Characterisation of genome-wide association epistasis signals for serum uric acid in human population isolates

Genome-wide association (GWA) studies have identified a number of loci underlying variation in human serum uric acid (SUA) levels with the SLC2A9 gene having the largest effect identified so far. Gene-gene interactions (epistasis) are largely unexplored in these GWA studies. We performed a full pair-wise genome scan in the Italian MICROS population (n = 1201) to characterise epistasis signals in SUA levels. In the resultant epistasis profile, no SNP pairs reached the Bonferroni adjusted threshold for the pair-wise genome-wide significance. However, SLC2A9 was found interacting with multiple loci across the genome, with NFIA - SLC2A9 and SLC2A9 - ESRRAP2 being significant based on a threshold derived for interactions between GWA significant SNPs and the genome and jointly explaining 8.0% of the phenotypic variance in SUA levels (3.4% by interaction components). Epistasis signal replication in a CROATIAN population (n = 1772) was limited at the SNP level but improved dramatically at the gene ontology level. In addition, gene ontology terms enriched by the epistasis signals in each population support links between SUA levels and neurological disorders. We conclude that GWA epistasis analysis is useful despite relatively low power in small isolated populations.     

Mitochondrial gene diversity in Cepaea– population structure, history and positive selection

Previous studies on the geographical distributions of both shell polymorphisms and mitochondrial haplotypes in Cepaea land snails have suggested varying contributions of natural selection, random genetic drift and population history to the origin and persistence of variation. We combine previous studies of polymorphism within two species of Cepaea , with new molecular data from two mitochondrial genes. The distributions of mitochondrial variants suggest that elements of population history may have been influential in creating patterns of diversity. However, some patterns of amino acid substitution that are found in a protein coding gene are also consistent with the action of diversifying selection. This suggests the possibility that in addition to stochastic processes such as repeated founder events, local extinctions and random genetic drift within a structured population, adaptive molecular change may have affected mitochondrial diversity.  © 2006 The Linnean Society of London, Biological Journal of the Linnean Society, 2006, 87 , 167–184.     

UniFrag and GenomePrimer: selection of primers for genome-wide production of unique amplicons

The complementary programs UniFrag and GenomePrimer were developed to provide a reliable high-throughput method to select the most unique regions within genomic DNA sequence(s) and design primers therein, involving minimal user intervention and maximum flexibility.     

Delineation of signals required for thymocyte positive selection

Peptide/MHC complexes capable of inducing positive selection in mouse fetal thymic organ cultures fail to do so in suspension culture. Furthermore, this type of culture does not promote initial stages of differentiation, such as coreceptor down-modulation, unless peptides used for stimulation have (at least) weak agonist activity. We show in this study that signals provided in suspension culture by nonagonist peptide/MHC complexes on the surface of macrophages, even though apparently silent, are sufficient to promote complete phenotypic differentiation when CD4+CD8+ thymocytes are subsequently placed in a proper anatomical setting. Furthermore, the synergistic actions of suboptimal concentrations of phorbol esters and nonagonist peptide/MHC complexes can make the initial stages of positive selection visible, without converting maturation into negative selection. Thus, the correlation between efficiency of positive selection and the degree of coreceptor down-modulation on CD4+CD8+ thymocytes is not linear. Furthermore, these results suggest that the unique role of thymic stromal cells in positive selection is related not to presentation of self-peptide/MHC complexes, but most likely to another ligand.     

Sex-specific population structure,natural selection,and linkage disequilibrium in a wild bird population as revealed by genome-wide microsatellite analyses

Background  

Sexual dimorphism in ecologically important traits is widespread, yet the differences in the genomic architecture between the two sexes are largely unexplored. We employed a genome-wide multilocus approach to examine the sexual differences in population subdivision, natural selection and linkage disequilibrium (LD) in a wild Siberian jay (Perisoreus infaustus) population, using genotypes at a total of 107 autosomal and Z-chromosomal microsatellites.     

