Was ADH1B under Selection in European Populations?
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ABSTRACT:
SUBMITTER: Shen QK
PROVIDER: S-EPMC5097933 | biostudies-literature | 2016 Nov
REPOSITORIES: biostudies-literature
Publications
Was ADH1B under Selection in European Populations?
Shen Quan-Kuan QK Sulaiman Xierzhatijiang X Yao Yong-Gang YG Peng Min-Sheng MS Zhang Ya-Ping YP
American journal of human genetics 20161101 5
Similar Datasets
Project description:A coding variant in alcohol dehydrogenase 1B (ADH1B) (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.24, 0.48) on alcohol dependence, with genome-wide significance (6.6 × 10(-10)). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24-hour period (lifetime), with P=3 × 10(-13). We also tested the effects of this allele on the development of alcoholism in adolescents and young adults, and demonstrated a significantly protective effect. This variant has the strongest effect on risk for alcohol dependence compared with any other tested variant in European populations.
| S-EPMC3252425 | biostudies-literature
Project description:Forkhead box P2 (FOXP2) is a highly conserved transcription factor that has been implicated in human speech and language disorders and plays important roles in the plasticity of the developing brain. The pattern of nucleotide polymorphisms in FOXP2 in modern populations suggests that it has been the target of positive (Darwinian) selection during recent human evolution. In our study, we searched for evidence of selection that might have followed FOXP2 adaptations in modern humans. We examined whether or not putative FOXP2 targets identified by chromatin-immunoprecipitation genomic screening show evidence of positive selection. We developed an algorithm that, for any given gene list, systematically generates matched lists of control genes from the Ensembl database, collates summary statistics for three frequency-spectrum-based neutrality tests from the low-coverage resequencing data of the 1000 Genomes Project, and determines whether these statistics are significantly different between the given gene targets and the set of controls. Overall, there was strong evidence of selection of FOXP2 targets in Europeans, but not in the Han Chinese, Japanese, or Yoruba populations. Significant outliers included several genes linked to cellular movement, reproduction, development, and immune cell trafficking, and 13 of these constituted a significant network associated with cardiac arteriopathy. Strong signals of selection were observed for CNTNAP2 and RBFOX1, key neurally expressed genes that have been consistently identified as direct FOXP2 targets in multiple studies and that have themselves been associated with neurodevelopmental disorders involving language dysfunction.
| S-EPMC3644635 | biostudies-literature
Project description:Population structure can provide novel insight into the human past, and recognizing and correcting for such stratification is a practical concern in gene mapping by many association methodologies. We investigate these patterns, primarily through principal component (PC) analysis of whole genome SNP polymorphism, in 2099 individuals from populations of Northern European origin (Ireland, United Kingdom, Netherlands, Denmark, Sweden, Finland, Australia, and HapMap European-American). The major trends (PC1 and PC2) demonstrate an ability to detect geographic substructure, even over a small area like the British Isles, and this information can then be applied to finely dissect the ancestry of the European-Australian and European-American samples. They simultaneously point to the importance of considering population stratification in what might be considered a small homogeneous region. There is evidence from F(ST)-based analysis of genic and nongenic SNPs that differential positive selection has operated across these populations despite their short divergence time and relatively similar geographic and environmental range. The pressure appears to have been focused on genes involved in immunity, perhaps reflecting response to infectious disease epidemic. Such an event may explain a striking selective sweep centered on the rs2508049-G allele, close to the HLA-G gene on chromosome 6. Evidence of the sweep extends over a 8-Mb/3.5-cM region. Overall, the results illustrate the power of dense genotype and sample data to explore regional population variation, the events that have crafted it, and their implications in both explaining disease prevalence and mapping these genes by association.
| S-EPMC2675969 | biostudies-literature
Project description:Analyzing genetic variation of human populations for detecting loci that have been affected by positive natural selection is important for understanding adaptive history and phenotypic variation in humans. In this study, we analyzed recent positive selection in Northern Europe from genome-wide data sets of 250 000 and 500 000 single-nucleotide polymorphisms (SNPs) in a total of 999 individuals from Great Britain, Northern Germany, Eastern and Western Finland, and Sweden. Coalescent simulations were used for demonstrating that the integrated haplotype score (iHS) and long-range haplotype (LRH) statistics have sufficient power in genome-wide data sets of different sample sizes and SNP densities. Furthermore, the behavior of the F(ST) statistic in closely related populations was characterized by allele frequency simulations. In the analysis of the North European data set, 60 regions in the genome showed strong signs of recent positive selection. Out of these, 21 regions have not been discovered in previous scans, and many contain genes with interesting functions (eg, RAB38, INFG, NOS1AP, and APOE). In the putatively selected regions, we observed a statistically significant overrepresentation of genetic association with complex disease, which emphasizes the importance of the analysis of positive selection in understanding the evolution of human disease. Altogether, this study demonstrates the potential of genome-wide data sets to discover loci that lie behind evolutionary adaptation in different human populations.
