, Grallert H, Schieck M, Tudor E, Illig T
Genetic variation in TLR pathway and the risk of pulmonary tuberculosis in a Moldavian population.
Dec 11, 2018
Infection, Genetics And Evolution : Journal Of Molecular Epidemiology And Evolutionary Genetics In Infectious Diseases
Toll-like receptors (TLRs) play a critical role in initiating an immune response to infections. In this study, we examined whether single nucleotide polymorphisms (SNPs) in TLR pathway genes are associated with pulmonary tuberculosis (PTB) in a Moldavian population. Thirty-four SNPs in genes associated with the TLR pathway and two SNPs in ASAP1 gene identified by GWAS were selected for genotyping in 272 patients and 251 community-matched healthy controls. Twenty-nine SNPs passed quality control and were statistically evaluated. SNPs TLR9 rs352139, TLR2 rs3804099 and MYD88 rs4988453 were associated with PTB in females (OR = 0.49, p = 0.0009; OR = 0.51, p = 0.0008; OR = 0.33, p = 0.027; here and below log-additive model with minor alleles assumed as effect associated alleles), while SNP TLR8 rs3764880 showed a significant association in males (OR = 0.44, p = 0.0087). Furthermore, SNPs TLR9 rs352139 and TLR8 rs3764880 were associated with PTB in the late-onset (≥39-year-old) patient group (OR = 0.60, p = 0.0029 and OR = 0.70, p = 0.021, respectively) and SNPs TLR2 rs3804099, TLR4 rs4986790 and TLR4 rs1927906 in the early-onset (≤ 38-year-old) group (OR = 0.53, p = 0.0012; OR = 3.45, p = 0.013; OR = 2.31, p = 0.044, respectively). After correction for multiple testing, only SNPs TLR9 rs352139 and TLR2 rs3804099 in the female group and SNP TLR2 rs3804099 in the early-onset group remained significant. In summary, we show an association of SNP TLR8 rs3764880 with PTB in the Moldavian male population, providing support to previous studies conducted on other populations. Polymorphisms rs3804099 (TLR2) and rs352139 (TLR9) may also be associated with PTB risk in the Moldavian population but their effect is less consistent across different studies. Additional large-scale association studies along with functional tests are required to dissect the relevance of these associations.
Plant compartment and genetic variation drive microbiome composition in switchgrass roots.
Dec 11, 2018   Environmental Microbiology Reports
Singer E, Bonnette J, Kenaley S, Woyke T, Juenger TE
Plant compartment and genetic variation drive microbiome composition in switchgrass roots.
Dec 11, 2018
Environmental Microbiology Reports
Switchgrass (Panicum virgatum) is a promising biofuel crop native to the United States with genotypes that are adapted to a wide range of distinct ecosystems. Various plants have been shown to undergo symbioses with plant growth promoting bacteria and fungi, however, plant-associated microbial communities of switchgrass have not been extensively studied to date. We present 16S ribosomal RNA gene and internal transcribed spacer (ITS) data of rhizosphere and root endosphere compartments of four switchgrass genotypes to test the hypothesis that host selection of its root microbiota prevails after transfer to non-native soil. We show that differences in bacterial, archaeal, and fungal community composition and diversity are strongly driven by plant compartment and switchgrass geno- and ecotypes. Plant-associated microbiota show an enrichment in Alphaproteobacteria and Actinobacteria as well as Sordariales and Pleosporales compared to the surrounding soil. Root associated compartments display low-complexity communities dominated and enriched in Actinobacteria, in particular Streptomyces, in the lowland genotypes, and in Alphaproteobacteria, specifically Sphingobium, in the upland genotypes. Our comprehensive root analysis serves as a snapshot into host-specific bacterial and fungal associations of switchgrass in the field and confirms that host-selected microbiomes persist after transfer to non-native soil. This article is protected by copyright. All rights reserved.

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