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• W2550871030 abstract "•Sequences inherited from archaic hominins were a source of beneficial mutations•Analysis of geographically diverse populations found 126 adaptive archaic loci•Many beneficial archaic loci influence gene expression levels•Immune and pigmentation traits frequent substrates of adaptive introgression As modern humans dispersed from Africa throughout the world, they encountered and interbred with archaic hominins, including Neanderthals and Denisovans [1Green R.E. Krause J. Briggs A.W. Maricic T. Stenzel U. Kircher M. Patterson N. Li H. Zhai W. Fritz M.H. et al.A draft sequence of the Neandertal genome.Science. 2010; 328: 710-722Crossref PubMed Scopus (2469) Google Scholar, 2Reich D. Green R.E. Kircher M. Krause J. Patterson N. Durand E.Y. Viola B. Briggs A.W. Stenzel U. Johnson P.L. et al.Genetic history of an archaic hominin group from Denisova Cave in Siberia.Nature. 2010; 468: 1053-1060Crossref PubMed Scopus (1137) Google Scholar]. Although genome-scale maps of introgressed sequences have been constructed [3Vernot B. Akey J.M. Resurrecting surviving Neandertal lineages from modern human genomes.Science. 2014; 343: 1017-1021Crossref PubMed Scopus (351) Google Scholar, 4Sankararaman S. Mallick S. Dannemann M. Prüfer K. Kelso J. Pääbo S. Patterson N. Reich D. The genomic landscape of Neanderthal ancestry in present-day humans.Nature. 2014; 507: 354-357Crossref PubMed Scopus (568) Google Scholar, 5Vernot B. Tucci S. Kelso J. Schraiber J.G. Wolf A.B. Gittelman R.M. Dannemann M. Grote S. McCoy R.C. Norton H. et al.Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.Science. 2016; 352: 235-239Crossref PubMed Scopus (250) Google Scholar, 6Sankararaman S. Mallick S. Patterson N. Reich D. The Combined Landscape of Denisovan and Neanderthal Ancestry in Present-Day Humans.Curr. Biol. 2016; 26: 1241-1247Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar], considerable gaps in knowledge remain about the functional, phenotypic, and evolutionary significance of archaic hominin DNA that persists in present-day individuals. Here, we describe a comprehensive set of analyses that identified 126 high-frequency archaic haplotypes as putative targets of adaptive introgression in geographically diverse populations. These loci are enriched for immune-related genes (such as OAS1/2/3, TLR1/6/10, and TNFAIP3) and also encompass genes (including OCA2 and BNC2) that influence skin pigmentation phenotypes. Furthermore, we leveraged existing and novel large-scale gene expression datasets to show many positively selected archaic haplotypes act as expression quantitative trait loci (eQTLs), suggesting that modulation of transcript abundance was a common mechanism facilitating adaptive introgression. Our results demonstrate that hybridization between modern and archaic hominins provided an important reservoir of advantageous alleles that enabled adaptation to out-of-Africa environments. As modern humans dispersed from Africa throughout the world, they encountered and interbred with archaic hominins, including Neanderthals and Denisovans [1Green R.E. Krause J. Briggs A.W. Maricic T. Stenzel U. Kircher M. Patterson N. Li H. Zhai W. Fritz M.H. et al.A draft sequence of the Neandertal genome.Science. 2010; 328: 710-722Crossref PubMed Scopus (2469) Google Scholar, 2Reich D. Green R.E. Kircher M. Krause J. Patterson N. Durand E.Y. Viola B. Briggs A.W. Stenzel U. Johnson P.L. et al.Genetic history of an archaic hominin group from Denisova Cave in Siberia.Nature. 2010; 468: 1053-1060Crossref PubMed Scopus (1137) Google Scholar]. Although genome-scale maps of introgressed sequences have been constructed [3Vernot B. Akey J.M. Resurrecting surviving Neandertal lineages from modern human genomes.Science. 