Population Branch Statistics Research Articles

Selection scan in Native Americans of Mexico identifies FADS2 rs174616: Evidence of gene-diet interactions affecting lipid levels and Delta-6-desaturase activity

Searching for positive selection signals across genomes has identified functional genetic variants responding to environmental change. In Native Americans of Mexico, we used the fixation index (Fst) and population branch statistic (PBS) to identify SNPs suggesting positive selection. The 103 most differentiated SNPs were tested for associations with metabolic traits, the most significant association was FADS2/rs174616 with body mass index (BMI). This variant lies within a linkage disequilibrium (LD) block independent of previously reported FADS selection signals and has not been clearly associated with metabolic phenotypes. We tested this variant in two independent cohorts with cardiometabolic data. In the Genetics of Atherosclerotic Disease (GEA) cohort, the derived allele (T) was associated with increased BMI, lower LDL-C levels and a decreased risk of subclinical atherosclerosis in women. Significant gene-diet interactions affected lipid, apolipoprotein and adiponectin levels with differences according to sex, involving mainly total and complex dietary carbohydrate%. In the Genotype-related Effects of PUFA trial, the derived allele was associated with lower Δ-6 desaturase activity and erythrocyte membrane dihomo-gamma-linolenic acid (DGLA) levels, and with increased Δ-5 desaturase activity and eicosapentaenoic acid levels. This variant interacted with dietary carbohydrate% affecting Δ-6 desaturase activity. Notably, the relationship of DGLA and other erythrocyte membrane LC-PUFA indices with HOMA-IR differed according to rs174616 genotype, which has implications regarding how these indices should be interpreted. In conclusion, this observational study identified rs174616 as a signal suggesting selection in an independent linkage disequilibrium block, was associated with cardiometabolic and erythrocyte measurements of LC-PUFA in two independent Mexican cohorts and showed significant gene-diet interactions.

Signatures of adaptation in myopia-related genes on the sunlight exposure hypothesis

BackgroundMyopia is a common eye disorder that results from gene-environment interactions. The prevalence of myopia varies across populations, and exposure to bright sunlight may prevent its development. We hypothesize that local adaptation to light environments during human migration played a role in shaping the genetic basis of myopia, and we aim to investigate how the environment influences the genetic basis of myopia.MethodWe utilized the whole-genome variant data of the 1000 Genomes Project for analysis. We searched myopia-associated loci that were under selection in Europeans using population branch statistics and the number of segregating sites by length statistics. The outliers of these statistics were enriched in the Kyoto Encyclopedia of Genes and Genomes pathways and the gene ontology biological process terms in searching for pathways that were under selection. We applied Bayesian inference to estimate the correlation between environmental factors and allele frequencies of the selected loci and performed causal inference of myopia using two-sample Mendelian randomization analysis.ResultsWe detected signatures of adaptation in vision and light perception pathways, supporting our hypothesis of sunlight adaptation. We discovered a strong correlation between latitude and allele frequencies in genes that are under significant selection, and we found pleiotropic effects of pigmentation or circadian rhythm genes on myopia, indicating that sunlight exposure influences the genetic diversity of myopia.ConclusionsMyopia genes involved in light perception showed signs of selection. Local adaptation during human migration shaped the genetic basis of myopia and may have influenced its global prevalence distribution.

Influence of Different Evolutive Forces on GDF5 Gene Variability.

The GDF5 gene is involved in the development of skeletal elements, synovial joint formation, tendons, ligaments, and cartilage. Several polymorphisms are present within the gene, and two of them, rs143384 and 143383, were reported to be correlated with osteoarticular disease or muscle flexibility. The aim of this research is to verify if the worldwide distribution of the rs143384 polymorphism among human populations was shaped by selective pressure, or if it was the result of random genetic drift events. Ninety-four individuals of both the male and female sexes, 18-28 years old, from Sardinia were analyzed. We observed the following genotype frequencies: 28.72% of AA homozygotes, 13.83% of GG homozygotes, and 57.45% of AG heterozygotes. The allele frequencies were 0.574 for allele A and 0.426 for allele G. The relationships between the populations were verified via Multidimensional Scaling (MDS). Our data show (i) a clear heterogeneity within the African populations; (ii) a strong differentiation between the African populations and the other populations; and that (iii) the Sardinian population is placed within the European cluster. To reveal possible traces of selective pressure, the Population Branch Statistic (PBS) was calculated; both the rs143384 and 143383 SNPs have low PBS values, suggesting that there are no signals of selective pressure in those areas of the gene.

