Distinct positions of genetic and oral histories: Perspectives from India.

Over the past decade, genomic data have contributed to several insights on global human population histories. These studies have been met both with interest and critically, particularly by populations with oral histories that are records of their past and often reference their origins. While several studies have reported concordance between oral and genetic histories, there is potential for tension that may stem from genetic histories being prioritized or used to confirm community-based knowledge and ethnography, especially if they differ. To investigate the interplay between oral and genetic histories, we focused on the southwestern region of India and analyzed whole-genome sequence data from 156 individuals identifying as Bunt, Kodava, Nair, and Kapla. We supplemented limited anthropological records on these populations with oral history accounts from community members and historical literature, focusing on references to non-local origins such as the ancient Scythians in the case of Bunt, Kodava, and Nair, members of Alexander the Great's army for the Kodava, and an African-related source for Kapla. We found these populations to be genetically most similar to other Indian populations, with the Kapla more similar to South Indian tribal populations that maximize a genetic ancestry related to Ancient Ancestral South Indians. We did not find evidence of additional genetic sources in the study populations than those known to have contributed to many other present-day South Asian populations. Our results demonstrate that oral and genetic histories may not always provide consistent accounts of population origins and motivate further community-engaged, multi-disciplinary investigations of non-local origin stories in these communities.

Genomic and epigenomic responses to aspirin in human colonic organoids.

Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer, though mechanisms underlying these effects are incompletely understood. Human organoids are an ideal system to study genomic and epigenomic host-environment interactions. We use human colonic organoids to profile ASA responses on genome-wide gene expression and chromatin accessibility. Human colonic organoids from one individual were cultured and treated in triplicate with 3 mM ASA or vehicle control (DMSO) for 24 h. Gene expression and chromatin accessibility were measured using RNA- and ATAC-sequencing, respectively. Differentially expressed genes were analyzed using DESeq2. Top genes were validated by qPCR. Gene set enrichment was performed by SetRank. Differentially accessible peaks were analyzed using DiffBind and edgeR. Peak annotation and differential transcription factor motifs were determined by HOMER and diffTF. The results showed robust transcriptional responses to ASA with significant enrichment for fatty acid oxidation and peroxisome proliferator-activated receptor (PPAR) signaling that were validated in independent organoid lines. A large number of differentially accessible chromatin regions were found in response to ASA with significant enrichment for Fos, Jun, and Hnf transcription factor motifs. Integrated analysis of epigenomic and genomic treatment responses highlighted gene regions that could mediate ASA's specific effects in the colon including those involved in chemoprotection and/or toxicity. Assessment of chromatin accessibility and transcriptional responses to ASA yielded new observations about genome-wide effects in the colon facilitated by application of human colonic organoids. This framework can be applied to study colonic ASA responses between individuals and populations in future studies.

A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans.

In Tibetans, noncoding alleles in EPAS1-whose protein product hypoxia-inducible factor 2α (HIF-2α) drives the response to hypoxia-carry strong signatures of positive selection; however, their functional mechanism has not been systematically examined. Here, we report that high-altitude alleles disrupt the activity of four EPAS1 enhancers in one or more cell types. We further characterize one enhancer (ENH5) whose activity is both allele specific and hypoxia dependent. Deletion of ENH5 results in down-regulation of EPAS1 and HIF-2α targets in acute hypoxia and in a blunting of the transcriptional response to sustained hypoxia. Deletion of ENH5 in mice results in dysregulation of gene expression across multiple tissues. We propose that pleiotropic adaptive effects of the Tibetan alleles in EPAS1 underlie the strong selective signal at this gene.

Ancient genomes from the Himalayas illuminate the genetic history of Tibetans and their Tibeto-Burman speaking neighbors.

