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Population Genetics
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation.
Feb 08, 2019   Journal Of Visualized Experiments : JoVE
Jones EG, Landstrom AP
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation.
Feb 08, 2019
Journal Of Visualized Experiments : JoVE
Advancements in the cost and speed of next generation genetic sequencing have generated an explosion of clinical whole exome and whole genome testing. While this has led to increased identification of likely pathogenic mutations associated with genetic syndromes, it has also dramatically increased the number of incidentally found genetic variants of unknown significance (VUS). Determining the clinical significance of these variants is a major challenge for both scientists and clinicians. An approach to assist in determining the likelihood of pathogenicity is signal-to-noise analysis at the protein sequence level. This protocol describes a method for amino acid-level signal-to-noise analysis that leverages variant frequency at each amino acid position of the protein with known protein topology to identify areas of the primary sequence with elevated likelihood of pathologic variation (relative to population "background" variation). This method can identify amino acid residue location "hotspots" of high pathologic signal, which can be used to refine the diagnostic weight of VUSs such as those identified by next generation genetic testing.
Spatial soft sweeps: Patterns of adaptation in populations with long-range dispersal.
Feb 11, 2019   PLoS Genetics
Paulose J, Hermisson J, Hallatschek O
Spatial soft sweeps: Patterns of adaptation in populations with long-range dispersal.
Feb 11, 2019
PLoS Genetics
Adaptation in extended populations often occurs through multiple independent mutations responding in parallel to a common selection pressure. As the mutations spread concurrently through the population, they leave behind characteristic patterns of polymorphism near selected loci-so-called soft sweeps-which remain visible after adaptation is complete. These patterns are well-understood in two limits of the spreading dynamics of beneficial mutations: the panmictic case with complete absence of spatial structure, and spreading via short-ranged or diffusive dispersal events, which tessellates space into distinct compact regions each descended from a unique mutation. However, spreading behaviour in most natural populations is not exclusively panmictic or diffusive, but incorporates both short-range and long-range dispersal events. Here, we characterize the spatial patterns of soft sweeps driven by dispersal events whose jump distances are broadly distributed, using lattice-based simulations and scaling arguments. We find that mutant clones adopt a distinctive structure consisting of compact cores surrounded by fragmented "haloes" which mingle with haloes from other clones. As long-range dispersal becomes more prominent, the progression from diffusive to panmictic behaviour is marked by two transitions separating regimes with differing relative sizes of halo to core. We analyze the implications of the core-halo structure for the statistics of soft sweep detection in small genomic samples from the population, and find opposing effects of long-range dispersal on the expected diversity in global samples compared to local samples from geographic subregions of the range. We also discuss consequences of the standing genetic variation induced by the soft sweep on future adaptation and mixing.
Structural, functional, and behavioral insights of dopamine dysfunction revealed by a deletion in SLC6A3.
Feb 13, 2019   Proceedings Of The National Academy Of Sciences Of The United States Of America
Campbell NG, Shekar A, Aguilar JI, Peng D, Navratna V,   . . . . . .   , Bellan LM, Matthies HJG, Gouaux E, Mchaourab HS, Galli A
Structural, functional, and behavioral insights of dopamine dysfunction revealed by a deletion in SLC6A3.
Feb 13, 2019
Proceedings Of The National Academy Of Sciences Of The United States Of America
The human dopamine (DA) transporter (hDAT) mediates clearance of DA. Genetic variants in hDAT have been associated with DA dysfunction, a complication associated with several brain disorders, including autism spectrum disorder (ASD). Here, we investigated the structural and behavioral bases of an ASD-associated in-frame deletion in hDAT at N336 (∆N336). We uncovered that the deletion promoted a previously unobserved conformation of the intracellular gate of the transporter, likely representing the rate-limiting step of the transport process. It is defined by a "half-open and inward-facing" state (HOIF) of the intracellular gate that is stabilized by a network of interactions conserved phylogenetically, as we demonstrated in hDAT by Rosetta molecular modeling and fine-grained simulations, as well as in its bacterial homolog leucine transporter by electron paramagnetic resonance analysis and X-ray crystallography. The stabilization of the HOIF state is associated both with DA dysfunctions demonstrated in isolated brains of Drosophila melanogaster expressing hDAT ∆N336 and with abnormal behaviors observed at high-time resolution. These flies display increased fear, impaired social interactions, and locomotion traits we associate with DA dysfunction and the HOIF state. Together, our results describe how a genetic variation causes DA dysfunction and abnormal behaviors by stabilizing a HOIF state of the transporter.
Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype.
Feb 12, 2019   Cancer Cell
Grolleman JE, de Voer RM, Elsayed FA, Nielsen M, Weren RDA,   . . . . . .   , Aretz S, Schindler D, van Wezel T, Hoogerbrugge N, Kuiper RP
Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype.
Feb 12, 2019
Cancer Cell
Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.
Multiple parapatric pollinators have radiated across a continental fig tree displaying clinal genetic variation.