Genetic differentiation and local adaptation of the Japanese honeybee, Apis cerana japonica.

We examine the population genetic structure and divergence among the regional populations of the Japanese honeybee, Apis cerana japonica, by re-sequencing the genomes of 105 individuals from the three main Japanese islands with diverse climates. The genetic structure results indicated that these individuals are distinct from the mainland Chinese A. cerana samples. Furthermore, population structure analyses have identified three genetically distinct geographic regions in Japan: Northern (Tohoku-Kanto-Chubu districts), Central (Chugoku district), and Southern (Kyushu district). In some districts, "possible non-native" individuals, likely introduced from other regions in recent years, were discovered. Then, genome-wide scans were conducted to detect candidate genes for adaptation by two different approaches. We performed a population branch statistics (PBS) analysis to identify candidate genes for population-specific divergence. A latent factor mixed model (LFMM) was used to identify genes associated with climatic variables along a geographic gradient. The PBSmax analysis identified 25 candidate genes for population-specific divergence whereas the LFMM analysis identified 73 candidate genes for adaptation to climatic variables along a geographic gradient. However, no common genes were identified by both methods.

Genomes of the extinct Bachman's warbler show high divergence and no evidence of admixture with other extant Vermivora warblers.

Bachman's warbler1 (Vermivora bachmanii)-last sighted in 1988-is one of the only North American passerines to recently go extinct.2,3,4 Given extensive ongoing hybridization of its two extant congeners-the blue-winged warbler (V.cyanoptera) and golden-winged warbler (V.chrysoptera)5,6,7,8-and shared patterns of plumage variation between Bachman's warbler and hybrids between those extant species, it has been suggested that Bachman's warbler might have also had a component of hybrid ancestry. Here, we use historic DNA (hDNA) and whole genomes of Bachman's warblers collected at the turn of the 20th century to address this. We combine these data with the two extant Vermivora species to examine patterns of population differentiation, inbreeding, and gene flow. In contrast to the admixture hypothesis, the genomic evidence is consistent with V.bachmanii having been a highly divergent, reproductively isolated species, with no evidence of introgression. We show that these three species have similar levels of runs of homozygosity (ROH), consistent with effects of a small long-term effective population size or population bottlenecks, with one V.bachmanii outlier showing numerous long ROH and a FROH greater than 5%. We also found-using population branch statistic estimates-previously undocumented evidence of lineage-specific evolution in V.chrysoptera near a pigmentation gene candidate, CORIN, which is a known modifier of ASIP, which is in turn involved in melanic throat and mask coloration in this family of birds. Together, these genomic results also highlight how natural history collections are such invaluable repositories of information about extant and extinct species.

Unraveling Signatures of Local Adaptation among Indigenous Groups from Mexico.

Few studies have addressed how selective pressures have shaped the genetic structure of the current Native American populations, and they have mostly limited their inferences to admixed Latin American populations. Here, we searched for local adaptation signals, based on integrated haplotype scores and population branch statistics, in 325 Mexican Indigenous individuals with at least 99% Native American ancestry from five previously defined geographical regions. Although each region exhibited its own local adaptation profile, only PPARG and AJAP1, both negative regulators of the Wnt/β catenin signaling pathway, showed significant adaptation signals in all the tested regions. Several signals were found, mainly in the genes related to the metabolic processes and immune response. A pathway enrichment analysis revealed the overrepresentation of selected genes related to several biological phenotypes/conditions, such as the immune response and metabolic pathways, in agreement with previous studies, suggesting that immunological and metabolic pressures are major drivers of human adaptation. Genes related to the gut microbiome measurements were overrepresented in all the regions, highlighting the importance of studying how humans have coevolved with the microbial communities that colonize them. Our results provide a further explanation of the human evolutionary history in response to environmental pressures in this region.

A chromosome-level genome of the human blood fluke Schistosoma japonicum identifies the genomic basis of host-switching.

The evolution and adaptation of S.japonicum, a zoonotic parasite that causes human schistosomiasis, remain unclear because of the lack of whole-genome data. We construct a chromosome-level S.japonicum genome and analyze it together with 72 samples representing six populations of the entire endemic region. We observe a Taiwan zoophilic lineage splitting from zoonotic populations ∼45,000 years ago, consistent with the divergent history of their intermediate hosts. Interestingly, we detect a severe population bottleneck in S.japonicum, largely coinciding with human history in Asia during the last glacial maximum. We identify several genomic regions underlying natural selection, including GATAD2A and Lmln, both showing remarkable differentiation among different areas. RNAi knockdown suggests association of GATAD2A with parasite development and infection in definitive hosts, while Lmln relates to the specificity of the intermediate hosts. Our study provides insights into the evolution of S.japonicum and serves as a resource for further studies.

