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Population Genetics
Polytropic Influence of TRIB3 rs2295490 Genetic Polymorphism on Response to Antihypertensive Agents in Patients With Essential Hypertension.
Apr 14, 2019   Frontiers In Pharmacology
Zhou J, He F, Sun B, Liu R, Gao Y,   . . . . . .   , Deng S, Xu H, Li J, Xu L, Zhang W
Polytropic Influence of TRIB3 rs2295490 Genetic Polymorphism on Response to Antihypertensive Agents in Patients With Essential Hypertension.
Apr 14, 2019
Frontiers In Pharmacology
Tribbles homolog 3 (TRIB3) mediating signaling pathways are closely related to blood pressure regulation. Our previous findings suggested a greater benefit on vascular outcomes in patients carrying TRIB3 (251, A > G, rs2295490) G allele with good glucose and blood pressure control. And TRIB3 (rs2295490) AG/GG genotypes were found to reduce primary vascular events in type 2 diabetic patients who received intensive glucose treatment as compared to those receiving standard glucose treatment. However, the effect of TRIB3 genetic variation on antihypertensives was not clear in essential hypertension patients. A total of 368 patients treated with conventional dosage of antihypertensives (6 groups, grouped by atenolol/bisoprolol, celiprolol, doxazosin, azelnidipine/nitrendipine, imidapril, and candesartan/irbesartan) were enrolled in our study. Genetic variations were successfully identified by sanger sequencing. A linear mixed model analysis was performed to evaluate blood pressures among TRIB3 (251, A > G) genotypes and adjusted for baseline age, gender, body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol and other biochemical factors appropriately. Our data suggested that TRIB3 (251, A > G) AA genotype carriers showed better antihypertensive effect than the AG/GG genotype carriers [P = 0.014 for DBP and P = 0.042 for mean arterial pressure (MAP)], with a maximal reduction of DBP by 4.2 mmHg and MAP by 3.56 mmHg after azelnidipine or nitrendipine treatment at the 4th week. Similar tendency of DBP-change and MAP-change was found for imidapril (ACEI) treatment, in which marginally significances were achieved (P = 0.073 and 0.075, respectively). Against that, we found that TRIB3 (251, A > G) AG/GG genotype carriers benefited from antihypertensive therapy of ARBs with a larger DBP-change during the period of observation (P = 0.036). Additionally, stratified analysis revealed an obvious difference of the maximal blood pressure change (13 mmHg for the MAP between male and female patients with AA genotype who took ARBs). Although no significant difference in antihypertensive effect between TRIB3 (251, A > G) genotypes in patients treated with α, β-ADRs was observed, we found significant difference in age-, sex-dependent manner related to α, β-ADRs. In conclusion, our data supported that TRIB3 (251, A > G) genetic polymorphism may serve as a useful biomarker in the treatment of hypertension.
Pervasive admixture between eucalypt species has consequences for conservation and assisted migration.
Apr 14, 2019   Evolutionary Applications
von Takach Dukai B, Jack C, Borevitz J, Lindenmayer DB, Banks SC
Pervasive admixture between eucalypt species has consequences for conservation and assisted migration.
Apr 14, 2019
Evolutionary Applications
Conservation management often uses information on genetic population structure to assess the importance of local provenancing for ecological restoration and reintroduction programs. For species that do not exhibit complete reproductive isolation, the estimation of population genetic parameters may be influenced by the extent of admixture. Therefore, to avoid perverse outcomes for conservation, genetically informed management strategies must determine whether hybridization between species is relevant, and the extent to which observed population genetic patterns are shaped by interspecific versus intraspecific gene flow. We used genotyping by sequencing to identify over 2,400 informative single nucleotide polymorphisms across 18 populations of Eucalyptus regnans F. Muell., a foundation tree species of montane forests in south-eastern Australia. We used these data to determine the extent of hybridization with another species, Eucalyptus obliqua L'Hér., and investigate how admixture influences genetic diversity parameters, by estimating metrics of genetic diversity and examining population genetic structure in datasets with and without admixed individuals. We found hybrid individuals at all sites and two highly introgressed populations. Hybrid individuals were not distributed evenly across environmental gradients, with logistic regression identifying hybrids as being associated with temperature. Removal of hybrids resulted in increases in genetic differentiation (F ST), expected heterozygosity, observed heterozygosity and the inbreeding coefficient, and different patterns of isolation by distance. After removal of hybrids and introgressed populations, mountain ash showed very little population genetic structure, with a small effect of isolation by distance, and very low global F ST(0.03). Our study shows that, in plants, decisions around provenancing of individuals for restoration depend on knowledge of whether hybridization is influencing population genetic structure. For species in which most genetic variation is held within populations, there may be little benefit in planning conservation strategies around environmental adaptation of seed sources. The possibility for adaptive introgression may also be relevant when species regularly hybridize.
DNA motifs are not general predictors of recombination in two Drosophila sister species.
Apr 13, 2019   Genome Biology And Evolution
Howie JM, Mazzucco R, Taus T, Nolte V, Schlötterer C
DNA motifs are not general predictors of recombination in two Drosophila sister species.