Feb 12, 2019   Molecular Ecology
Yu H, Tian E, Zheng L, Deng X, Cheng Y, Chen L, Wu W, Tanming W, Zhang D, Compton SG, Kjellberg F
Multiple parapatric pollinators have radiated across a continental fig tree displaying clinal genetic variation.
Feb 12, 2019
Molecular Ecology
The ways that plant-feeding insects have diversified is central to our understanding of terrestrial ecosystems. Obligate nursery pollination mutualisms provide highly relevant model systems of how plants and their insect associates have diversified and the over 800 species of fig trees (Ficus) allow comparative studies. Fig trees can have one or more pollinating fig wasp species (Agaonidae) that breed within their figs, but factors influencing their number remain to be established. In some widely distributed fig trees, the plants form populations isolated by large swathes of sea, and the different populations are pollinated by different wasp species. Other Ficus species with continuous distributions may present genetic signatures of isolation by distance, suggesting more limited pollinator dispersal, which may also facilitate pollinator speciation. We tested the hypothesis that Ficus hirta, a species for which preliminary data showed genetic isolation by distance, would support numerous pollinator species across its range. Our results show that across its range Ficus hirta displays clinal genetic variation and is pollinated by nine parapatric species of Valisia. This is the highest number of pollinators reported to date for any Ficus species and it is the first demonstration of the occurrence of parapatric pollinator species on a fig host displaying continuous genetic structure. Future comparative studies across Ficus species should be able to establish the plant traits that have driven the evolution of pollinator dispersal behaviour, pollinator speciation and host plant spatial genetic structure. This article is protected by copyright. All rights reserved.
Signals of variation in human mutation rate at multiple levels of sequence context.
Feb 12, 2019   Molecular Biology And Evolution
Aikens RC, Johnson KE, Voight BF
Signals of variation in human mutation rate at multiple levels of sequence context.
Feb 12, 2019
Molecular Biology And Evolution
Our understanding of the human mutation rate helps us build evolutionary models and interpret patterns of genetic variation observed in human populations. Recent work indicates that the frequencies of specific polymorphism types have been elevated in Europe, and that many more, subtler signatures of global polymorphism variation may yet remain unidentified. Here, we present an analysis of the 1,000 Genomes Project supported by analysis in the Simons Genome Diversity Panel, suggesting additional putative signatures of mutation rate variation across populations and the extent to which they are shaped by local sequence context. First, we compiled a list of the most significantly variable polymorphism types in a cross-continental statistical test. Clustering polymorphisms together, we observe three sets that showed distinct shared patterns of relative enrichment among ancestral populations, and we characterize each one of these putative 'signatures' of polymorphism variation. For three of these signatures, we found that a single flanking base pair of sequence context was sufficient to determine the majority of enrichment or depletion of a polymorphism type. However, local genetic context up to 2-3 base pairs away contributes additional variability and may help to interpret a previously noted enrichment of certain polymorphism types in some East Asian groups. Moreover, considering broader local genetic context highlights patterns of polymorphism variation which were not captured by previous approaches. Building our understanding of mutation rate in this way can help us to construct more accurate evolutionary models and better understand the mechanisms that underlie genetic change.
Stress response, behavior, and development are shaped by transposable element-induced mutations in Drosophila.
Feb 12, 2019   PLoS Genetics
Rech GE, Bogaerts-Márquez M, Barrón MG, Merenciano M, Villanueva-Cañas JL, Horváth V, Fiston-Lavier AS, Luyten I, Venkataram S, Quesneville H, Petrov DA, González J
Stress response, behavior, and development are shaped by transposable element-induced mutations in Drosophila.
Feb 12, 2019
PLoS Genetics
Most of the current knowledge on the genetic basis of adaptive evolution is based on the analysis of single nucleotide polymorphisms (SNPs). Despite increasing evidence for their causal role, the contribution of structural variants to adaptive evolution remains largely unexplored. In this work, we analyzed the population frequencies of 1,615 Transposable Element (TE) insertions annotated in the reference genome of Drosophila melanogaster, in 91 samples from 60 worldwide natural populations. We identified a set of 300 polymorphic TEs that are present at high population frequencies, and located in genomic regions with high recombination rate, where the efficiency of natural selection is high. The age and the length of these 300 TEs are consistent with relatively young and long insertions reaching high frequencies due to the action of positive selection. Besides, we identified a set of 21 fixed TEs also likely to be adaptive. Indeed, we, and others, found evidence of selection for 84 of these reference TE insertions. The analysis of the genes located nearby these 84 candidate adaptive insertions suggested that the functional response to selection is related with the GO categories of response to stimulus, behavior, and development. We further showed that a subset of the candidate adaptive TEs affects expression of nearby genes, and five of them have already been linked to an ecologically relevant phenotypic effect. Our results provide a more complete understanding of the genetic variation and the fitness-related traits relevant for adaptive evolution. Similar studies should help uncover the importance of TE-induced adaptive mutations in other species as well.