| S-EPMC2987258 | biostudies-literature
Project description:In sexual populations, selection operates neither on the whole genome, which is repeatedly taken apart and reassembled by recombination, nor on individual alleles that are tightly linked to the chromosomal neighborhood. The resulting interference between linked alleles reduces the efficiency of selection and distorts patterns of genetic diversity. Inference of evolutionary history from diversity shaped by linked selection requires an understanding of these patterns. Here, we present a simple but powerful scaling analysis identifying the unit of selection as the genomic "linkage block" with a characteristic length, , determined in a self-consistent manner by the condition that the rate of recombination within the block is comparable to the fitness differences between different alleles of the block. We find that an asexual model with the strength of selection tuned to that of the linkage block provides an excellent description of genetic diversity and the site frequency spectra compared with computer simulations. This linkage block approximation is accurate for the entire spectrum of strength of selection and is particularly powerful in scenarios with many weakly selected loci. The latter limit allows us to characterize coalescence, genetic diversity, and the speed of adaptation in the infinitesimal model of quantitative genetics.
| S-EPMC3785765 | biostudies-literature
Project description:A population's spatial structure affects the rate of genetic change and the outcome of natural selection. These effects can be modeled mathematically using the Birth-death process on graphs. Individuals occupy the vertices of a weighted graph, and reproduce into neighboring vertices based on fitness. A key quantity is the probability that a mutant type will sweep to fixation, as a function of the mutant's fitness. Graphs that increase the fixation probability of beneficial mutations, and decrease that of deleterious mutations, are said to amplify selection. However, fixation probabilities are difficult to compute for an arbitrary graph. Here we derive an expression for the fixation probability, of a weakly-selected mutation, in terms of the time for two lineages to coalesce. This expression enables weak-selection fixation probabilities to be computed, for an arbitrary weighted graph, in polynomial time. Applying this method, we explore the range of possible effects of graph structure on natural selection, genetic drift, and the balance between the two. Using exhaustive analysis of small graphs and a genetic search algorithm, we identify families of graphs with striking effects on fixation probability, and we analyze these families mathematically. Our work reveals the nuanced effects of graph structure on natural selection and neutral drift. In particular, we show how these notions depend critically on the process by which mutations arise.
| S-EPMC7880501 | biostudies-literature
Project description:The ADH1B (Alcohol Dehydrogenase 1B (class I), Beta Polypeptide) gene and its best-known functional alleles, Arg48His (rs1229984, ADH1B*2) and Arg370Cys (rs2066702, ADH1B*3), have been investigated in relation to many phenotypic traits; most frequently including alcohol metabolism and alcohol drinking behaviors, but also human evolution, liver function, cancer, and, recently, the comprehensive human phenome. To understand ADH1B functions and consequences, we provide here a bioinformatic analysis of its gene regulation and molecular functions, literature review of studies focused on this gene, and a discussion regarding future research perspectives. Certain ADH1B alleles have large effects on alcohol metabolism, and this relationship particularly encourages further investigations in relation to alcoholism and alcohol-associated cancer to understand better the mechanisms by which alcohol metabolism contributes to alcohol abuse and carcinogenesis. We also observed that ADH1B has complex mechanisms that regulate its expression across multiple human tissues, and these may be involved in cardiac and metabolic traits. Evolutionary data strongly suggest that the selection signatures at the ADH1B locus are primarily related to effects other than those on alcohol metabolism. This is also supported by the involvement of ADH1B in multiple molecular pathways and by the findings of our recent phenome-wide association study. Accordingly, future studies should also investigate other functions of ADH1B potentially relevant for the human phenome. © 2017 Wiley Periodicals, Inc.