Apr 13, 2019
Genome Biology And Evolution
Meiotic recombination is crucial for chromosomal segregation, and facilitates the spread of beneficial and removal of deleterious mutations. Recombination rates frequently vary along chromosomes and Drosophila melanogaster exhibits a remarkable pattern. Recombination rates gradually decrease towards centromeres and telomeres, with a dramatic impact on levels of variation in natural populations. Two close sister species, D. simulans and D. mauritiana do not only have higher recombination rates, but also exhibit a much more homogeneous recombination rate that only drops sharply very close to centromeres and telomeres. Because certain sequence motifs are associated with recombination rate variation in D. melanogaster, we tested whether the difference in recombination landscape between D. melanogaster and D. simulans can be explained by the genomic distribution of recombination-rate associated sequence motifs. We constructed the first high-resolution recombination map for D. simulans based on 189 haplotypes from a natural D. simulans population, and searched for short sequence motifs linked with higher than average recombination in both sister species. We identified five consensus motifs significantly associated with higher than average chromosome-wide recombination rates in at least one species and present in both. Testing fine resolution associations between motif density and recombination, we found strong and positive associations genome-wide over a range of scales in D. melanogaster, while the results were equivocal in D. simulans. Despite the strong association in D. melanogaster, we did not find a decreasing density of these short-repeat motifs towards centromeres and telomeres. We conclude that the density of recombination-associated repeat motifs cannot explain the large-scale recombination landscape in D. melanogaster, nor the differences to D. simulans. The strong association seen for the sequence motifs in D. melanogaster likely reflects their impact influencing local differences in recombination rates along the genome.
Contrasting paternal and maternal genetic histories of Thai and Lao populations.
Apr 13, 2019   Molecular Biology And Evolution
Kutanan W, Kampuansai J, Srikummool M, Brunelli A, Ghirotto S, Arias L, Macholdt E, Hübner A, Schröder R, Stoneking M
Contrasting paternal and maternal genetic histories of Thai and Lao populations.
Apr 13, 2019
Molecular Biology And Evolution
The human demographic history of Mainland Southeast Asia (MSEA) has not been well-studied; in particular there have been very few sequence-based studies of variation in the male-specific portions of the Y chromosome (MSY). Here, we report new MSY sequences of ∼2.3 mB from 914 males, and combine these with previous data for a total of 928 MSY sequences belonging to 59 populations from Thailand and Laos who speak languages belonging to three major MSEA families: Austroasiatic (AA), Tai-Kadai (TK) and Sino-Tibetan (ST). Among the 92 MSY haplogroups, two main MSY lineages (O1b1a1a* (O-M95*) and O2a* (O-M324*)) contribute substantially to the paternal genetic makeup of Thailand and Laos. We also analyse complete mtDNA genome sequences published previously from the same groups, and find contrasting pattern of male and female genetic variation and demographic expansions, especially for the hill tribes, Mon, and some major Thai groups. In particular, we detect an effect of post-marital residence pattern on genetic diversity in patrilocal vs. matrilocal groups. Additionally, both male and female demographic expansions were observed during the early Mesolithic (∼10 kya), with two later major male-specific expansions during the Neolithic period (∼4-5 kya) and the Bronze/Iron Age (∼2.0-2.5 kya). These two later expansions are characteristic of the modern AA and TK groups, respectively, consistent with recent ancient DNA studies. We simulate MSY data based on three demographic models (continuous migration, demic diffusion and cultural diffusion) of major Thai groups and find different results from mtDNA simulations, supporting contrasting male and female genetic histories.
The importance of slow canopy wilting in drought tolerance in soybean.
Apr 13, 2019   Journal Of Experimental Botany
Ye H, Song L, Schapaugh WT, Ali ML, Sinclair TR,   . . . . . .   , Klepadlo M, Song Q, Shannon JG, Chen P, Nguyen HT
The importance of slow canopy wilting in drought tolerance in soybean.
Apr 13, 2019
Journal Of Experimental Botany
Slow canopy wilting (SW) is a water-conservation trait controlled by quantitative trait loci (QTL) in late maturity-group soybeans [Glycine max (L.) Merr.]. Recently, two exotic (landraces) plant-introductions (PI 567690 and PI 567731) were identified as new SW lines in early maturity-groups. Here, we show that the two PIs share the same water conservation strategy of limited-maximum transpiration rates as PI 416937. However, in contrast to PI 416937, the transpiration rates of these PIs were sensitive to an aquaporin inhibitor, indicating an independence between limited-maximum transpiration and the lack of silver-sensitive aquaporins. Yield tests of selected recombinant-inbred lines from two elite/exotic crosses provide direct evidence to support the benefit of SW in drought tolerance. Four SW QTL mapped in a Pana × PI 567690 cross at multiple environments were found to be co-located with previous reports. Moreover, two new SW QTL were mapped on chromosomes 6 and 10 from a Magellan × PI 567731 cross. These two QTL explain the observed relatively large contributions of 20 to 30% and were confirmed in a near-isogenic background. These findings demonstrate the importance of SW in yield protection under drought and provide genetic resources for improving drought tolerance in early maturity-group soybeans.
The Future of Genomic Studies Must Be Globally Representative: Perspectives from PAGE.
Apr 12, 2019   Annual Review Of Genomics And Human Genetics
Bien SA, Wojcik GL, Hodonsky CJ, Gignoux CR, Cheng I, Matise TC, Peters U, Kenny EE, North KE
The Future of Genomic Studies Must Be Globally Representative: Perspectives from PAGE.