Exploration of signals of positive selection derived from genotype-based human genome scans using re-sequencing data

We have investigated whether regions of the genome showing signs of positive selection in scans based on haplotype structure also show evidence of positive selection when sequence-based tests are applied, whether the target of selection can be localized more precisely, and whether such extra evidence can lead to increased biological insights. We used two tools: simulations under neutrality or selection, and experimental investigation of two regions identified by the HapMap2 project as putatively selected in human populations. Simulations suggested that neutral and selected regions should be readily distinguished and that it should be possible to localize the selected variant to within 40 kb at least half of the time. Re-sequencing of two ~300 kb regions (chr4:158Mb and chr10:22Mb) lacking known targets of selection in HapMap CHB individuals provided strong evidence for positive selection within each and suggested the micro-RNA gene hsa-miR-548c as the best candidate target in one region, and changes in regulation of the sperm protein gene SPAG6 in the other.     

Haplotype structure and evidence for positive selection at the human IL13 locus

Interleukin-13 (IL13) is believed to play an important role in the pathogenesis of atopy and allergic asthma. To better understand genetic variation at the IL13 locus, we resequenced a 5.1-kb genomic region spanning the entire locus and identified 26 single-nucleotide polymorphisms (SNPs) in 74 individuals from three major populations-Chinese, Caucasian, and African. Our survey suggests exceptionally high and significant geographic structure at the IL13 locus between African and outside Africa populations. This unusual pattern suggests that positive selection that acts in some local populations may have played a role on the IL13 locus. In support of this suggestion, we found a significant excess of high frequency-derived SNPs in the Chinese population and Caucasian population, respectively, as expected after a recent episode of positive selection. Further, the unusual haplotype structure indicates that different scenarios of the action of positive selection on the IL13 locus in different populations may exist. In the Caucasian population, the skewed haplotype distribution dominated by one common haplotype supports the hypothesis of simple directional selection. Whereas, in the Chinese population, the two-round hitchhiking hypothesis may explain the skewed haplotype structure with three dominant ones. These findings may provide insight into the likely relative roles of selection and population history in establishing present-day variation at the IL13 locus, and, motivate further studies of this locus as an important candidate in common diseases association studies.     

Evidence for recent positive selection at the human AIM1 locus in a European population

Two missense polymorphisms (E272K and L374F) of the AIM1 locus,encoding a melanocyte differentiation antigen, were shown tohave a clear association with human ethnicities. These two nonpathogenicsingle nucleotide polymorphisms (SNPs) may be associated withhuman pigmentation variation. In this study, we investigatedsequence variation in the coding region and exon-flanking sequenceand found low genetic variation only in subjects of Europeandescent. All four statistical tests applied to the 7.55-kb regionsurrounding the L374F polymorphism detected statistically significantdeviations from selective neutrality in Europeans. In addition,haplotype analysis revealed that one haplotype carrying 374Fwas overrepresented in this population, and the low rate ofvariation, with some features of selective sweeps, was shownto be statistically significant. These results suggest thatpositive selection recently has been acting or has acted onat least this region of the melanogenic gene and that an advantageoushaplotype spread rapidly in Europe.     

Genome scan in the mosquito Aedes rusticus: population structure and detection of positive selection after insecticide treatment

Identification of genes involved in local adaptation is particularly challenging for species functioning as a network of interconnected populations undergoing frequent extinctions–recolonizations, because populations are submitted to contrasted evolutionary pressures. Using amplified fragment length polymorphism markers, population genetic structure of the mosquito Aedes rusticus was analysed in five geographical areas of the French Rhône‐Alpes region. We included a number of sites that were treated with the bio‐insecticide Bacillus thuringiensis israelensis (Bti) for more than 15 years. Analysis of molecular variance revealed that most of the genetic variability was found within populations (96%), with no significant variation among geographical areas, although variation among populations within areas (4%) was significant. The global genetic differentiation index F_ST was low (0.0366 ± 0.167). However, pairwise F_ST values were significant and no isolation‐by‐distance at the regional level was observed, suggesting a metapopulation structure in this species. Bti‐treatment had no effect on genetic structure and on within‐population genetic diversity. Potential signatures of positive selection associated with Bti‐treatment were detected for five loci, even though toxicological bioassays performed on field‐collected larvae showed no significant difference in mortality between Bti‐treated and nontreated sites. The difficulty of detecting moderate resistance in field‐collected larvae together with possible differential persistence of toxins in the environment may explain our inability to detect a toxicological response to Bti in treated sites. The evidence for positive selection occurring at several genomic regions suggests a first step towards Bti resistance in natural mosquito populations treated with this bio‐insecticide. Furthermore, this signal was detectable using genomic tools before any toxicological evidence for resistance could be identified.     