Present-day Tibetans have adapted both genetically and culturally to the high altitude environment of the Tibetan Plateau, but fundamental questions about their origins remain unanswered. Recent archaeological and genetic research suggests the presence of an early population on the Plateau within the past 40 thousand years, followed by the arrival of subsequent groups within the past 10 thousand years. Here, we obtain new genome-wide data for 33 ancient individuals from high elevation sites on the southern fringe of the Tibetan Plateau in Nepal, who we show are most closely related to present-day Tibetans. They derive most of their ancestry from groups related to Late Neolithic populations at the northeastern edge of the Tibetan Plateau but also harbor a minor genetic component from a distinct and deep Paleolithic Eurasian ancestry. In contrast to their Tibetan neighbors, present-day non-Tibetan Tibeto-Burman speakers living at mid-elevations along the southern and eastern margins of the Plateau form a genetic cline that reflects a distinct genetic history. Finally, a comparison between ancient and present-day highlanders confirms ongoing positive selection of high altitude adaptive alleles.

Genomic and epigenomic active vitamin D responses in human colonic organoids.

Active vitamin D, 1α,25(OH)2D3, is a nuclear hormone with roles in colonic homeostasis and carcinogenesis; yet, mechanisms underlying these effects are incompletely understood. Human organoids are an ideal system to study genomic and epigenomic host-environment interactions. Here, we use human colonic organoids to measure 1α,25(OH)2D3 responses on genome-wide gene expression and chromatin accessibility over time. Human colonic organoids were cultured and treated in triplicate with 100 nM 1α,25(OH)2D3 or vehicle control for 4 h and 18 h for chromatin accessibility, and 6 h and 24 h for gene expression. ATAC- and RNA-sequencing were performed. Differentially accessible peaks were analyzed using DiffBind and edgeR; differentially expressed genes were analyzed using DESeq2. Motif enrichment was determined using HOMER. At 6 h and 24 h, 2,870 and 2,721 differentially expressed genes, respectively (false discovery rate, FDR < 5%), were identified with overall stronger responses with 1α,25(OH)2D3. Similarly, 1α,25(OH)2D3 treatment led to stronger chromatin accessibility especially at 4 h. The vitamin D receptor (VDR) motif was strongly enriched among accessible chromatin peaks with 1α,25(OH)2D3 treatment accounting for 30.5% and 11% of target sequences at 4 h and 18 h, respectively (FDR < 1%). A number of genes such as CYP24A1, FGF19, MYC, FOS, and TGFBR2 showed significant transcriptional and chromatin accessibility responses to 1α,25(OH)2D3 treatment with accessible chromatin located distant from promoters for some gene regions. Assessment of chromatin accessibility and transcriptional responses to 1α,25(OH)2D3 yielded new observations about vitamin D genome-wide effects in the colon facilitated by application of human colonic organoids. This framework can be applied to study host-environment interactions between individuals and populations in the future.

The genetic prehistory of the Andean highlands 7000 years BP though European contact.

The peopling of the Andean highlands above 2500 m in elevation was a complex process that included cultural, biological, and genetic adaptations. Here, we present a time series of ancient whole genomes from the Andes of Peru, dating back to 7000 calendar years before the present (BP), and compare them to 42 new genome-wide genetic variation datasets from both highland and lowland populations. We infer three significant features: a split between low- and high-elevation populations that occurred between 9200 and 8200 BP; a population collapse after European contact that is significantly more severe in South American lowlanders than in highland populations; and evidence for positive selection at genetic loci related to starch digestion and plausibly pathogen resistance after European contact. We do not find selective sweep signals related to known components of the human hypoxia response, which may suggest more complex modes of genetic adaptation to high altitude.

Detecting past and ongoing natural selection among ethnically Tibetan women at high altitude in Nepal.

Adaptive evolution in humans has rarely been characterized for its whole set of components, i.e. selective pressure, adaptive phenotype, beneficial alleles and realized fitness differential. We combined approaches for detecting polygenic adaptations and for mapping the genetic bases of physiological and fertility phenotypes in approximately 1000 indigenous ethnically Tibetan women from Nepal, adapted to high altitude. The results of genome-wide association analyses and tests for polygenic adaptations showed evidence of positive selection for alleles associated with more pregnancies and live births and evidence of negative selection for those associated with higher offspring mortality. Lower hemoglobin level did not show clear evidence for polygenic adaptation, despite its strong association with an EPAS1 haplotype carrying selective sweep signals.