Linked selection, ancient polymorphism, and ecological adaptation shape the genomic landscape of divergence in Quercus dentata

AbstractMultiple evolutionary forces contribute to heterogeneous genomic landscapes; however, disentangling their relative contributions is challenging. We sampled nine populations across the distribution of Quercus dentata, a dominant forest tree in East Asia, and used whole‐genome sequencing data to investigate mechanisms underlying divergence. We identified two genetic groups (north and south) that diverged ~1.84 million years ago, consistent with the uplift of the Qinling Mountains during the Pleistocene. The north group experienced a bottleneck during the middle–late Pleistocene and expanded from multiple refugia. The south group experienced a more severe bottleneck and showed high population differentiation, probably due to long‐term isolation and habitat fragmentation. We detected genomic islands with elevated relative differentiation (FST) scattered across the genome. Among these, 65.9% showed reduced absolute divergence (dXY) consistent with linked selection, while the remaining (34.1%) showed elevated dXY suggestive of divergent sorting of ancient polymorphisms. The recombination rate in genomic islands was lower than background, suggesting the importance of genome structure in shaping the genomic landscape. We detected 108 single nucleotide polymorphisms significantly associated with environmental factors, 12 of which clustered in a region of ~500 kb. This region showed multiple signals of positive selection in the north group, including the enrichment of XP‐extended haplotype homozygosity scores, an elevated population branch statistic, and an excess of high‐frequency derived alleles. In addition, we found that linkage disequilibrium was low and derived haplotypes declined rapidly in this region, indicating selection on standing variation. Our results clarify the evolutionary processes driving genomic divergence in Q. dentata.

Adaptive eQTLs reveal the evolutionary impacts of pleiotropy and tissue-specificity while contributing to health and disease.

Large numbers of expression quantitative trait loci (eQTLs) have recently been identified in humans, and many of these regulatory variants have large allele frequency differences between populations. Here, we conducted genome-wide scans of selection to identify adaptive eQTLs (i.e., eQTLs with large population branch statistics). We then tested if tissue pleiotropy affects whether eQTLs are more or less likely to be adaptive and identified tissues that have been key targets of positive selection during the last 100,000 years. Top adaptive eQTL outliers include rs1043809, rs66899053, and rs2814778 (a SNP that is associated with malaria resistance). We found that effect sizes of eQTLs were negatively correlated with population branch statistics and that adaptive eQTLs affect two-thirds as many tissues as do non-adaptive eQTLs. Because the tissue breadth of an eQTL can be viewed as a measure of pleiotropy, these results imply that pleiotropy inhibits adaptation. The proportion of eQTLs that are adaptive varies by tissue, and we found that eQTLs that regulate expression in testis, thyroid, blood, or sun-exposed skin are enriched for signatures of positive selection. By contrast, eQTLs that regulate expression in the cerebrum or female-specific tissues have a relative lack of adaptive outliers. Scans of selections also reveal that many adaptive eQTLs are closely linked to disease-associated loci. Taken together, our results indicate that eQTLs have played an important role in recent human evolution.

Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes

Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease. We analyzed whole exome sequencing data from 80 unique individuals from India coming from families with two or more individuals with severe mental illness. We used Population Branch Statistics (PBS) to identify variants and genes under positive selection and identified 74 genes as candidates for positive selection. Of these, 20 were previously associated with Schizophrenia, Alzheimer’s disease and cognitive abilities in genome wide association studies. We then checked whether any of these 74 genes were involved in common biological pathways or related to specific cellular or molecular functions. We found that immune related pathways and functions related to innate immunity such as antigen binding were over-represented. We also evaluated for the presence of Neanderthal introgressed segments in these genes and found Neanderthal introgression in a single gene out of the 74 candidate genes. However, the introgression pattern indicates the region is unlikely to be the source for selection. Our findings hint at how selection pressures in individuals from families with a history of severe mental illness may diverge from the general population. Further, it also provides insights into the genetic architecture of severe mental illness, such as schizophrenia and its link to immune factors.

Improving Selection Detection with Population Branch Statistic on Admixed Populations.