Apr 12, 2019
Annual Review Of Genomics And Human Genetics
The past decade has seen a technological revolution in human genetics that has empowered population-level investigations into genetic associations with phenotypes. Although these discoveries rely on genetic variation across individuals, association studies have overwhelmingly been performed in populations of European descent. In this review, we describe limitations faced by single-population studies and provide an overview of strategies to improve global representation in existing data sets and future human genomics research via diversity-focused, multiethnic studies. We highlight the successes of individual studies and meta-analysis consortia that have provided unique knowledge. Additionally, we outline the approach taken by the Population Architecture Using Genomics and Epidemiology (PAGE) study to develop best practices for performing genetic epidemiology in multiethnic contexts. Finally, we discuss how limiting investigations to single populations impairs findings in the clinical domain for both rare-variant identification and genetic risk prediction. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 30, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
SNP and indel frequencies at transcription start sites and at canonical and alternative translation initiation sites in the human genome.
Apr 12, 2019   PloS One
Neininger K, Marschall T, Helms V
SNP and indel frequencies at transcription start sites and at canonical and alternative translation initiation sites in the human genome.
Apr 12, 2019
PloS One
Single-nucleotide polymorphisms (SNPs) are the most common form of genetic variation in humans and drive phenotypic variation. Due to evolutionary conservation, SNPs and indels (insertion and deletions) are depleted in functionally important sequence elements. Recently, population-scale sequencing efforts such as the 1000 Genomes Project and the Genome of the Netherlands Project have catalogued large numbers of sequence variants. Here, we present a systematic analysis of the polymorphisms reported by these two projects in different coding and non-coding genomic elements of the human genome (intergenic regions, CpG islands, promoters, 5' UTRs, coding exons, 3' UTRs, introns, and intragenic regions). Furthermore, we were especially interested in the distribution of SNPs and indels in direct vicinity to the transcription start site (TSS) and translation start site (CSS). Thereby, we discovered an enrichment of dinucleotides CpG and CpA and an accumulation of SNPs at base position -1 relative to the TSS that involved primarily CpG and CpA dinucleotides. Genes having a CpG dinucleotide at TSS position -1 were enriched in the functional GO terms "Phosphoprotein", "Alternative splicing", and "Protein binding". Focusing on the CSS, we compared SNP patterns in the flanking regions of canonical and alternative AUG and near-cognate start sites where we considered alternative starts previously identified by experimental ribosome profiling. We observed similar conservation patterns of canonical and alternative translation start sites, which underlines the importance of alternative translation mechanisms for cellular function.
Environmental heterogeneity can tip the population genetics of range expansions.
Apr 12, 2019   ELife
Gralka M, Hallatschek O
Environmental heterogeneity can tip the population genetics of range expansions.
Apr 12, 2019
ELife
The population genetics of most range expansions is thought to be shaped by the competition between Darwinian selection and random genetic drift at the range margins. Here, we show that the evolutionary dynamics during range expansions is highly sensitive to additional fluctuations induced by environmental heterogeneities. Tracking mutant clones with a tunable fitness effect in bacterial colonies grown on randomly patterned surfaces we found that environmental heterogeneity can dramatically reduce the efficacy of selection. Time-lapse microscopy and computer simulations suggest that this effect arises generically from a local 'pinning' of the expansion front, whereby stretches of the front are slowed down on a length scale that depends on the structure of the environmental heterogeneity. This pinning focuses the range expansion into a small number of 'lucky' individuals with access to expansion paths, altering the neutral evolutionary dynamics and increasing the importance of chance relative to selection.
Testing for Hardy-Weinberg Equilibrium in Structured Populations using Genotype or Low-Depth NGS Data.
Apr 12, 2019   Molecular Ecology Resources
Meisner J, Albrechtsen A
Testing for Hardy-Weinberg Equilibrium in Structured Populations using Genotype or Low-Depth NGS Data.
Apr 12, 2019
Molecular Ecology Resources
Testing for deviations from Hardy-Weinberg Equilibrium (HWE) is a common practice for quality control in genetic studies. Variable sites violating HWE may be identified as technical errors in the sequencing or genotyping process, or they may be of special evolutionary interest. Large-scale genetic studies based on next-generation sequencing (NGS) methods have become more prevalent as cost is decreasing but these methods are still associated with statistical uncertainty. The large-scale studies usually consist of samples from diverse ancestries that make the existence of some degree of population structure almost inevitable. Precautions are therefore needed when analyzing these datasets, as population structure causes deviations from HWE. Here we propose a method that takes population structure into account in the testing for HWE, such that other factors causing deviations from HWE can be detected. We show the effectiveness of PCAngsd in low-depth NGS data, as well as in genotype data, for both simulated and real datasets, where the use of genotype likelihoods enables us to model the uncertainty. This article is protected by copyright. All rights reserved.
Genome-wide association study and candidate gene analysis of alkalinity tolerance in japonica rice germplasm at the seedling stage.
Apr 12, 2019   Rice (New York, N.Y.)
Li N, Zheng H, Cui J, Wang J, Liu H, Sun J, Liu T, Zhao H, Lai Y, Zou D
Genome-wide association study and candidate gene analysis of alkalinity tolerance in japonica rice germplasm at the seedling stage.
Apr 12, 2019
Rice (New York, N.Y.)