Colonic transcriptional response to 1α,25(OH)2 vitamin D3 in African- and European-Americans.

Colorectal cancer (CRC) is a significant health burden especially among African Americans (AA). Epidemiological studies have correlated low serum vitamin D with CRC risk, and, while hypovitaminosis D is more common and more severe in AA, the mechanisms by which vitamin D modulates CRC risk and how these differ by race are not well understood. Active vitamin D (1α,25(OH)2D3) has chemoprotective effects primarily through transcriptional regulation of target genes in the colon. We hypothesized that transcriptional response to 1α,25(OH)2D3 differs between AA and European Americans (EA) irrespective of serum vitamin D and that regulatory variants could impact transcriptional response. We treated ex vivo colon cultures from 34 healthy subjects (16 AA and 18 EA) with 0.1µM 1α,25(OH)2D3 or vehicle control for 6h and performed genome-wide transcriptional profiling. We found 8 genes with significant differences in transcriptional response to 1α,25(OH)2D3 between AA and EA with definitive replication of inter-ethnic differences for uridine phosphorylase 1 (UPP1) and zinc finger-SWIM containing 4 (ZSWIM4). We performed expression quantitative trait loci (eQTL) mapping and identified response cis-eQTLs for ZSWIM4 as well as for histone deacetylase 3 (HDAC3), the latter of which showed a trend toward significant inter-ethnic differences in transcriptional response. Allele frequency differences of eQTLs for ZSWIM4 and HDAC3 accounted for observed transcriptional differences between populations. Taken together, our results demonstrate that transcriptional response to 1α,25(OH)2D3 differs between AA and EA independent of serum 25(OH)D levels. We provide evidence in support of a genetic regulatory mechanism underlying transcriptional differences between populations for ZSWIM4 and HDAC3. Further work is needed to elucidate how response eQTLs modify vitamin D response and whether genotype and/or transcriptional response correlate with chemopreventive effects. Relevant biomarkers, such as tissue-specific 1α,25(OH)2D3 transcriptional response, could identify individuals likely to benefit from vitamin D for CRC prevention as well as elucidate basic mechanisms underlying CRC disparities.

Mapping Variation in Cellular and Transcriptional Response to 1,25-Dihydroxyvitamin D3 in Peripheral Blood Mononuclear Cells.

The active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is an important modulator of the immune system, inhibiting cellular proliferation and regulating transcription of immune response genes. In order to characterize the genetic basis of variation in the immunomodulatory effects of 1,25D, we mapped quantitative traits of 1,25D response at both the cellular and the transcriptional level. We carried out a genome-wide association scan of percent inhibition of cell proliferation (Imax) induced by 1,25D treatment of peripheral blood mononuclear cells from 88 healthy African-American individuals. Two genome-wide significant variants were identified: rs1893662 in a gene desert on chromosome 18 (p = 2.32 x 10-8) and rs6451692 on chromosome 5 (p = 2.55 x 10-8), which may influence the anti-proliferative activity of 1,25D by regulating the expression of nearby genes such as the chemokine gene, CCL28, and the translation initiation gene, PAIP1. We also identified 8 expression quantitative trait loci at a FDR<0.10 for transcriptional response to 1,25D treatment, which include the transcriptional regulator ets variant 3-like (ETV3L) and EH-domain containing 4 (EHD4). In addition, we identified response eQTLs in vitamin D receptor binding sites near genes differentially expressed in response to 1,25D, such as FERM Domain Containing 6 (FRMD6), which plays a critical role in regulating both cell proliferation and apoptosis. Combining information from the GWAS of Imax and the response eQTL mapping enabled identification of putative Imax-associated candidate genes such as PAIP1 and the transcriptional repressor gene ZNF649. Overall, the variants identified in this study are strong candidates for immune traits and diseases linked to vitamin D, such as multiple sclerosis.

Long-term genetic stability and a high-altitude East Asian origin for the peoples of the high valleys of the Himalayan arc.