Mediterranean and Northern Iberian gene pools of wild Castanea sativa Mill. are two differentiated ecotypes originated under natural divergent selection.
Feb 12, 2019   PloS One
Míguez-Soto B, Fernández-Cruz J, Fernández-López J
Mediterranean and Northern Iberian gene pools of wild Castanea sativa Mill. are two differentiated ecotypes originated under natural divergent selection.
Feb 12, 2019
PloS One
Nine wild Iberian provenances of Castanea sativa Mill. grouped in two gene pools, North Iberian Peninsula and Mediterranean, were evaluated for several adaptive traits in two provenance-progeny trials with the aim of evaluating the role of natural selection in shaping adaptive variation and increasing our understanding of the genetic structure of this species, as well as reporting complete information on the genetic variation among and within the studied populations. An annual growth rhythm experiment was evaluated during the first 3 years after establishment for phenology, growth, stem form and survival, and a periodic drought-stress experiment was evaluated for dry weight, growth, survival and other related drought traits in both well-watered and drought-stress treatments. The high genetic variability reported in both trials is largely due to the genetic variation among populations. The significant differences reported between quantitative genetic and neutral marker differentiation indicated the local adaptation of these populations through directional selection, mainly for phenology, growth and biomass allocation. A clinal variation among populations was determined through correlations of phenology with latitude and xerothermic index of the provenances, showing that central and southern Mediterranean populations had earlier phenology than northern populations and that drought played a relevant role in this differentiation. The significant correlation between phenological traits and the ancestry values in the Mediterranean gene pool supported the different pattern of behavior between both gene pools and also indicated the existence of two ecotypes: xeric and mesophytic ecotypes, corresponding to Mediterranean and North Iberian gene pools, respectively. The results obtained in the drought-stress experiment confirmed that, in general terms, xeric populations showed a greater adaptability to drought, with more developed root systems and higher survival than northern populations. Moreover, the genetic variability observed within populations indicated the potential response capacity of Iberian C. sativa populations to undergo fast adaptive evolution.
Genetic structure and forensic parameters of 30 InDels for human identification purposes in 10 Tibetan populations of China.
Feb 12, 2019   Forensic Science International. Genetics
Li L, Ye Y, Song F, Wang Z, Hou Y
Genetic structure and forensic parameters of 30 InDels for human identification purposes in 10 Tibetan populations of China.
Feb 12, 2019
Forensic Science International. Genetics
Insertion/deletion analysis can serve as a promising and useful supporting tool in forensic research. The Qiagen Investigator® DIPplex Kit contained 30 well-chosen autosomal InDels was targeted to reveal the population genetic variation. In the present study, 10 Tibetan populations residing in different geographic areas of China were recruited and genotyped by Investigator® DIPplex Kit. Allele frequencies and forensic parameters were determined. No significant departures from Hard-Weinberg equilibrium (HWE) in all loci/populations after Bonferroni correction. The combined matching probability values range from 1.7148 × 10-11 to 5.3516 × 10-1° in 10 Tibetan populations. Our results revealed 10 Tibetan populations in China are genetically very similar. Intercontinental population differentiation analysis indicated Tibetan populations had a close genetic relationship with East Asian populations using Hierarchical clustering, multi-dimensional scaling (MDS), principal component analysis (PCA) and STRUCTURE. Comprehensive population genetic studies revealed that the 30-InDels assay was similarly efficient in forensic personal identification and could be regarded as an effective supplementary protocol for kinship testing.
Identification of copy number variations using high density whole-genome SNP markers in Chinese Dongxiang spotted pigs.
Feb 12, 2019   Asian-Australasian Journal Of Animal Sciences
Wang C, Chen H, Wang X, Wu Z, Liu W, Guo Y, Ren J, Ding N
Identification of copy number variations using high density whole-genome SNP markers in Chinese Dongxiang spotted pigs.
Feb 12, 2019
Asian-Australasian Journal Of Animal Sciences
Objective: Copy number variations (CNVs) are a major source of genetic diversity complementary to single nucleotide polymorphism (SNP) in animals. The aim of the study was to performed a comprehensive genomic analysis of CNVs based on high density whole-genome SNP markers in Chinese Dongxiang spotted pigs. Methods: We used customized Affymetrix Axiom Pig1.4M array plates containing 1.4 million SNPs and the PennCNV algorithm to identify porcine CNVs on autosomes in Chinese Dongxiang spotted pigs. Then, the next generation sequence data was used to confirm the detected CNVs. Next, functional analysis was performed for gene contents in copy number variation regions (CNVRs). In addition, we compared the identified CNVRs with those reported ones and quantitative trait loci (QTL) in the pig QTL database. Results: We identified 871 putative CNVs belonging to 2,221 CNVRs on 17 autosomes. We further discarded CNVRs that were detected only in one individual, leaving us 166 CNVRs in total. The 166 CNVRs ranged from 2.89 kb to 617.53 kb with a mean value of 93.65 kb and a genome coverage of 15.55 Mb, corresponding to 0.58% of the pig genome. A total of 119 (71.69%) of the identified CNVRs were confirmed by next generation sequence data. Moreover, functional annotation showed that these CNVRs are involved in a variety of molecular functions. More than half (56.63%) of the CNVRs (n = 94) have been reported in previous studies, while 72 CNVRs are reported for the first time. In addition, 162 (97.59%) CNVRs were found to overlap with 2,765 previously reported QTLs affecting 378 phenotypic traits. Conclusion: The findings improve the catalog of pig CNVs and provide insights and novel molecular markers for further genetic analyses of Chinese indigenous pigs.