Mitochondrial cytochrome b sequence variations and population structure of Siberian chipmunk (Tamias sibiricus) in Northeastern Asia and population substructure in South Korea

Twenty-five chipmunk species occur in the world, of which only the Siberian chipmunk, Tamias sibiricus, inhabits Asia. To investigate mitochondrial cytochrome b sequence variations and population structure of the Siberian chipmunk in northeastern Asia, we examined mitochondrial cytochrome b sequences (1140 bp) from 3 countries. Analyses of 41 individuals from South Korea and 33 individuals from Russia and northeast China resulted in 37 haplotypes and 27 haplotypes, respectively. There were no shared haplotypes between South Korea and Russia--northeast China. Phylogenetic trees and network analysis showed 2 major maternal lineages for haplotypes, referred to as the S and R lineages. Haplotype grouping in each cluster was nearly coincident with its geographic affinity. In particular, 3 distinct groups were found that mostly clustered in the northern, central and southern parts of South Korea. Nucleotide diversity of the S lineage was twice that of lineage R. The divergence between S and R lineages was estimated to be 2.98-0.98 Myr. During the ice age, there may have been at least 2 refuges in South Korea and Russia--northeast China. The sequence variation between the S and R lineages was 11.3% (K2P), which is indicative of specific recognition in rodents. These results suggest that T. sibiricus from South Korea could be considered a separate species. However, additional information, such as details of distribution, nuclear genes data or morphology, is required to strengthen this hypothesis.     

Shared and unique features of evolutionary diversification

A fundamental question in evolutionary biology asks whether organisms experiencing similar selective pressures will evolve similar solutions or whether historical contingencies dominate the evolutionary process and yield disparate evolutionary outcomes. It is perhaps most likely that both shared selective forces as well as unique histories play key roles in the course of evolution. Consequently, when multiple species face a common environmental gradient, their patterns of divergence might exhibit both shared and unique elements. Here we describe a general framework for investigating and evaluating the relative importance of these contrasting features of diversification. We examined morphological diversification in three species of livebearing fishes across a predation gradient. All species (Gambusia affinis from the United States of America, Brachyrhaphis rhabdophora from Costa Rica, and Poecilia reticulata from Trinidad) exhibited more elongate bodies, a larger caudal peduncle, and a relatively lower position of the eye in predator populations. This shared response suggests that common selective pressures generated parallel outcomes within three different species. However, each species also exhibited unique features of divergence, which might reflect phylogenetic tendencies, chance events, or localized environmental differences. In this system, we found that shared aspects of divergence were of larger magnitude than unique elements, suggesting common natural selective forces have played a greater role than unique histories in producing the observed patterns of morphological diversification. Assessing the nature and relative importance of shared and unique responses should aid in elucidating the relative generality or peculiarity in evolutionary divergence.     

A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection

We have performed a metabolite quantitative trait locus (mQTL) study of the (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11)相似文献   

Dissecting the genetic structure of Korean population using genome-wide SNP arrays