The high-altitude transverse valleys [>3,000 m above sea level (masl)] of the Himalayan arc from Arunachal Pradesh to Ladahk were among the last habitable places permanently colonized by prehistoric humans due to the challenges of resource scarcity, cold stress, and hypoxia. The modern populations of these valleys, who share cultural and linguistic affinities with peoples found today on the Tibetan plateau, are commonly assumed to be the descendants of the earliest inhabitants of the Himalayan arc. However, this assumption has been challenged by archaeological and osteological evidence suggesting that these valleys may have been originally populated from areas other than the Tibetan plateau, including those at low elevation. To investigate the peopling and early population history of this dynamic high-altitude contact zone, we sequenced the genomes (0.04×-7.25×, mean 2.16×) and mitochondrial genomes (20.8×-1,311.0×, mean 482.1×) of eight individuals dating to three periods with distinct material culture in the Annapurna Conservation Area (ACA) of Nepal, spanning 3,150-1,250 y before present (yBP). We demonstrate that the region is characterized by long-term stability of the population genetic make-up despite marked changes in material culture. The ancient genomes, uniparental haplotypes, and high-altitude adaptive alleles suggest a high-altitude East Asian origin for prehistoric Himalayan populations.

Patterns of Transcriptional Response to 1,25-Dihydroxyvitamin D3 and Bacterial Lipopolysaccharide in Primary Human Monocytes.

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), plays an important immunomodulatory role, regulating transcription of genes in the innate and adaptive immune system. The present study examines patterns of transcriptome-wide response to 1,25D, and the bacterial lipopolysaccharide (LPS) in primary human monocytes, to elucidate pathways underlying the effects of 1,25D on the immune system. Monocytes obtained from healthy individuals of African-American and European-American ancestry were treated with 1,25D, LPS, or both, simultaneously. The addition of 1,25D during stimulation with LPS induced significant upregulation of genes in the antimicrobial and autophagy pathways, and downregulation of proinflammatory response genes compared to LPS treatment alone. A joint Bayesian analysis enabled clustering of genes into patterns of shared transcriptional response across treatments. The biological pathways enriched within these expression patterns highlighted several mechanisms through which 1,25D could exert its immunomodulatory role. Pathways such as mTOR signaling, EIF2 signaling, IL-8 signaling, and Tec Kinase signaling were enriched among genes with opposite transcriptional responses to 1,25D and LPS, respectively, highlighting the important roles of these pathways in mediating the immunomodulatory activity of 1,25D. Furthermore, a subset of genes with evidence of interethnic differences in transcriptional response was also identified, suggesting that in addition to the well-established interethnic variation in circulating levels of vitamin D, the intensity of transcriptional response to 1,25D and LPS also varies between ethnic groups. We propose that dysregulation of the pathways identified in this study could contribute to immune-mediated disease risk.

Admixture facilitates genetic adaptations to high altitude in Tibet.

Admixture is recognized as a widespread feature of human populations, renewing interest in the possibility that genetic exchange can facilitate adaptations to new environments. Studies of Tibetans revealed candidates for high-altitude adaptations in the EGLN1 and EPAS1 genes, associated with lower haemoglobin concentration. However, the history of these variants or that of Tibetans remains poorly understood. Here we analyse genotype data for the Nepalese Sherpa, and find that Tibetans are a mixture of ancestral populations related to the Sherpa and Han Chinese. EGLN1 and EPAS1 genes show a striking enrichment of high-altitude ancestry in the Tibetan genome, indicating that migrants from low altitude acquired adaptive alleles from the highlanders. Accordingly, the Sherpa and Tibetans share adaptive haemoglobin traits. This admixture-mediated adaptation shares important features with adaptive introgression. Therefore, we identify a novel mechanism, beyond selection on new mutations or on standing variation, through which populations can adapt to local environments.

Genetic mapping with multiple levels of phenotypic information reveals determinants of lymphocyte glucocorticoid sensitivity.