BACKGROUND: Salinity-alkalinity stress is one of the major factors limiting rice production. The damage caused by alkaline salt stress to rice growth is more severe than that caused by neutral salt stress. At present, the genetic resources (quantitative trait loci (QTLs) and genes) that can be used by rice breeders to improve alkalinity tolerance are limited. Here, we assessed the alkalinity tolerance of rice at the seedling stage and performed a genome-wide association study (GWAS) based on genotypic data including 788,396 single-nucleotide polymorphisms (SNPs) developed by re-sequencing 295 japonica rice varieties. RESULTS: We used the score of alkalinity tolerance (SAT), the concentrations of Na+ and K+ in the shoots (SNC and SKC, respectively) and the Na+/K+ ratio of shoots (SNK) as indices to assess alkalinity tolerance at the seedling stage in rice. Based on population structure analysis, the japonica rice panel was divided into three subgroups. Linkage disequilibrium (LD) analysis showed that LD decay occurred at 109.77 kb for the whole genome and varied between 13.79 kb and 415.77 kb across the 12 chromosomes, at which point the pairwise squared correlation coefficient (r2) decreased to half of its maximum value. A total of eight QTLs significantly associated with the SAT, SNC and SNK were identified by genome-wide association mapping. A common QTL associated with the SAT, SNC and SNK on chromosome 3 at the position of 15.0 Mb, which explaining 13.36~13.64% of phenotypic variation, was selected for further analysis. The candidate genes were filtered based on LD decay, Gene Ontology (GO) enrichment, RNA sequencing data, and quantitative real-time PCR (qRT-PCR) analysis. Moreover, sequence analysis revealed one 7-bp insertion/deletion (indel) difference in LOC_Os03g26210 (OsIRO3) between the alkalinity-tolerant and alkalinity-sensitive rice varieties. OsIRO3 encodes a bHLH-type transcription factor and has been shown to be a negative regulator of the Fe-deficiency response in rice. CONCLUSION: Based on these results, OsIRO3 maybe a novel functional gene associated with alkalinity tolerance in japonica rice. This study provides resources for improving alkalinity tolerance in rice, and the functional molecular marker could be verified to breed new rice varieties with alkalinity tolerance via marker-assisted selection (MAS).
STX1A gene variations contribute to the susceptibility of children attention-deficit/hyperactivity disorder: a case-control association study.
Apr 12, 2019   European Archives Of Psychiatry And Clinical Neuroscience
Wang M, Gu X, Huang X, Zhang Q, Chen X, Wu J
STX1A gene variations contribute to the susceptibility of children attention-deficit/hyperactivity disorder: a case-control association study.
Apr 12, 2019
European Archives Of Psychiatry And Clinical Neuroscience
It was presumed syntaxin-1A (STX1A) might relate to the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), but the results were inconsistent. The present study aims to confirm whether the STX1A gene is involved in the susceptibility of children ADHD. We genotyped three single nucleotide polymorphisms (SNPs) of STX1A gene using Sequenom MassARRAY technology. A case-control study was performed among Chinese Han population including 754 cases and 772 controls from two different provinces. The Conners Parent Symptom Questionnaire and Integrated Visual and Auditory Continuous Performance Test were used to assess ADHD clinical symptoms. We found for the first time that rs3793243 GG genotype carriers had a lower risk of ADHD compared with AA genotype (OR 0.564, 95% confidence interval (CI) 0.406-0.692, P = 0.001), and rs875342 was also associated with children ADHD (OR 1.806, 95% CI 1.349-2.591, P = 0.001). In addition, the two positive SNPs were also significantly associated with the clinical characteristics of ADHD. Expression quantitative trait loci analysis indicated that rs3793243 might mediate STX1A gene expression. Using a case-control study to explore the association between STX1A gene and children ADHD in Chinese Han population, our results suggest STX1A genetic variants might contribute to the susceptibility of children ADHD.
A wheat/rye polymorphism affects seminal root length and yield across different irrigation regimes.
Apr 12, 2019   Journal Of Experimental Botany
Howell T, Moriconi JI, Zhao X, Hegarty J, Fahima T, Santa-Maria GE, Dubcovsky J
A wheat/rye polymorphism affects seminal root length and yield across different irrigation regimes.
Apr 12, 2019
Journal Of Experimental Botany
The introgression of a small segment of wheat (Triticumaestivum L.) chromosome arm 1BS in the distal region of rye (Secalecereale L.) 1RS.1BL arm translocation in wheat (henceforth 1RSRW) was previously associated with reduced grain yield, carbon isotope discrimination and stomatal conductance, suggesting reduced access to soil moisture. Here we show that lines with the normal 1RS arm have longer roots than lines with the 1RSRW arm in both field and hydroponic experiments. In the 1RSRW lines, differences in seminal root length were associated with a developmentally regulated arrest of the root apical meristem (RAM). Approximately 10 days after germination, the seminal roots of the 1RSRW plants showed a gradual reduction in elongation rate, and stopped growing a week later. Seventeen days after germination, the roots of the 1RSRW plants showed altered gradients of reactive oxygen species and emergence of lateral roots close to the RAM, suggesting changes in the root meristem. The 1RSRW lines also showed reduced biomass (estimated by Normalized Differences Vegetation Index) and grain yield relative to the 1RS lines, with larger differences under reduced or excessive irrigation than under normal irrigation. These results suggest that this genetic variation could be useful to modulate root architecture.
Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders.
Apr 12, 2019   Molecular Psychiatry
Xia Y, Dai R, Wang K, Jiao C, Zhang C, Xu Y, Li H, Jing X, Chen Y, Jiang Y, Kopp RF, Giase G, Chen C, Liu C
Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders.