Analysis of a Prophage Gene Frequency Revealed Population Variation of 'Candidatus Liberibacter asiaticus' from Two Citrus-Growing Provinces in China.
Feb 12, 2019   Plant Disease
Liu R, Zhang P, Pu X, Xing X, Chen J, Deng X
Analysis of a Prophage Gene Frequency Revealed Population Variation of 'Candidatus Liberibacter asiaticus' from Two Citrus-Growing Provinces in China.
Feb 12, 2019
Plant Disease
Prophages are important genetic elements of bacterial genomes and are involved in lateral gene transfer, pathogenicity, environmental adaptations, and interstrain genetic variability. In this study, the sequence of a prophage terminase gene of 'Candidatus Liberibacter asiaticus', a bacterium associated with citrus Huanglongbing (HLB), was selected as a molecular marker to assess the genetic variation in two 'Ca. L. asiaticus' populations from geographically distinct provinces (Guangdong and Yunnan) in China. The frequency of the prophage terminase gene was 15.8% (19/120) in Guangdong (altitude 2,000 m). The difference was highly significant (P < 0.0001) based on χ2 analysis. However, the partial prophage terminase gene sequences obtained from 10 Guangdong strains and 6 Yunnan strains were identical or highly similar, suggesting that at least some bacterial strains in the two locations shared a common recent origin. This is the first report on population variation of 'Ca. L. asiaticus' in China, where HLB was first described. The population variation of 'Ca. L. asiaticus' in the two geographical regions and the related HLB epidemiology were discussed.
Differential accumulation of pelargonidin glycosides in petals at three different developmental stages of the orange-flowered gentian (Gentiana lutea L. var. aurantiaca).
Feb 11, 2019   PloS One
Diretto G, Jin X, Capell T, Zhu C, Gomez-Gomez L
Differential accumulation of pelargonidin glycosides in petals at three different developmental stages of the orange-flowered gentian (Gentiana lutea L. var. aurantiaca).
Feb 11, 2019
PloS One
Corolla color in Gentiana lutea L. exhibits a yellow/orange variation. We previously demonstrated that the orange petal color of G. lutea L. var. aurantiaca is predominantly caused by newly synthesized pelargonidin glycosides that confer a reddish hue to the yellow background color, derived from the carotenoids. However, the anthocyanin molecules of these pelargonidin glycosides are not yet fully identified and characterized. Here, we investigated the regulation, content and type of anthocyanins determining the petal coloration of the orange-flowered G. lutea L. var. aurantiaca. Anthocyanins from the petals of G. lutea L. var. aurantiaca were characterized and quantified by HPLC-ESI-MS/MS (High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry) coupled with a diode array detector in flowers at three different stages of development (S1, S3 and S5). Eleven pelargonidin derivatives were identified in the petals of G. lutea L. var. aurantiaca for the first time, but quantitative and qualitative differences were observed at each developmental stage. The highest levels of these pelargonidin derivatives were reached at the fully open flower stage (S5) where all anthocyanins were detected. In contrast, not all the anthocyanins were detected at the budlet stage (S1) and mature bud stage (S3) and those corresponded to more complex pelargonidin derivatives. The major pelargonidin derivatives found at all the stages were pelargonidin 3-O-glucoside, pelargonidin 3,5-O-diglucoside and pelargonidin 3-O-rutinoside. Furthermore, the expression of DFR (dihydroflavonol 4-reductase), ANS (anthocyanidin synthase), 3GT (UDP-glucose:flavonoid 3-O-glucosyltransferase), 5GT (UDP-glucose:flavonoid 5-O-glucosyltransferase) and 5AT (anthocyanin 5-aromatic acyltransferase) genes was analyzed in the petals of three developmental stages, showing that the expression level of DFR, ANS and 3GT parallels the accumulation of the pelargonidin glucosides. Overall, this study enhances the knowledge of the biochemical basis of flower coloration in Gentiana species, and lays a foundation for breeding of flower color and genetic variation studies on Gentiana varieties.
Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration.
Feb 11, 2019   Nature Genetics Add nature.com free-link Cancel
Ratnapriya R, Sosina OA, Starostik MR, Kwicklis M, Kapphahn RJ,   . . . . . .   , Battle A, Abecasis GR, Ferrington DA, Chatterjee N, Swaroop A
Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration.