Clinical response to glucocorticoids, steroid hormones widely used as pharmaceuticals, varies extensively in that many individuals (∼30%) show a weak response to treatment. Although little is known about the molecular basis of this variation, regulatory polymorphisms are likely to play a key role given that glucocorticoids act largely through activation of a transcription factor, the glucocorticoid receptor. In an effort to characterize the molecular basis of variation in glucocorticoid sensitivity, we measured in vitro lymphocyte glucocorticoid sensitivity and transcriptome-wide response to glucocorticoids in peripheral-blood mononuclear cells from African American healthy donors. We found that variation in lymphocyte glucocorticoid sensitivity was correlated with transcriptional response at 27 genes (false-discovery rate < 0.1). Furthermore, a genome-wide association scan revealed a quantitative trait locus (QTL) for lymphocyte glucocorticoid sensitivity (rs11129354, p = 4 × 10(-8)); it was also associated with transcriptional response at multiple genes, including many (14/27) where transcriptional response was correlated with lymphocyte glucocorticoid sensitivity. Using allelic-imbalance assays, we show that this QTL is a glucocorticoid-dependent cis-regulatory polymorphism for RBMS3, which encodes an RNA-binding protein known as a tumor suppressor. We found that siRNA-mediated knockdown of RBMS3 expression increased cellular proliferation in PBMCs, consistent with the role of the gene as a negative regulator of proliferation. We propose that differences in lymphocyte glucocorticoid sensitivity reflect variation in transcriptional response, which is influenced by a glucocorticoid-dependent regulatory polymorphism that acts in cis relative to RBMS3 and in trans to affect the transcriptional response of multiple distant genes.

Genetic, functional and molecular features of glucocorticoid receptor binding.

Glucocorticoids (GCs) are key mediators of stress response and are widely used as pharmacological agents to treat immune diseases, such as asthma and inflammatory bowel disease, and certain types of cancer. GCs act mainly by activating the GC receptor (GR), which interacts with other transcription factors to regulate gene expression. Here, we combined different functional genomics approaches to gain molecular insights into the mechanisms of action of GC. By profiling the transcriptional response to GC over time in 4 Yoruba (YRI) and 4 Tuscans (TSI) lymphoblastoid cell lines (LCLs), we suggest that the transcriptional response to GC is variable not only in time, but also in direction (positive or negative) depending on the presence of specific interacting transcription factors. Accordingly, when we performed ChIP-seq for GR and NF-κB in two YRI LCLs treated with GC or with vehicle control, we observed that features of GR binding sites differ for up- and down-regulated genes. Finally, we show that eQTLs that affect expression patterns only in the presence of GC are 1.9-fold more likely to occur in GR binding sites, compared to eQTLs that affect expression only in its absence. Our results indicate that genetic variation at GR and interacting transcription factors binding sites influences variability in gene expression, and attest to the power of combining different functional genomic approaches.

The genetic architecture of adaptations to high altitude in Ethiopia.

Although hypoxia is a major stress on physiological processes, several human populations have survived for millennia at high altitudes, suggesting that they have adapted to hypoxic conditions. This hypothesis was recently corroborated by studies of Tibetan highlanders, which showed that polymorphisms in candidate genes show signatures of natural selection as well as well-replicated association signals for variation in hemoglobin levels. We extended genomic analysis to two Ethiopian ethnic groups: Amhara and Oromo. For each ethnic group, we sampled low and high altitude residents, thus allowing genetic and phenotypic comparisons across altitudes and across ethnic groups. Genome-wide SNP genotype data were collected in these samples by using Illumina arrays. We find that variants associated with hemoglobin variation among Tibetans or other variants at the same loci do not influence the trait in Ethiopians. However, in the Amhara, SNP rs10803083 is associated with hemoglobin levels at genome-wide levels of significance. No significant genotype association was observed for oxygen saturation levels in either ethnic group. Approaches based on allele frequency divergence did not detect outliers in candidate hypoxia genes, but the most differentiated variants between high- and lowlanders have a clear role in pathogen defense. Interestingly, a significant excess of allele frequency divergence was consistently detected for genes involved in cell cycle control and DNA damage and repair, thus pointing to new pathways for high altitude adaptations. Finally, a comparison of CpG methylation levels between high- and lowlanders found several significant signals at individual genes in the Oromo.

Reconstructing Native American population history.

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.

Interactions between glucocorticoid treatment and cis-regulatory polymorphisms contribute to cellular response phenotypes.