Apr 12, 2019
Molecular Psychiatry
Many psychiatric disorders are characterized by a strong sex difference, but the mechanisms behind sex-bias are not fully understood. DNA methylation plays important roles in regulating gene expression, ultimately impacting sexually different characteristics of the human brain. Most previous literature focused on DNA methylation alone without considering the regulatory network and its contribution to sex-bias of psychiatric disorders. Since DNA methylation acts in a complex regulatory network to connect genetic and environmental factors with high-order brain functions, we investigated the regulatory networks associated with different DNA methylation and assessed their contribution to the risks of psychiatric disorders. We compiled data from 1408 postmortem brain samples in 3 collections to identify sex-differentially methylated positions (DMPs) and regions (DMRs). We identified and replicated thousands of DMPs and DMRs. The DMR genes were enriched in neuronal related pathways. We extended the regulatory networks related to sex-differential methylation and psychiatric disorders by integrating methylation quantitative trait loci (meQTLs), gene expression, and protein-protein interaction data. We observed significant enrichment of sex-associated genes in psychiatric disorder-associated gene sets. We prioritized 2080 genes that were sex-biased and associated with psychiatric disorders, such as NRXN1, NRXN2, NRXN3, FDE4A, and SHANK2. These genes are enriched in synapse-related pathways and signaling pathways, suggesting that sex-differential genes of these neuronal pathways may cause the sex-bias of psychiatric disorders.
A QTL for Number of Teats Shows Breed Specific Effects on Number of Vertebrae in Pigs: Bridging the Gap Between Molecular and Quantitative Genetics.
Apr 14, 2019   Frontiers In Genetics
van Son M, Lopes MS, Martell HJ, Derks MFL, Gangsei LE, Kongsro J, Wass MN, Grindflek EH, Harlizius B
A QTL for Number of Teats Shows Breed Specific Effects on Number of Vertebrae in Pigs: Bridging the Gap Between Molecular and Quantitative Genetics.
Apr 14, 2019
Frontiers In Genetics
Modern breeding schemes for livestock species accumulate a large amount of genotype and phenotype data which can be used for genome-wide association studies (GWAS). Many chromosomal regions harboring effects on quantitative traits have been reported from these studies, but the underlying causative mutations remain mostly undetected. In this study, we combine large genotype and phenotype data available from a commercial pig breeding scheme for three different breeds (Duroc, Landrace, and Large White) to pinpoint functional variation for a region on porcine chromosome 7 affecting number of teats (NTE). Our results show that refining trait definition by counting number of vertebrae (NVE) and ribs (RIB) helps to reduce noise from other genetic variation and increases heritability from 0.28 up to 0.62 NVE and 0.78 RIB in Duroc. However, in Landrace, the effect of the same QTL on NTE mainly affects NVE and not RIB, which is reflected in reduced heritability for RIB (0.24) compared to NVE (0.59). Further, differences in allele frequencies and accuracy of rib counting influence genetic parameters. Correction for the top SNP does not detect any other QTL effect on NTE, NVE, or RIB in Landrace or Duroc. At the molecular level, haplotypes derived from 660K SNP data detects a core haplotype of seven SNPs in Duroc. Sequence analysis of 16 Duroc animals shows that two functional mutations of the Vertnin (VRTN) gene known to increase number of thoracic vertebrae (ribs) reside on this haplotype. In Landrace, the linkage disequilibrium (LD) extends over a region of more than 3 Mb also containing both VRTN mutations. Here, other modifying loci are expected to cause the breed-specific effect. Additional variants found on the wildtype haplotype surrounding the VRTN region in all sequenced Landrace animals point toward breed specific differences which are expected to be present also across the whole genome. This Landrace specific haplotype contains two missense mutations in the ABCD4 gene, one of which is expected to have a negative effect on the protein function. Together, the integration of largescale genotype, phenotype and sequence data shows exemplarily how population parameters are influenced by underlying variation at the molecular level.
DNA methylation of dopamine-related gene promoters is associated with line bisection deviation in healthy adults.
Apr 17, 2019   Scientific Reports
Schmitz J, Kumsta R, Moser D, Güntürkün O, Ocklenburg S
DNA methylation of dopamine-related gene promoters is associated with line bisection deviation in healthy adults.
Apr 17, 2019
Scientific Reports
Handedness and language lateralization are the most investigated phenotypes among functional hemispheric asymmetries, i.e. differences in function between the left and the right half of the human brain. Both phenotypes are left hemisphere-dominant, while investigations of the molecular factors underlying right hemisphere-dominant phenotypes are less prominent. In the classical line bisection task, healthy subjects typically show a leftward attentional bias due to a relative dominance of the right hemisphere for visuospatial attention. Based on findings of variations in dopamine-related genes affecting performance in the line bisection task, we first tested whether DNA methylation in non-neuronal tissue in the promoter regions of DBH, SLC6A3, and DRD2 are associated with line bisection deviation. We replicated the typical behavioral pattern and found an effect of DNA methylation in the DBH promoter region on line bisection deviation in right-aligned trials. A second exploratory analysis indicated that an overall DNA methylation profile of genes involved in dopamine function predicts line bisection performance in right-aligned trials. Genetic variation in dopamine-related genes has been linked to attention deficit hyperactivity disorder (ADHD), a neurodevelopmental trait associated with rightward attentional bias. Overall, our findings point towards epigenetic markers for functional hemispheric asymmetries in non-neuronal tissue not only for left hemisphere-dominant, but also for right hemisphere-dominant phenotypes.
Exome array analysis of rare and low frequency variants in amyotrophic lateral sclerosis.
Apr 17, 2019   Scientific Reports
Dekker AM, Diekstra FP, Pulit SL, Tazelaar GHP, van der Spek RA,   . . . . . .   , Ludolph AC, Weishaupt JH, Pardina JSM, van den Berg LH, Veldink JH
Exome array analysis of rare and low frequency variants in amyotrophic lateral sclerosis.