Feb 11, 2019
Nature Genetics
Genome-wide association studies (GWAS) have identified genetic variants at 34 loci contributing to age-related macular degeneration (AMD)1-3. We generated transcriptional profiles of postmortem retinas from 453 controls and cases at distinct stages of AMD and integrated retinal transcriptomes, covering 13,662 protein-coding and 1,462 noncoding genes, with genotypes at more than 9 million common SNPs for expression quantitative trait loci (eQTL) analysis of a tissue not included in Genotype-Tissue Expression (GTEx) and other large datasets4,5. Cis-eQTL analysis identified 10,474 genes under genetic regulation, including 4,541 eQTLs detected only in the retina. Integrated analysis of AMD-GWAS with eQTLs ascertained likely target genes at six reported loci. Using transcriptome-wide association analysis (TWAS), we identified three additional genes, RLBP1, HIC1 and PARP12, after Bonferroni correction. Our studies expand the genetic landscape of AMD and establish the Eye Genotype Expression (EyeGEx) database as a resource for post-GWAS interpretation of multifactorial ocular traits.
Fast and flexible linear mixed models for genome-wide genetics.
Feb 08, 2019   PLoS Genetics
Runcie DE, Crawford L
Fast and flexible linear mixed models for genome-wide genetics.
Feb 08, 2019
PLoS Genetics
Linear mixed effect models are powerful tools used to account for population structure in genome-wide association studies (GWASs) and estimate the genetic architecture of complex traits. However, fully-specified models are computationally demanding and common simplifications often lead to reduced power or biased inference. We describe Grid-LMM (https://github.com/deruncie/GridLMM), an extendable algorithm for repeatedly fitting complex linear models that account for multiple sources of heterogeneity, such as additive and non-additive genetic variance, spatial heterogeneity, and genotype-environment interactions. Grid-LMM can compute approximate (yet highly accurate) frequentist test statistics or Bayesian posterior summaries at a genome-wide scale in a fraction of the time compared to existing general-purpose methods. We apply Grid-LMM to two types of quantitative genetic analyses. The first is focused on accounting for spatial variability and non-additive genetic variance while scanning for QTL; and the second aims to identify gene expression traits affected by non-additive genetic variation. In both cases, modeling multiple sources of heterogeneity leads to new discoveries.
Identification of Alzheimer's Disease-Related Genes Based on Data Integration Method.
Feb 14, 2019   Frontiers In Genetics
Hu Y, Zhao T, Zang T, Zhang Y, Cheng L
Identification of Alzheimer's Disease-Related Genes Based on Data Integration Method.
Feb 14, 2019
Frontiers In Genetics
Alzheimer disease (AD) is the fourth major cause of death in the elderly following cancer, heart disease and cerebrovascular disease. Finding candidate causal genes can help in the design of Gene targeted drugs and effectively reduce the risk of the disease. Complex diseases such as AD are usually caused by multiple genes. The Genome-wide association study (GWAS), has identified the potential genetic variants for most diseases. However, because of linkage disequilibrium (LD), it is difficult to identify the causative mutations that directly cause diseases. In this study, we combined expression quantitative trait locus (eQTL) studies with the GWAS, to comprehensively define the genes that cause Alzheimer disease. The method used was the Summary Mendelian randomization (SMR), which is a novel method to integrate summarized data. Two GWAS studies and five eQTL studies were referenced in this paper. We found several candidate SNPs that have a strong relationship with AD. Most of these SNPs overlap in different data sets, providing relatively strong reliability. We also explain the function of the novel AD-related genes we have discovered.
Genome-wide association study of inflorescence length of cultivated soybean based on the high-throughout single-nucleotide markers.
Feb 10, 2019   Molecular Genetics And Genomics : MGG
Wang J, Zhao X, Wang W, Qu Y, Teng W, Qiu L, Zheng H, Han Y, Li W
Genome-wide association study of inflorescence length of cultivated soybean based on the high-throughout single-nucleotide markers.