Detecting natural selection signals in admixed populations can be problematic since the source of the signal typically dates back prior to the admixture event. On one hand, it is now possible to study various source populations before a particular admixture thanks to the developments in ancient DNA (aDNA) in the last decade. However, aDNA availability is limited to certain geographical regions and the sample sizes and quality of the data might not be sufficient for selection analysis in many cases. In this study, we explore possible ways to improve detection of pre-admixture signals in admixed populations using a local ancestry inference approach. We used masked haplotypes for population branch statistic (PBS) and full haplotypes constructed following our approach from Yelmen et al. (2019) for cross-population extended haplotype homozygosity (XP-EHH), utilizing forward simulations to test the power of our analysis. The PBS results on simulated data showed that using masked haplotypes obtained from ancestry deconvolution instead of the admixed population might improve detection quality. On the other hand, XP-EHH results using the admixed population were better compared with the local ancestry method. We additionally report correlation for XP-EHH scores between source and admixed populations, suggesting that haplotype-based approaches must be used cautiously for recently admixed populations. Additionally, we performed PBS on real South Asian populations masked with local ancestry deconvolution and report here the first possible selection signals on the autochthonous South Asian component of contemporary South Asian populations.

Limited Evidence for Selection at the FADS Locus in Native American Populations.

The FADS locus contains the genes FADS1 and FADS2 that encode enzymes involved in the synthesis of long-chain polyunsaturated fatty acids. This locus appears to have been a repeated target of selection in human evolution, likely because dietary input of long-chain polyunsaturated fatty acids varied over time depending on environment and subsistence strategy. Several recent studies have identified selection at the FADS locus in Native American populations, interpreted as evidence for adaptation during or subsequent to the passage through Beringia. Here, we show that these signals are confounded by independent selection—postdating the split from Native Americans—in the European and, possibly, the East Asian populations used in the population branch statistic test. This is supported by direct evidence from ancient DNA that one of the putatively selected haplotypes was already common in Northern Eurasia at the time of the separation of Native American ancestors. An explanation for the present-day distribution of the haplotype that is more consistent with the data is that Native Americans retain the ancestral state of Paleolithic Eurasians. Another haplotype at the locus may reflect a secondary selection signal, although its functional impact is unknown.

Genome-Wide Selection Scan in an Arabian Peninsula Population Identifies a TNKS Haplotype Linked to Metabolic Traits and Hypertension.

Despite the extreme and varying environmental conditions prevalent in the Arabian Peninsula, it has experienced several waves of human migrations following the out-of-Africa diaspora. Eventually, the inhabitants of the peninsula region adapted to the hot and dry environment. The adaptation and natural selection that shaped the extant human populations of the Arabian Peninsula region have been scarcely studied. In an attempt to explore natural selection in the region, we analyzed 662,750 variants in 583 Kuwaiti individuals. We searched for regions in the genome that display signatures of positive selection in the Kuwaiti population using an integrative approach in a conservative manner. We highlight a haplotype overlapping TNKS that showed strong signals of positive selection based on the results of the multiple selection tests conducted (integrated Haplotype Score, Cross Population Extended Haplotype Homozygosity, Population Branch Statistics, and log-likelihood ratio scores). Notably, the TNKS haplotype under selection potentially conferred a fitness advantage to the Kuwaiti ancestors for surviving in the harsh environment while posing a major health risk to present-day Kuwaitis.

Genome scan for selection in South American chickens reveals a region under selection associated with aggressiveness

ABSTRACT Domestic chicken populations have been subjected to selection strategies to improve different production traits. Throughout history, selection coupled with diverse demographic dynamics have shaped the genome of many local populations which might harbor important genetic combinations with potential for production and survival to future unknown climate changes. South American local chickens include several well-adapted local breeds that thrive in extreme environments (e.g., tropical rain forest, high altitude and desert). In addition, there has been a long tradition of game fowl breeding in South America about which very little is known. As game fowl display distinct phenotypes compared to other types of chickens, i.e., aggressiveness, we have screened for single nucleotide polymorphisms (SNPs) localized in genes related to behavior that depart from neutrality (i.e., outliers) and therefore might be influenced by selection. Here we used restriction site-associated DNA sequencing (RADseq) to identify 122,801 SNPs distributed across the genome to scan for selection signatures in South American chicken populations. We detected 892 SNPs that were under selection. Two SNPs under positive selection localized in a genomic region harboring the Dopamine Receptor 2 (DRD2) gene and the Ankyrin Repeat and Kinase Domain Containing 1 (ANKK1) gene which have been associated with behavior. The population branch statistics analysis (PBS) on these two SNPs provided further evidence that these two variants have been under positive selection in game fowl. These findings contribute to the understanding of the genetic architecture behind the aggressiveness behavior in chickens, a trait of paramount importance in the poultry industry.