Apr 17, 2019
Scientific Reports
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 1 in ~350 individuals. Genetic association studies have established ALS as a multifactorial disease with heritability estimated at ~61%, and recent studies show a prominent role for rare variation in its genetic architecture. To identify rare variants associated with disease onset we performed exome array genotyping in 4,244 cases and 3,106 controls from European cohorts. In this largest exome-wide study of rare variants in ALS to date, we performed single-variant association testing, gene-based burden, and exome-wide individual set-unique burden (ISUB) testing to identify single or aggregated rare variation that modifies disease risk. In single-variant testing no variants reached exome-wide significance, likely due to limited statistical power. Gene-based burden testing of rare non-synonymous and loss-of-function variants showed NEK1 as the top associated gene. ISUB analysis did not show an increased exome-wide burden of deleterious variants in patients, possibly suggesting a more region-specific role for rare variation. Complete summary statistics are released publicly. This study did not implicate new risk loci, emphasizing the immediate need for future large-scale collaborations in ALS that will expand available sample sizes, increase genome coverage, and improve our ability to detect rare variants associated to ALS.
Genetic Variation for Ontogenetic Shifts in Metabolism Underlies Physiological Homeostasis in Drosophila.
Apr 12, 2019   Genetics
Matoo OB, Julick CR, Montooth KL
Genetic Variation for Ontogenetic Shifts in Metabolism Underlies Physiological Homeostasis in Drosophila.
Apr 12, 2019
Genetics
Organismal physiology emerges from metabolic pathways and subcellular structures like the mitochondria that can vary across development and among individuals. Here we tested whether genetic variation at one level of physiology can be buffered at higher biological levels of organization during development by the inherent capacity for homeostasis in physiological systems. We found that the fundamental scaling relationship between mass and metabolic rate, as well as the oxidative capacity per mitochondria, changed significantly across development in the fruit fly Drosophila However, mitochondrial respiration rate was maintained at similar levels across development. Furthermore, larvae clustered into two types-those that switched to aerobic, mitochondrial ATP production before the second instar and those that relied on anaerobic, glycolytic production of ATP through the second instar. Despite genetic variation for the timing of this metabolic shift, metabolic rate in second-instar larvae was more robust to genetic variation than was the metabolic rate of other instars. We found that larvae with a mitochondrial-nuclear incompatibility that disrupts mitochondrial function had increased aerobic capacity and relied more on anaerobic ATP production throughout development relative to larvae from wild-type strains. By taking advantage of both ways of making ATP, larvae with this mitochondrial-nuclear incompatibility maintained mitochondrial respiratory capacity, but also had higher levels of whole-body reactive oxygen species and decreased mitochondrial membrane potential, potentially as a physiological defense mechanism. Thus, genetic defects in core physiology can be buffered at the organismal level via physiological plasticity and natural populations may harbor genetic variation for distinct metabolic strategies in development that generate similar organismal outcomes.
Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population.
Apr 12, 2019   Journal Of The American Society Of Nephrology : JASN
Tanikawa C, Kamatani Y, Terao C, Usami M, Takahashi A,   . . . . . .   , Yu ASL, Yasui T, Murakami Y, Kubo M, Matsuda K
Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population.
Apr 12, 2019
Journal Of The American Society Of Nephrology : JASN
BACKGROUND: A family history of urolithiasis is associated with a more than doubling of urolithiasis risk, and a twin study estimating 56% heritability of the condition suggests a pivotal role for host genetic factors. However, previous genome-wide association studies (GWAS) have identified only six risk-related loci. METHODS: To identify novel urolithiasis-related loci in the Japanese population, we performed a large-scale GWAS of 11,130 cases and 187,639 controls, followed by a replication analysis of 2289 cases and 3817 controls. Diagnosis of urolithiasis was confirmed either by a clinician or using medical records or self-report. We also assessed the association of urolithiasis loci with 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (such as body mass index, lipid storage, eGFR, serum uric acid, and serum calcium), using up to 160,000 samples from BioBank Japan. RESULTS: The analysis identified 14 significant loci, including nine novel loci. Ten regions showed a significant association with at least one quantitative trait, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic basis for urolithiasis and these quantitative traits. Four novel loci were related to metabolic traits, obesity, hypertriglyceridemia, or hyperuricemia. The remaining ten loci were associated with kidney- or electrolyte-related traits; these may affect crystallization. Weighted genetic risk score analysis indicated that the highest risk group (top 20%) showed an odds ratio of 1.71 (95% confidence interval, 1.42 to 2.06) - 2.13 (95% confidence interval, 2.00 to 2.27) compared with the reference group (bottom 20%). CONCLUSIONS: Our findings provide evidence that host genetic factors related to regulation of metabolic and crystallization pathways contribute to the development of urolithiasis.
Acute effects of ∆9-tetrahydrocannabinol (THC) on resting state brain function and their modulation by COMT genotype.
Apr 12, 2019   European Neuropsychopharmacology : The Journal Of The European College Of Neuropsychopharmacology
Bossong MG, van Hell HH, Schubart CD, van Saane W, Iseger TA, Jager G, van Osch MJP, Jansma JM, Kahn RS, Boks MP, Ramsey NF
Acute effects of ∆9-tetrahydrocannabinol (THC) on resting state brain function and their modulation by COMT genotype.