2014; 343: 1017-1021Crossref PubMed Scopus (351) Google Scholar, 4Sankararaman S. Mallick S. Dannemann M. Prüfer K. Kelso J. Pääbo S. Patterson N. Reich D. The genomic landscape of Neanderthal ancestry in present-day humans.Nature. 2014; 507: 354-357Crossref PubMed Scopus (568) Google Scholar, 5Vernot B. Tucci S. Kelso J. Schraiber J.G. Wolf A.B. Gittelman R.M. Dannemann M. Grote S. McCoy R.C. Norton H. et al.Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.Science. 2016; 352: 235-239Crossref PubMed Scopus (250) Google Scholar, 6Sankararaman S. Mallick S. Patterson N. Reich D. The Combined Landscape of Denisovan and Neanderthal Ancestry in Present-Day Humans.Curr. Biol. 2016; 26: 1241-1247Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar], considerable gaps in knowledge remain about the functional, phenotypic, and evolutionary significance of archaic hominin DNA that persists in present-day individuals. Here, we describe a comprehensive set of analyses that identified 126 high-frequency archaic haplotypes as putative targets of adaptive introgression in geographically diverse populations. These loci are enriched for immune-related genes (such as OAS1/2/3, TLR1/6/10, and TNFAIP3) and also encompass genes (including OCA2 and BNC2) that influence skin pigmentation phenotypes. Furthermore, we leveraged existing and novel large-scale gene expression datasets to show many positively selected archaic haplotypes act as expression quantitative trait loci (eQTLs), suggesting that modulation of transcript abundance was a common mechanism facilitating adaptive introgression. Our results demonstrate that hybridization between modern and archaic hominins provided an important reservoir of advantageous alleles that enabled adaptation to out-of-Africa environments. Non-African individuals inherited∼2% of their genomes from Neanderthal ancestors [1Green R.E. Krause J. Briggs A.W. Maricic T. Stenzel U. Kircher M. Patterson N. Li H. Zhai W. Fritz M.H. et al.A draft sequence of the Neandertal genome.Science. 2010; 328: 710-722Crossref PubMed Scopus (2469) Google Scholar, 7Prüfer K. Racimo F. Patterson N. Jay F. Sankararaman S. Sawyer S. Heinze A. Renaud G. Sudmant P.H. de Filippo C. et al.The complete genome sequence of a Neanderthal from the Altai Mountains.Nature. 2014; 505: 43-49Crossref PubMed Scopus (1248) Google Scholar], and individuals of Melanesian ancestry have an additional 2%–4% of their genomes inherited from Denisovan ancestors [2Reich D. Green R.E. Kircher M. Krause J. Patterson N. Durand E.Y. Viola B. Briggs A.W. Stenzel U. Johnson P.L. et al.Genetic history of an archaic hominin group from Denisova Cave in Siberia.Nature. 2010; 468: 1053-1060Crossref PubMed Scopus (1137) Google Scholar, 8Meyer M. Kircher M. Gansauge M.-T. Li H. Racimo F. Mallick S. Schraiber J.G. Jay F. Prüfer K. de Filippo C. et al.A high-coverage genome sequence from an archaic Denisovan individual.Science. 2012; 338: 222-226Crossref PubMed Scopus (1133) Google Scholar]. Considerable progress has been made in cataloging Neanderthal and Denisovan sequences that persist in modern individuals [3Vernot B. Akey J.M. Resurrecting surviving Neandertal lineages from modern human genomes.Science. 2014; 343: 1017-1021Crossref PubMed Scopus (351) Google Scholar, 4Sankararaman S. Mallick S. Dannemann M. Prüfer K. Kelso J. Pääbo S. Patterson N. Reich D. The genomic landscape of Neanderthal ancestry in present-day humans.Nature. 2014; 507: 354-357Crossref PubMed Scopus (568) Google Scholar, 5Vernot B. Tucci S. Kelso J. Schraiber J.G. Wolf A.B. Gittelman R.M. Dannemann M. Grote S. McCoy R.C. Norton H. et al.Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.Science. 