The genomic basis of adaptation to high-altitude habitats in the eastern honey bee (Apis cerana).

The eastern honey bee (Apis cerana) is of central importance for agriculture in Asia. It has adapted to a wide variety of environmental conditions across its native range in southern and eastern Asia, which includes high-altitude regions. eastern honey bees inhabiting mountains differ morphologically from neighbouring lowland populations and may also exhibit differences in physiology and behaviour. We compared the genomes of 60 eastern honey bees collected from high and low altitudes in Yunnan and Gansu provinces, China, to infer their evolutionary history and to identify candidate genes that may underlie adaptation to high altitude. Using a combination of FST -based statistics, long-range haplotype tests and population branch statistics, we identified several regions of the genome that appear to have been under positive selection. These candidate regions were strongly enriched for coding sequences and had high haplotype homozygosity and increased divergence specifically in highland bee populations, suggesting they have been subjected to recent selection in high-altitude habitats. Candidate loci in these genomic regions included genes related to reproduction and feeding behaviour in honey bees. Functional investigation of these candidate loci is necessary to fully understand the mechanisms of adaptation to high-altitude habitats in the eastern honey bee.

Evidence of Early-Stage Selection on EPAS1 and GPR126 Genes in Andean High Altitude Populations

The aim of this study is to identify genetic variants that harbour signatures of recent positive selection and may facilitate physiological adaptations to hypobaric hypoxia. To achieve this, we conducted whole genome sequencing and lung function tests in 19 Argentinean highlanders (>3500 m) comparing them to 16 Native American lowlanders. We developed a new statistical procedure using a combination of population branch statistics (PBS) and number of segregating sites by length (nSL) to detect beneficial alleles that arose since the settlement of the Andes and are currently present in 15–50% of the population. We identified two missense variants as significant targets of selection. One of these variants, located within the GPR126 gene, has been previously associated with the forced expiratory volume/forced vital capacity ratio. The other novel missense variant mapped to the EPAS1 gene encoding the hypoxia inducible factor 2α. EPAS1 is known to be the major selection candidate gene in Tibetans. The derived allele of GPR126 is associated with lung function in our sample of highlanders (p < 0.05). These variants may contribute to the physiological adaptations to hypobaric hypoxia, possibly by altering lung function. The new statistical approach might be a useful tool to detect selected variants in population studies.

Evolutionary triangulation: informing genetic association studies with evolutionary evidence.

Genetic studies of human diseases have identified many variants associated with pathogenesis and severity. However, most studies have used only statistical association to assess putative relationships to disease, and ignored other factors for evaluation. For example, evolution is a factor that has shaped disease risk, changing allele frequencies as human populations migrated into and inhabited new environments. Since many common variants differ among populations in frequency, as does disease prevalence, we hypothesized that patterns of disease and population structure, taken together, will inform association studies. Thus, the population distributions of allelic risk variants should reflect the distributions of their associated diseases. Evolutionary Triangulation (ET) exploits this evolutionary differentiation by comparing population structure among three populations with variable patterns of disease prevalence. By selecting populations based on patterns where two have similar rates of disease that differ substantially from a third, we performed a proof of principle analysis for this method. We examined three disease phenotypes, lactase persistence, melanoma, and Type 2 diabetes mellitus. We show that for lactase persistence, a phenotype with a simple genetic architecture, ET identifies the key gene, lactase. For melanoma, ET identifies several genes associated with this disease and/or phenotypes related to it, such as skin color genes. ET was less obviously successful for Type 2 diabetes mellitus, perhaps because of the small effect sizes in known risk loci and recent environmental changes that have altered disease risk. Alternatively, ET may have revealed new genes involved in conferring disease risk for diabetes that did not meet nominal GWAS significance thresholds. We also compared ET to another method used to filter for phenotype associated genes, population branch statistic (PBS), and show that ET performs better in identifying genes known to associate with diseases appropriately distributed among populations. Our results indicate that ET can filter association results to improve our ability to discover disease loci.Electronic supplementary materialThe online version of this article (doi:10.1186/s13040-016-0091-7) contains supplementary material, which is available to authorized users.

Genetic and phenotypic differentiation of an Andean intermediate altitude population.