Glucocorticoids (GCs) mediate physiological responses to environmental stress and are commonly used as pharmaceuticals. GCs act primarily through the GC receptor (GR, a transcription factor). Despite their clear biomedical importance, little is known about the genetic architecture of variation in GC response. Here we provide an initial assessment of variability in the cellular response to GC treatment by profiling gene expression and protein secretion in 114 EBV-transformed B lymphocytes of African and European ancestry. We found that genetic variation affects the response of nearby genes and exhibits distinctive patterns of genotype-treatment interactions, with genotypic effects evident in either only GC-treated or only control-treated conditions. Using a novel statistical framework, we identified interactions that influence the expression of 26 genes known to play central roles in GC-related pathways (e.g. NQO1, AIRE, and SGK1) and that influence the secretion of IL6.

A reduced representation approach to population genetic analyses and applications to human evolution.

Second-generation sequencing technologies allow surveys of sequence variation on an unprecedented scale. However, despite the rapid decrease in sequencing costs, collecting whole-genome sequence data on a population scale is still prohibitive for many laboratories. We have implemented an inexpensive, reduced representation protocol for preparing resequencing targets, and we have developed the analytical tools necessary for making population genetic inferences. This approach can be applied to any species for which a draft or complete reference genome sequence is available. The new tools we have developed include methods for aligning reads, calling genotypes, and incorporating sample-specific sequencing error rates in the estimate of evolutionary parameters. When applied to 19 individuals from a total of 18 human populations, our approach allowed sampling regions that are largely overlapping across individuals and that are representative of the entire genome. The resequencing data were used to test the serial founder model of human dispersal and to estimate the time of the Out of Africa migration. Our results also represent the first attempt to provide a time frame for the colonization of Australia based on large-scale resequencing data.

A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk.

UDP-glucuronosyltransferase 2 family, polypeptide B4 (UGT2B4) is an important metabolizing enzyme involved in the clearance of many xenobiotics and endogenous substrates, especially steroid hormones and bile acids. The HapMap data show that numerous SNPs upstream of UGT2B4 are in near-perfect linkage disequilibrium with each other and occur at intermediate frequency, indicating that this region might contain a target of natural selection. To investigate this possibility, we chose three regions (4.8 kb in total) for resequencing and observed a striking excess of intermediate-frequency alleles that define two major haplotypes separated by many mutation events and with little differentiation across populations, thus suggesting that the variation pattern upstream UGT2B4 is highly unusual and may be the result of balancing selection. We propose that this pattern is due to the maintenance of a regulatory polymorphism involved in the fine tuning of UGT2B4 expression so that heterozygous genotypes result in optimal enzyme levels. Considering the important role of steroid hormones in breast cancer susceptibility, we hypothesized that variation in this region could predispose to breast cancer. To test this hypothesis, we genotyped tag SNP rs13129471 in 1,261 patients and 825 normal women of African ancestry from three populations. The frequency comparison indicated that rs13129471 was significantly associated with breast cancer after adjusting for ethnicity [P = 0.003; heterozygous odds ratio (OR) 1.02, 95% confidence interval (CI) 0.81-1.28; homozygous OR 1.50, 95% CI 1.15-1.95]. Our results provide new insights into UGT2B4 sequence variation and indicate that a signal of natural selection may lead to the identification of disease susceptibility variants.

Adaptations to climate-mediated selective pressures in humans.

Humans inhabit a remarkably diverse range of environments, and adaptation through natural selection has likely played a central role in the capacity to survive and thrive in extreme climates. Unlike numerous studies that used only population genetic data to search for evidence of selection, here we scan the human genome for selection signals by identifying the SNPs with the strongest correlations between allele frequencies and climate across 61 worldwide populations. We find a striking enrichment of genic and nonsynonymous SNPs relative to non-genic SNPs among those that are strongly correlated with these climate variables. Among the most extreme signals, several overlap with those from GWAS, including SNPs associated with pigmentation and autoimmune diseases. Further, we find an enrichment of strong signals in gene sets related to UV radiation, infection and immunity, and cancer. Our results imply that adaptations to climate shaped the spatial distribution of variation in humans.