Apr 12, 2019
European Neuropsychopharmacology : The Journal Of The European College Of Neuropsychopharmacology
Cannabis produces a broad range of acute, dose-dependent psychotropic effects. Only a limited number of neuroimaging studies have mapped these effects by examining the impact of cannabis on resting state brain neurophysiology. Moreover, how genetic variation influences the acute effects of cannabis on resting state brain function is unknown. Here we investigated the acute effects of ∆9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on resting state brain neurophysiology, and their modulation by catechol-methyl-transferase (COMT) Val158Met genotype. Thirty-nine healthy volunteers participated in a pharmacological MRI study, where we applied Arterial Spin Labelling (ASL) to measure perfusion and functional MRI to assess resting state connectivity. THC increased perfusion in bilateral insula, medial superior frontal cortex, and left middle orbital frontal gyrus. This latter brain area showed significantly decreased connectivity with the precuneus after THC administration. THC effects on perfusion in the left insula were significantly related to subjective changes in perception and relaxation. These findings indicate that THC enhances metabolism and thus neural activity in the salience network. Furthermore, results suggest that recruitment of brain areas within this network is involved in the acute effects of THC. Resting state perfusion was modulated by COMT genotype, indicated by a significant interaction effect between drug and genotype on perfusion in the executive network, with increased perfusion after THC in Val/Met heterozygotes only. This finding suggests that prefrontal dopamine levels are involved in the susceptibility to acute effects of cannabis.
Human Salivary Amylase Gene Copy Number Impacts Oral and Gut Microbiomes.
Apr 11, 2019   Cell Host & Microbe
Poole AC, Goodrich JK, Youngblut ND, Luque GG, Ruaud A, Sutter JL, Waters JL, Shi Q, El-Hadidi M, Johnson LM, Bar HY, Huson DH, Booth JG, Ley RE
Human Salivary Amylase Gene Copy Number Impacts Oral and Gut Microbiomes.
Apr 11, 2019
Cell Host & Microbe
Host genetic variation influences microbiome composition. While studies have focused on associations between the gut microbiome and specific alleles, gene copy number (CN) also varies. We relate microbiome diversity to CN variation of the AMY1 locus, which encodes salivary amylase, facilitating starch digestion. After imputing AMY1-CN for ∼1,000 subjects, we identified taxa differentiating fecal microbiomes of high and low AMY1-CN hosts. In a month-long diet intervention study, we show that diet standardization drove gut microbiome convergence, and AMY1-CN correlated with oral and gut microbiome composition and function. The microbiomes of low-AMY1-CN subjects had enhanced capacity to break down complex carbohydrates. High-AMY1-CN subjects had higher levels of salivary Porphyromonas; their gut microbiota had increased abundance of resistant starch-degrading microbes, produced higher levels of short-chain fatty acids, and drove higher adiposity when transferred to germ-free mice. This study establishes AMY1-CN as a genetic factor associated with microbiome composition and function.
TMEM106B Effect on Cognition in Parkinson's Disease and Frontotemporal Dementia.
Apr 11, 2019   Annals Of Neurology
Tropea TF, Mak J, Guo MH, Xie SX, Suh E, Rick J, Siderowf A, Weintraub D, Grossman M, Irwin D, Wolk DA, Trojanowski JQ, Van Deerlin V, Chen-Plotkin AS
TMEM106B Effect on Cognition in Parkinson's Disease and Frontotemporal Dementia.
Apr 11, 2019
Annals Of Neurology
OBJECTIVE: Common variants near TMEM106B associate with risk of developing frontotemporal dementia (FTD). Emerging evidence suggests a role for TMEM106B in neurodegenerative processes beyond FTD. The objective of this study is to evaluate the effect of TMEM106B genotype on cognitive decline across multiple neurogenerative diseases. METHODS: 870 subjects with diagnoses of Parkinson's disease (PD, N=179), FTD (N=179), Alzheimer's disease (AD, N=300), or memory-predominant mild cognitive impairment (MCI, N=75), and neurologically-normal control subjects (NC, N=137) were followed longitudinally at the University of Pennsylvania (UPenn). All participants had annual MMSE (median follow-up duration 3.0 years), and were genotyped at TMEM106B index SNP rs1990622. Genotype effects on cognition were confirmed by extending analyses to additional cognitive instruments (Mattis Dementia Rating Scale-2 (DRS-2) and Montreal Cognitive Assessment (MoCA)) and to an international validation cohort (Parkinson's Progression Markers Initiative (PPMI), N=371). RESULTS: The TMEM106B rs1990622T allele, linked to increased risk of FTD, associated with greater MMSE decline over time in PD subjects, but not in AD or MCI subjects. For FTD subjects, rs1990622T associated with more rapid decrease in MMSE only under the minor-allele, rs1990622C , dominant model. Among PD patients, rs1990622T carriers from the UPenn cohort demonstrated more rapid longitudinal decline in DRS-2 scores. Finally, in the PPMI cohort, TMEM106B risk allele carriers demonstrated more rapid longitudinal decline in MoCA scores. INTERPRETATION: Irrespective of cognitive instrument or cohort assessed, TMEM106B acts as a genetic modifier for cognitive trajectory in PD. Our results implicate lysosomal dysfunction in the pathogenesis of cognitive decline in two different proteinopathies. This article is protected by copyright. All rights reserved.
Genetic variation in FCER1A predicts peginterferon alfa-2a-induced hepatitis B surface antigen clearance in East Asian patients with chronic hepatitis B.
Apr 11, 2019   Journal Of Viral Hepatitis
Wei L, Pavlovic V, Bansal AT, Chen X, Foster GR, He H, Kao JH, Lampertico P, Liaw YF, Motoc A, Papatheodoridis GV, Piratvisuth T, Plesniak R, Wat C
Genetic variation in FCER1A predicts peginterferon alfa-2a-induced hepatitis B surface antigen clearance in East Asian patients with chronic hepatitis B.