Highland populations living permanently under hypobaric hypoxia have been subject of extensive research because of the relevance of their physiological adaptations for the understanding of human health and disease. In this context, what is considered high altitude is a matter of interpretation and while the adaptive processes at high altitude (above 3000 m) are well documented, the effects of moderate altitude (below 3000 m) on the phenotype are less well established. In this study, we compare physiological and anthropometric characteristics as well as genetic variations in two Andean populations: the Calchaquíes (2300 m) and neighboring Collas (3500 m). We compare their phenotype and genotype to the sea-level Wichí population. We measured physiological (heart rate, oxygen saturation, respiration rate, and lung function) as well as anthropometric traits (height, sitting height, weight, forearm, and tibia length). We conducted genome-wide genotyping on a subset of the sample (n = 74) and performed various scans for positive selection. At the phenotypic level (n = 179), increased lung capacity stood out in both Andean groups, whereas a growth reduction in distal limbs was only observed at high altitude. At the genome level, Calchaquíes revealed strong signals around PRKG1, suggesting that the nitric oxide pathway may be a target of selection. PRKG1 was highlighted by one of four selection tests among the top five genes using the population branch statistic. Selection tests results of Collas were reported previously. Overall, our study shows that some phenotypic and genetic differentiation occurs at intermediate altitude in response to moderate lifelong selection pressures.

Biased Gene Conversion Skews Allele Frequencies in Human Populations, Increasing the Disease Burden of Recessive Alleles

Gene conversion results in the nonreciprocal transfer of genetic information between two recombining sequences, and there is evidence that this process is biased toward G and C alleles. However, the strength of GC-biased gene conversion (gBGC) in human populations and its effects on hereditary disease have yet to be assessed on a genomic scale. Using high-coverage whole-genome sequences of African hunter-gatherers, agricultural populations, and primate outgroups, we quantified the effects of GC-biased gene conversion on population genomic data sets. We find that genetic distances (FST and population branch statistics) are modified by gBGC. In addition, the site frequency spectrum is left-shifted when ancestral alleles are favored by gBGC and right-shifted when derived alleles are favored by gBGC. Allele frequency shifts due to gBGC mimic the effects of natural selection. As expected, these effects are strongest in high-recombination regions of the human genome. By comparing the relative rates of fixation of unbiased and biased sites, the strength of gene conversion was estimated to be on the order of Nb ≈ 0.05 to 0.09. We also find that derived alleles favored by gBGC are much more likely to be homozygous than derived alleles at unbiased SNPs (+42.2% to 62.8%). This results in a curse of the converted, whereby gBGC causes substantial increases in hereditary disease risks. Taken together, our findings reveal that GC-biased gene conversion has important population genetic and public health implications.

Population-specific common SNPs reflect demographic histories and highlight regions of genomic plasticity with functional relevance.

BackgroundPopulation differentiation is the result of demographic and evolutionary forces. Whole genome datasets from the 1000 Genomes Project (October 2012) provide an unbiased view of genetic variation across populations from Europe, Asia, Africa and the Americas. Common population-specific SNPs (MAF > 0.05) reflect a deep history and may have important consequences for health and wellbeing. Their interpretation is contextualised by currently available genome data.ResultsThe identification of common population-specific (CPS) variants (SNPs and SSV) is influenced by admixture and the sample size under investigation. Nine of the populations in the 1000 Genomes Project (2 African, 2 Asian (including a merged Chinese group) and 5 European) revealed that the African populations (LWK and YRI), followed by the Japanese (JPT) have the highest number of CPS SNPs, in concordance with their histories and given the populations studied. Using two methods, sliding 50-SNP and 5-kb windows, the CPS SNPs showed distinct clustering across large genome segments and little overlap of clusters between populations. iHS enrichment score and the population branch statistic (PBS) analyses suggest that selective sweeps are unlikely to account for the clustering and population specificity. Of interest is the association of clusters close to recombination hotspots. Functional analysis of genes associated with the CPS SNPs revealed over-representation of genes in pathways associated with neuronal development, including axonal guidance signalling and CREB signalling in neurones.ConclusionsCommon population-specific SNPs are non-randomly distributed throughout the genome and are significantly associated with recombination hotspots. Since the variant alleles of most CPS SNPs are the derived allele, they likely arose in the specific population after a split from a common ancestor. Their proximity to genes involved in specific pathways, including neuronal development, suggests evolutionary plasticity of selected genomic regions. Contrary to expectation, selective sweeps did not play a large role in the persistence of population-specific variation. This suggests a stochastic process towards population-specific variation which reflects demographic histories and may have some interesting implications for health and susceptibility to disease.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-437) contains supplementary material, which is available to authorized users.