Genome-wide SNP arrays have generated unprecedented quantities of data allow the detection of human evolutionary history and dense genome-wide data also enable the identification of distance ancestry among individuals or ethnic groups. To explain wider aspects of the genetic structure of Koreans and the East Asian population, we analyzed 79 individuals from the Korean HapMap project at 555,352 common single-nucleotide polymorphism loci, and compared this data with the worldwide population groups with the 53 ethnic groups from Human Genome Diversity Panel (HGDP-CEPH). Population differentiation (F_ST), Principal Component Analyses, STRUCTURE and ADMIXTURE are examined. In general, all the individual samples studies here were classified into subset of ethnic groups according to their geographical origins. Korean HapMap individuals were grouped together with East Asian populations from HGDP panel. Recently, a sub-population structure within Korean population has been reported. Our result, however, revealed the genetic homogeneity of Korean population. The ADMIXTURE analysis showed that, overall the Korean populations derive 79 % of their genomic ancestry from southern Asia and have relatively little northern Asian ancestry (21 %). The present work, therefore, provide the evidence that the male-biased southern-to-northern migration influenced not only for the genetic make up of the Y chromosome in the Korean population but also, its autosomal composition.     

Scanning the human genome for signals of selection

The search for adaptive evolution in the human genome has reached a new era with the advent of genome-wide surveys of genetic variation. However, making sense, let alone use, of such experiments is far from straightforward. Key problems include the way in which the data have been collected, the need to control for factors such as population history and variable recombination rates, which influence the discovery rates for both true and false positives, and the inherent difficulty of falsification. Nevertheless, recent work has shown that genome scans can be used to identify both functional polymorphisms underlying selected traits and entire classes of genes enriched for signals of adaptation.     

The maintenance of a positive spatial correlation between South African bird species richness and human population density

Aim To investigate explanations for the maintenance of a positive spatial species richness–human population density correlation at broad scales, despite the negative impact of humans on species richness. These are (hypotheses 1–4): (1) human activities that create a habitat mosaic and (2) a more favourable climate, and (3) adequate conservation measures (e.g. sufficient natural habitat), maintain the positive species richness–human density correlation; or (4) the full range of human densities decrease the slope of the correlation without changing its form. Location South Africa. Methods Avian species richness data from atlas distribution maps and human population density data derived from 2001 census results were converted to a quarter‐degree resolution. We investigated the number of land transformation types (anthropogenic habitat heterogeneity), irrigated area (increasing productivity), and other covarying factors (e.g. primary productivity) as predictors of species richness. We compared species richness–human density relationships among regions with different amounts of natural habitat, and investigated whether the full range of human densities decrease species richness in relation to primary productivity. Results Hypotheses 1, 2 and 3 were supported. Human densities and activities that increase habitat heterogeneity and productivity are important beneficial factors to common species, but not to rare species. The species richness–human density relationship persists only at low land transformation levels, and no significant relationship exists at higher levels. For common species, the relationship becomes non‐significant at lower land transformation levels than for rare species. Main conclusions The persistence of the species richness–human density relationship depends mostly on the amount of remaining natural habitat. In addition, certain human activities benefit especially common species. Common species seem to be more flexible than rare species in response to human activity and habitat loss.     

Low-pass genome-wide sequencing and variant inference using identity-by-descent in an isolated human population

Whole-genome sequencing in an isolated population with few founders directly ascertains variants from the population bottleneck that may be rare elsewhere. In such populations, shared haplotypes allow imputation of variants in unsequenced samples without resorting to complex statistical methods as in studies of outbred cohorts. We focus on an isolated population cohort from the Pacific Island of Kosrae, Micronesia, where we previously collected SNP array and rich phenotype data for the majority of the population. We report identification of long regions with haplotypes co-inherited between pairs of individuals and methodology to leverage such shared genetic content for imputation. Our estimates show that sequencing as few as 40 personal genomes allows for inference in up to 60% of the 3000-person cohort at the average locus. We ascertained a pilot data set of whole-genome sequences from seven Kosraean individuals, with average 5× coverage. This assay identified 5,735,306 unique sites of which 1,212,831 were previously unknown. Additionally, these variants are unusually enriched for alleles that are rare in other populations when compared to geographic neighbors (published Korean genome SJK). We used the presence of shared haplotypes between the seven Kosraen individuals to estimate expected imputation accuracy of known and novel homozygous variants at 99.6% and 97.3%, respectively. This study presents whole-genome analysis of a homogenous isolate population with emphasis on optimal rare variant inference.