Feb 10, 2019
Molecular Genetics And Genomics : MGG
As an important and complex trait, inflorescence length (IL) of soybean [Glycine max (L.) Merr.] significantly affected seed yields. Therefore, elucidating molecular basis of inflorescence architecture, especially for IL, was important for improving soybean yield potentials. Longer IL meaned to have more pod and seed in soybean. Hence, increasing IL and improving yield are targets for soybean breeding. In this study, a association panel, comprising 283 diverse samples, was used to dissect the genetic basis of IL based on genome-wide association analysis (GWAS) and haplotype analysis. GWAS and haplotype analysis were conducted through high-throughout single-nucleotide polymorphisms (SNP) developed by SLAF-seq methodology. A total of 39, 057 SNPs (minor allele frequency ≥ 0.2 and missing data ≤ 10%) were utilized to evaluate linkage disequilibrium (LD) level in the tested association panel. A total of 30 association signals were identified to be associated with IL via GWAS. Among them, 13 SNPs were novel, and another 17 SNPs were overlapped or located near the linked regions of known quantitative trait nucleotide (QTN) with soybean seed yield or yield component. The functional genes, located in the 200-kb genomic region of each peak SNP, were considered as candidate genes, such as the cell division/ elongation, specific enzymes, and signaling or transport of specific proteins. These genes have been reported to participant in the regulation of IL. Ten typical long-IL lines and ten typical short-IL lines were re-sequencing, and then, six SNPs from five genes were obtained based on candidate gene-based association. In addition, 42 haplotypes were defined based on haplotype analysis. Of them, 11 haplotypes were found to regulate long IL (> 14 mm) in soybean. The identified 30 QTN with beneficial alleles and their candidate genes might be valuable for dissecting the molecular mechanisms of IL and further improving the yield potential of soybean.
Predicting the effect of reference population on the accuracy of within, across, and multibreed genomic prediction.
Feb 10, 2019   Journal Of Dairy Science
van den Berg I, Meuwissen THE, MacLeod IM, Goddard ME
Predicting the effect of reference population on the accuracy of within, across, and multibreed genomic prediction.
Feb 10, 2019
Journal Of Dairy Science
Genomic prediction is widely used to select candidates for breeding. Size and composition of the reference population are important factors influencing prediction accuracy. In Holstein dairy cattle, large reference populations are used, but this is difficult to achieve in numerically small breeds and for traits that are not routinely recorded. The prediction accuracy is usually estimated using cross-validation, requiring the full data set. It would be useful to have a method to predict the benefit of multibreed reference populations that does not require the availability of the full data set. Our objective was to study the effect of the size and breed composition of the reference population on the accuracy of genomic prediction using genomic BLUP and Bayes R. We also examined the effect of trait heritability and validation breed on prediction accuracy. Using these empirical results, we investigated the use of a formula to predict the effect of the size and composition of the reference population on the accuracy of genomic prediction. Phenotypes were simulated in a data set containing real genotypes of imputed sequence variants for 22,752 dairy bulls and cows, including Holstein, Jersey, Red Holstein, and Australian Red cattle. Different reference populations were constructed, varying in size and composition, to study within-breed, multibreed, and across-breed prediction. Phenotypes were simulated varying in heritability, number of chromosomes, and number of quantitative trait loci. Genomic prediction was carried out using genomic BLUP and Bayes R. We used either the genomic relationship matrix (GRM) to estimate the number of independent chromosomal segments and subsequently to predict accuracy, or the accuracies obtained from single-breed reference populations to predict the accuracies of larger or multibreed reference populations. Using the GRM overestimated the accuracy; this overestimation was likely due to close relationships among some of the reference animals. Consequently, the GRM could not be used to predict the accuracy of genomic prediction reliably. However, a method using the prediction accuracies obtained by cross-validation using a small, single-breed reference population predicted the accuracy using a multibreed reference population well and slightly overestimated the accuracy for a larger reference population of the same breed, but gave a reasonably close estimate of the accuracy for a multibreed reference population. This method could be useful for making decisions regarding the size and composition of the reference population.
Human papillomavirus 16 sub-lineage dispersal and cervical cancer risk worldwide: Whole viral genome sequences from 7116 HPV16-positive women.
Feb 15, 2019   Papillomavirus Research (Amsterdam, Netherlands)
Clifford GM, Tenet V, Georges D, Alemany L, Pavón MA,   . . . . . .   , Wentzensen N, Walker J, Zuna R, Schiffman M, Mirabello L
Human papillomavirus 16 sub-lineage dispersal and cervical cancer risk worldwide: Whole viral genome sequences from 7116 HPV16-positive women.
Feb 15, 2019
Papillomavirus Research (Amsterdam, Netherlands)
BACKGROUND: Human papillomavirus (HPV)16 can be separated into genetic sub-lineages (A1-4, B1-4, C1-4, D1-4) which may have differential cervical cancer risk. METHODS: A next-generation sequencing assay was used to whole-genome sequence 7116 HPV16-positive cervical samples from well-characterised international epidemiological studies, including 2076 controls, 1878 squamous cell carcinoma (SCC) and 186 adenocarcinoma/adenosquamous cell carcinoma (ADC), and to assign HPV16 sub-lineage. Logistic regression was used to estimate region-stratified country-adjusted odds ratios (OR) and 95%CI. RESULTS: A1 was the most globally widespread sub-lineage, with others showing stronger regional specificity (A3 and A4 for East Asia, B1-4 and C1-4 for Africa, D2 for the Americas, B4, C4 and D4 for North Africa). Increased cancer risks versus A1 were seen for A3, A4 and D (sub)lineages in regions where they were common: A3 in East Asia (OR=2.2, 95%CI:1.0-4.7); A4 in East Asia (6.6, 3.1-14.1) and North America (3.8, 1.7-8.3); and D in North (6.2, 4.1-9.3) and South/Central America (2.2, 0.8-5.7), where D lineages were also more frequent in ADC than SCC (3.2, 1.5-6.5; 12.1, 5.7-25.6, respectively). CONCLUSIONS: HPV16 genetic variation can strongly influence cervical cancer risk. However, burden of cervical cancer attributable to different sub-lineages worldwide is largely driven by historical HPV16 sub-lineage dispersal.