2016; 352: 235-239Crossref PubMed Scopus (250) Google Scholar, 6Sankararaman S. Mallick S. Patterson N. Reich D. The Combined Landscape of Denisovan and Neanderthal Ancestry in Present-Day Humans.Curr. Biol. 2016; 26: 1241-1247Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar, 9Vattathil S. Akey J.M. Small Amounts of Archaic Admixture Provide Big Insights into Human History.Cell. 2015; 163: 281-284Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar], but the consequences of hybridization remain poorly understood. Recent studies suggest that introgressed sequences experienced widespread purifying selection [3Vernot B. Akey J.M. Resurrecting surviving Neandertal lineages from modern human genomes.Science. 2014; 343: 1017-1021Crossref PubMed Scopus (351) Google Scholar, 4Sankararaman S. Mallick S. Dannemann M. Prüfer K. Kelso J. Pääbo S. Patterson N. Reich D. The genomic landscape of Neanderthal ancestry in present-day humans.Nature. 2014; 507: 354-357Crossref PubMed Scopus (568) Google Scholar, 5Vernot B. Tucci S. Kelso J. Schraiber J.G. Wolf A.B. Gittelman R.M. Dannemann M. Grote S. McCoy R.C. Norton H. et al.Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.Science. 2016; 352: 235-239Crossref PubMed Scopus (250) Google Scholar, 6Sankararaman S. Mallick S. Patterson N. Reich D. The Combined Landscape of Denisovan and Neanderthal Ancestry in Present-Day Humans.Curr. Biol. 2016; 26: 1241-1247Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar] and influence susceptibility to a broad spectrum of diseases [4Sankararaman S. Mallick S. Dannemann M. Prüfer K. Kelso J. Pääbo S. Patterson N. Reich D. The genomic landscape of Neanderthal ancestry in present-day humans.Nature. 2014; 507: 354-357Crossref PubMed Scopus (568) Google Scholar, 10Simonti C.N. Vernot B. Bastarache L. Bottinger E. Carrell D.S. Chisholm R.L. Crosslin D.R. Hebbring S.J. Jarvik G.P. Kullo I.J. et al.The phenotypic legacy of admixture between modern humans and Neandertals.Science. 2016; 351: 737-741Crossref PubMed Scopus (172) Google Scholar]. Conversely, archaic admixture may have also resulted in the acquisition of advantageous alleles that allowed modern humans to adapt to emergent selective pressures as they dispersed into new environments. Indeed, several examples of adaptive introgression have been hypothesized [11Dannemann M. Andrés A.M. Kelso J. Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors.Am. J. Hum. Genet. 2016; 98: 22-33Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar, 12Racimo F. Sankararaman S. Nielsen R. Huerta-Sánchez E. Evidence for archaic adaptive introgression in humans.Nat. Rev. Genet. 2015; 16: 359-371Crossref PubMed Scopus (300) Google Scholar], including a Denisovan like haplotype of the EPAS1 gene that confers adaptation to high altitude in Tibetans [13Huerta-Sánchez E. Jin X. Asan Bianba Z. Peter B.M. Vinckenbosch N. Liang Y. Yi X. He M. Somel M. et al.Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA.Nature. 2014; 512: 194-197Crossref PubMed Scopus (585) Google Scholar]. Nonetheless, many important questions remain, including the number of loci subjected to adaptive introgression, the population genetics characteristics of such loci, and what the functional and phenotypic consequences of adaptive Neanderthal and Denisovan sequences are in modern humans. To more comprehensively understand how adaptive introgression has shaped patterns of human genomic variation, we leveraged recently constructed genome-scale maps of Neanderthal and Denisovan sequences identified in 1,523 geographically diverse individuals [5Vernot B. Tucci S. Kelso J. Schraiber J.G. Wolf A.B. Gittelman R.M. Dannemann M. Grote S. McCoy R.C. Norton H. et al.Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.Science. 