Apr 11, 2019
Journal Of Viral Hepatitis
In a multicenter, genome-wide association study to identify host genetic factors associated with treatment response in adult chronic hepatitis B patients, genotype data were obtained by microarray analysis from 1669 patients who received peginterferon alfa-2a for ≥24 weeks with/without a nucleos(t)ide analog. Treatment response was assessed at least 24 weeks post-treatment, using serological and/or virological endpoints. Thirty-six single-marker analyses and a gene-by-gene analysis were conducted. No single nucleotide polymorphisms (SNPs) achieved genome-wide significance (P
Non-fertilizing sperm in Lepidoptera show little evidence for recurrent positive selection.
Apr 13, 2019   Molecular Ecology
Mongue AJ, Hansen ME, Gu L, Sorenson CE, Walters JR
Non-fertilizing sperm in Lepidoptera show little evidence for recurrent positive selection.
Apr 13, 2019
Molecular Ecology
Sperm are among the most variable cells in nature. Some of this variation results from non-adaptive errors in spermatogenesis, but many species consistently produce multiple sperm morphs, the adaptive significance of which remains unknown. Here, we investigate the evolution of dimorphic sperm in Lepidoptera, the butterflies and moths. Males of this order produce both fertilizing sperm and a secondary, non-fertilizing type that lacks DNA. Previous organismal studies suggested a role for non-fertilizing sperm in sperm competition, but this hypothesis has never been evaluated from a molecular framework. We combined published datasets with new sequencing in two species, the monandrous Carolina sphinx moth and the highly polyandrous monarch butterfly. Based on population genetic analyses, we see evidence for increased adaptive evolution in fertilizing sperm, but only in the polyandrous species. This signal comes primarily from a decrease in non-synonymous polymorphism in sperm proteins compared to the rest of the genome, suggesting stronger purifying selection, consistent with selection via sperm competition. Non-fertilizing sperm proteins, in contrast, do not show an effect of mating system and do not appear to evolve differently from the background genome in either species, arguing against the involvement of non-fertilizing sperm in direct sperm competition. Based on our results and previous work, we suggest that non-fertilizing sperm may be used to delay female remating in these insects and decrease the risk of sperm competition rather than directly affect its outcome.
Linkage mapping and GWAS reveal candidate genes conferring thermotolerance of seed-set in maize.
Apr 11, 2019   Journal Of Experimental Botany
Gao J, Wang S, Zhou Z, Wang S, Dong C,   . . . . . .   , He K, Han C, Chen J, Yu H, Wu J
Linkage mapping and GWAS reveal candidate genes conferring thermotolerance of seed-set in maize.
Apr 11, 2019
Journal Of Experimental Botany
High temperature stress (HS) will increasingly affect crop yield worldwide. In order to determine the genetic basis of thermotolerance of seed-set in maize in field conditions, a QTL mapping in a recombinant inbred line (RIL) population was performed using a collection of 8329 high-density single nucleotide polymorphisms (SNP) markers developed in this study, combined with a genome-wide association study (GWAS) of 261 diverse maize lines using 259,973 SNPs. In total, 4 quantitative trait loci (QTLs) and 17 genes associated with 42 SNPs related to thermotolerance of seed-set were identified by linkage mapping and GWAS, respectively. Four candidate genes among them were found in both linkage mapping and GWAS. Thermotolerance on seed-set were increased significantly in the near-isogenic lines (NILs) incorporating the four candidate genes in a susceptible parent background. Moreover, the expression profiles of two of the four candidate genes showed that they were induced by high temperature in maize tassel in the tolerant parent background. These genetic analyses indicated that thermotolerance of maize seed-set is regulated by multiple genes with minor effect, in which calcium signaling plays a core role. The pyramiding breeding with beneficial alleles and candidate genes could improve seed-set and yield of maize under HS.
Population genetics of Paramecium mitochondrial genomes: recombination, mutation spectrum, and efficacy of selection.
Apr 13, 2019   Genome Biology And Evolution
Johri P, Marinov GK, Doak TG, Lynch M
Population genetics of Paramecium mitochondrial genomes: recombination, mutation spectrum, and efficacy of selection.
Apr 13, 2019
Genome Biology And Evolution
The evolution of mitochondrial genomes and their population-genetic environment among unicellular eukaryotes are understudied. Ciliate mitochondrial genomes exhibit a unique combination of characteristics, including a linear organization and the presence of multiple genes with no known function or detectable homologs in other eukaryotes. Here we study the variation of ciliate mitochondrial genomes both within and across thirteen highly diverged Paramecium species, including multiple species from the P. aurelia species complex, with four outgroup species: P. caudatum, P. multimicronucleatum, and two strains that may represent novel related species. We observe extraordinary conservation of gene order and protein-coding content in Paramecium mitochondria across species. In contrast, significant differences are observed in tRNA content and copy number, which is highly conserved in species belonging to the P. aurelia complex but variable among and even within the other Paramecium species. There is an increase in GC content from ∼20% to ∼40% on the branch leading to the P. aurelia complex. Patterns of polymorphism in population-genomic data and mutation-accumulation experiments suggest that the increase in GC content is primarily due to changes in the mutation spectra in the P. aurelia species. Finally, we find no evidence of recombination in Paramecium mitochondria and find that the mitochondrial genome appears to experience either similar or stronger efficacy of purifying selection than the nucleus.

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