Lymphocyte innateness defined by transcriptional states reflects a balance between proliferation and effector functions.
Feb 13, 2019   Nature Communications
Gutierrez-Arcelus M, Teslovich N, Mola AR, Polidoro RB, Nathan A, Kim H, Hannes S, Slowikowski K, Watts GFM, Korsunsky I, Brenner MB, Raychaudhuri S, Brennan PJ
Lymphocyte innateness defined by transcriptional states reflects a balance between proliferation and effector functions.
Feb 13, 2019
Nature Communications
How innate T cells (ITC), including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells, maintain a poised effector state has been unclear. Here we address this question using low-input and single-cell RNA-seq of human lymphocyte populations. Unbiased transcriptomic analyses uncover a continuous 'innateness gradient', with adaptive T cells at one end, followed by MAIT, iNKT, γδ T and natural killer cells at the other end. Single-cell RNA-seq reveals four broad states of innateness, and heterogeneity within canonical innate and adaptive populations. Transcriptional and functional data show that innateness is characterized by pre-formed mRNA encoding effector functions, but impaired proliferation marked by decreased baseline expression of ribosomal genes. Together, our data shed new light on the poised state of ITC, in which innateness is defined by a transcriptionally-orchestrated trade-off between rapid cell growth and rapid effector function.
Environmental sources of bacteria and genetic variation in behavior influence host-associated microbiota.
Feb 09, 2019   Applied And Environmental Microbiology
Mushegian AA, Arbore R, Walser JC, Ebert D
Environmental sources of bacteria and genetic variation in behavior influence host-associated microbiota.
Feb 09, 2019
Applied And Environmental Microbiology
In many organisms, host-associated microbial communities are acquired horizontally after birth. This process is believed to be shaped by a combination of environmental and host genetic factors. We examined whether genetic variation in animal behavior could affect the composition of the animal's microbiota in different environments. The freshwater crustacean Daphnia magna is primarily planktonic, but exhibits variation in the degree to which it browses in benthic sediments. We performed an experiment with clonal lines of D. magna showing different levels of sediment-browsing intensity exposed to either bacteria-rich or bacteria-poor sediment or whose access to sediments was prevented. We find that the bacterial composition of the environment and genotype-specific browsing intensity together influence the composition of the Daphnia-associated bacterial community. Exposure to more diverse bacteria did not lead to a more diverse microbiome, but greater abundances of environment-specific bacteria were found associated with host genotypes that exhibited greater browsing behavior. Our results indicate that, although there is a great deal of variation between individuals, behavior can mediate genotype-by-environment interaction effects on microbiome composition.Importance: An animal's behavior can affect its risk of infection, but it's not well understood how behavior affects microbiome composition. The aquatic crustacean Daphnia exhibits genetic variation in the extent to which it browses in the sediment at the bottoms of ponds. We show that this behavior affects the Daphnia microbiome, indicating that genetic variation among individuals may affect microbiome composition and the movement of bacteria in different environments.
Clinical spectrum of STX1B-related epileptic disorders.
Feb 09, 2019   Neurology
Wolking S, May P, Mei D, Møller RS, Balestrini S,   . . . . . .   , Weber YG, Lal D, Marini C, Lerche H, Schubert J
Clinical spectrum of STX1B-related epileptic disorders.
Feb 09, 2019
Neurology
OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.
Predicting Polygenic Risk of Psychiatric Disorders.
Feb 09, 2019   Biological Psychiatry
Martin AR, Daly MJ, Robinson EB, Hyman SE, Neale BM
Predicting Polygenic Risk of Psychiatric Disorders.
Feb 09, 2019
Biological Psychiatry
Genetics provides two major opportunities for understanding human disease-as a transformative line of etiological inquiry and as a biomarker for heritable diseases. In psychiatry, biomarkers are very much needed for both research and treatment, given the heterogenous populations identified by current phenomenologically based diagnostic systems. To date, however, useful and valid biomarkers have been scant owing to the inaccessibility and complexity of human brain tissue and consequent lack of insight into disease mechanisms. Genetic biomarkers are therefore especially promising for psychiatric disorders. Genome-wide association studies of common diseases have matured over the last decade, generating the knowledge base for increasingly informative individual-level genetic risk prediction. In this review, we discuss fundamental concepts involved in computing genetic risk with current methods, strengths and weaknesses of various approaches, assessments of utility, and applications to various psychiatric disorders and related traits. Although genetic risk prediction has become increasingly straightforward to apply and common in published studies, there are important pitfalls to avoid. At present, the clinical utility of genetic risk prediction is still low; however, there is significant promise for future clinical applications as the ancestral diversity and sample sizes of genome-wide association studies increase. We discuss emerging data and methods aimed at improving the value of genetic risk prediction for disentangling disease mechanisms and stratifying subjects for epidemiological and clinical studies. For all applications, it is absolutely critical that polygenic risk prediction is applied with appropriate methodology and control for confounding to avoid repeating some mistakes of the candidate gene era.