| S-EPMC5617762 | biostudies-literature
Project description:In single-step analyses, missing genotypes are explicitly or implicitly imputed, and this requires centering the observed genotypes using the means of the unselected founders. If genotypes are only available for selected individuals, centering on the unselected founder mean is not straightforward. Here, computer simulation is used to study an alternative analysis that does not require centering genotypes but fits the mean [Formula: see text] of unselected individuals as a fixed effect. Starting with observed diplotypes from 721 cattle, a five-generation population was simulated with sire selection to produce 40,000 individuals with phenotypes, of which the 1000 sires had genotypes. The next generation of 8000 genotyped individuals was used for validation. Evaluations were undertaken with (J) or without (N) [Formula: see text] when marker covariates were not centered; and with (JC) or without (C) [Formula: see text] when all observed and imputed marker covariates were centered. Centering did not influence accuracy of genomic prediction, but fitting [Formula: see text] did. Accuracies were improved when the panel comprised only quantitative trait loci (QTL); models JC and J had accuracies of 99.4%, whereas models C and N had accuracies of 90.2%. When only markers were in the panel, the 4 models had accuracies of 80.4%. In panels that included QTL, fitting [Formula: see text] in the model improved accuracy, but had little impact when the panel contained only markers. In populations undergoing selection, fitting [Formula: see text] in the model is recommended to avoid bias and reduction in prediction accuracy due to selection.
| S-EPMC5555473 | biostudies-other
Project description:Transposable elements (TEs) are ubiquitous sequences in genomes of virtually all species. While TEs have been investigated for several decades, only recently we have the opportunity to study their genome-wide population dynamics. Most of the studies so far have been restricted either to the analysis of the insertions annotated in the reference genome or to the analysis of a limited number of populations. Taking advantage of the European Drosophila population genomics consortium (DrosEU) sequencing data set, we have identified and measured the dynamics of TEs in a large sample of European Drosophila melanogaster natural populations. We showed that the mobilome landscape is population-specific and highly diverse depending on the TE family. In contrast with previous studies based on SNP variants, no geographical structure was observed for TE abundance or TE divergence in European populations. We further identified de novo individual insertions using two available programs and, as expected, most of the insertions were present at low frequencies. Nevertheless, we identified a subset of TEs present at high frequencies and located in genomic regions with a high recombination rate. These TEs are candidates for being the target of positive selection, although neutral processes should be discarded before reaching any conclusion on the type of selection acting on them. Finally, parallel patterns of association between the frequency of TE insertions and several geographical and temporal variables were found between European and North American populations, suggesting that TEs can be potentially implicated in the adaptation of populations across continents.
| S-EPMC6849870 | biostudies-literature
Project description:UnlabelledBackgroundADH1B is one of the most studied human genes with many polymorphic sites. One of the single nucleotide polymorphism (SNP), rs1229984, coding for the Arg48His substitution, have been associated with many serious diseases including alcoholism and cancers of the digestive system. The derived allele, ADH1B*48His, reaches high frequency only in East Asia and Southwest Asia, and is highly associated with agriculture. Micro-evolutionary study has defined seven haplogroups for ADH1B based on seven SNPs encompassing the gene. Three of those haplogroups, H5, H6, and H7, contain the ADH1B*48His allele. H5 occurs in Southwest Asia and the other two are found in East Asia. H7 is derived from H6 by the derived allele of rs3811801. The H7 haplotype has been shown to have undergone significant positive selection in Han Chinese, Hmong, Koreans, Japanese, Khazak, Mongols, and so on.MethodsIn the present study, we tested whether Tibetans also showed evidence for selection by typing 23 SNPs in the region covering the ADH1B gene in 1,175 individuals from 12 Tibetan populations representing all districts of the Tibet Autonomous Region. Multiple statistics were estimated to examine the gene diversities and positive selection signals among the Tibetans and other populations in East Asia.ResultsThe larger Tibetan populations (Qamdo, Lhasa, Nagqu, Nyingchi, Shannan, and Shigatse) comprised mostly farmers, have around 12% of H7, and 2% of H6. The smaller populations, living on hunting or recently switched to farming, have lower H7 frequencies (Tingri 9%, Gongbo 8%, Monba and Sherpa 6%). Luoba (2%) and Deng (0%) have even lower frequencies. Long-range haplotype analyses revealed very weak signals of positive selection for H7 among Tibetans. Interestingly, the haplotype diversity of H7 is higher in Tibetans than in any other populations studied, indicating a longer diversification history for that haplogroup in Tibetans. Network analysis on the long-range haplotypes revealed that H7 in the Han Chinese did not come from the Tibetans but from a common ancestor of the two populations.ConclusionsWe argue that H7 of ADH1B originated in the ancestors of Sino-Tibetan populations and flowed to Tibetans very early. However, as Tibetans depend less on crops, and therefore were not significantly affected by selection. Thus, H7 has not risen to a high frequency, whereas the diversity of the haplogroup has accumulated to a very high level.
| S-EPMC3528464 | biostudies-literature