Co-Expression Network Analysis and Hub Gene Selection for High-Quality Fiber in Upland Cotton (Gossypium hirsutum) Using RNA Sequencing Analysis.
Feb 09, 2019   Genes
Zou X, Liu A, Zhang Z, Ge Q, Fan S,   . . . . . .   , Zhang S, Jia T, Zhang L, Yuan Y, Shang H
Co-Expression Network Analysis and Hub Gene Selection for High-Quality Fiber in Upland Cotton (Gossypium hirsutum) Using RNA Sequencing Analysis.
Feb 09, 2019
Genes
Upland cotton (Gossypium hirsutum) is grown for its elite fiber. Understanding differential gene expression patterns during fiber development will help to identify genes associated with fiber quality. In this study, we used two recombinant inbred lines (RILs) differing in fiber quality derived from an intra-hirsutum population to explore expression profiling differences and identify genes associated with high-quality fiber or specific fiber-development stages using RNA sequencing. Overall, 72/27, 1137/1584, 437/393, 1019/184, and 2555/1479 differentially expressed genes were up-/down-regulated in an elite fiber line (L1) relative to a poor-quality fiber line (L2) at 10, 15, 20, 25, and 30 days post-anthesis, respectively. Three-hundred sixty-three differentially expressed genes (DEGs) between two lines were colocalized in fiber strength (FS) quantitative trait loci (QTL). Short Time-series Expression Miner (STEM) analysis discriminated seven expression profiles; gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation were performed to identify difference in function between genes unique to L1 and L2. Co-expression network analysis detected five modules highly associated with specific fiber-development stages, especially for high-quality fiber tissues. The hub genes in each module were identified by weighted gene co-expression network analysis. Hub genes encoding actin 1, Rho GTPase-activating protein with PAK-box, TPX2 protein, bHLH transcription factor, and leucine-rich repeat receptor-like protein kinase were identified. Correlation networks revealed considerable interaction among the hub genes, transcription factors, and other genes.
Setting our AdipoSIGHTS on Stem Cells in Pharmacogenomics.
Feb 08, 2019   Cell Stem Cell
Kovacs P
Setting our AdipoSIGHTS on Stem Cells in Pharmacogenomics.
Feb 08, 2019
Cell Stem Cell
In a recent study published in Cell Stem Cell, Hu et al. (2019) used human adipose stem cell-derived adipocytes to demonstrate that genetic variation predicts anti-diabetic response to thiazolidinediones (TZDs) by modulating PPARγ binding.
Epigenomic analysis reveals DNA motifs regulating histone modifications in human and mouse.
Feb 16, 2019   Proceedings Of The National Academy Of Sciences Of The United States Of America
Ngo V, Chen Z, Zhang K, Whitaker JW, Wang M, Wang W
Epigenomic analysis reveals DNA motifs regulating histone modifications in human and mouse.
Feb 16, 2019
Proceedings Of The National Academy Of Sciences Of The United States Of America
Histones are modified by enzymes that act in a locus, cell-type, and developmental stage-specific manner. The recruitment of enzymes to chromatin is regulated at multiple levels, including interaction with sequence-specific DNA-binding factors. However, the DNA-binding specificity of the regulatory factors that orchestrate specific histone modifications has not been broadly mapped. We have analyzed 6 histone marks (H3K4me1, H3K4me3, H3K27ac, H3K27me3, K3H9me3, H3K36me3) across 121 human cell types and tissues from the NIH Roadmap Epigenomics Project as well as 8 histone marks (with addition of H3K4me2 and H3K9ac) from the mouse ENCODE Consortium. We have identified 361 and 369 DNA motifs in human and mouse, respectively, that are the most predictive of each histone mark. Interestingly, 107 human motifs are conserved between the two species. In human embryonic cell line H1, we mutated only the found DNA motifs at particular loci and the significant reduction of H3K27ac levels validated the regulatory roles of the perturbed motifs. The functionality of these motifs was also supported by the evidence that histone-associated motifs, especially H3K4me3 motifs, significantly overlap with the expression of quantitative trait loci SNPs in cancer patients more than the known and random motifs. Furthermore, we observed possible feedbacks to control chromatin dynamics as the found motifs appear in the promoters or enhancers associated with various histone modification enzymes. These results pave the way toward revealing the molecular mechanisms of epigenetic events, such as histone modification dynamics and epigenetic priming.

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