2016; 352: 235-239Crossref PubMed Scopus (250) Google Scholar] (Figure 1A). Collectively, we analyzed 1.34 Gb and 303 Mb of Neanderthal and Denisovan sequences, respectively, that segregate in 504 East Asians, 503 Europeans, 489 South Asians, and 27 individuals from Island Melanesia. We first carefully identified SNPs that “tag” archaic haplotypes (Experimental Procedures) and performed extensive coalescent simulations to compare the number of observed high-frequency haplotypes to neutral expectations across a range of demographic models (Experimental Procedures; Figure S1). Consistent with previous studies [14Teshima K.M. Coop G. Przeworski M. How reliable are empirical genomic scans for selective sweeps?.Genome Res. 2006; 16: 702-712Crossref PubMed Scopus (291) Google Scholar, 15Kelley J.L. Madeoy J. Calhoun J.C. Swanson W. Akey J.M. Genomic signatures of positive selection in humans and the limits of outlier approaches.Genome Res. 2006; 16: 980-989Crossref PubMed Scopus (166) Google Scholar], our simulations suggest that simple outlier approaches are effective in enriching for positively selected loci, although the false discovery rate (FDR) can be high (Figure 1B). For example, at FDR ≤ 50% (corresponding to extreme outliers in the >99th percentile of the empirical frequency distribution), we identify 126 candidate adaptively introgressed loci (44, 45, 22, and 38 in East Asians, Europeans, Melanesians, and South Asians, respectively; Table S1). Thus, we estimate that there are on the order of 10–20 true cases of adaptive introgression per population, and this estimate is robust to different FDR thresholds (Supplemental Experimental Procedures). Note that recent work [16Fu Q. Posth C. Hajdinjak M. Petr M. Mallick S. Fernandes D. Furtwängler A. Haak W. Meyer M. Mittnik A. et al.The genetic history of Ice Age Europe.Nature. 2016; 534: 200-205Crossref PubMed Scopus (509) Google Scholar, 17Juric I. Aeschbacher S. Coop G. The strength of selection against Neanderthal introgression.bioRxiv. 2015; https://doi.org/10.1101/030148Crossref Google Scholar] suggests that Neanderthal sequences were on average deleterious in modern human backgrounds, which is reflected in the positive correlation of B values [18McVicker G. Gordon D. Davis C. Green P. Widespread genomic signatures of natural selection in hominid evolution.PLoS Genet. 2009; 5: e1000471Crossref PubMed Scopus (252) Google Scholar] and introgressed haplotype frequency (p = 3.0 × 10−5, p = 1.9 × 10−05, p = 3.4 × 10−05, and p = 1.5 × 10−05 for East Asians, Europeans, Melanesians, and South Asians, respectively), we therefore included mild purifying selection against introgressed sequences in our simulation framework. However, our inferences are robust if Neanderthal sequences are instead assumed to be on average neutral (Supplemental Experimental Procedures). Unless otherwise noted, we focus subsequent analyses on this set of 126 loci (and provide locus-specific estimates of FDR; Table S1). Of the 126 distinct archaic haplotypes that are found at unusually high frequencies, seven have previously been highlighted as putative targets of adaptive introgression [5Vernot B. Tucci S. Kelso J. Schraiber J.G. Wolf A.B. Gittelman R.M. Dannemann M. Grote S. McCoy R.C. Norton H. et al.Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.Science. 2016; 352: 235-239Crossref PubMed Scopus (250) Google Scholar, 11Dannemann M. Andrés A.M. Kelso J. Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors.Am. J. Hum. Genet. 2016; 98: 22-33Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar, 12Racimo F. Sankararaman S. Nielsen R. Huerta-Sánchez E. Evidence for archaic adaptive introgression in humans.Nat. Rev. Genet. 2015; 16: 359-371Crossref PubMed Scopus (300) Google Scholar]. High-frequency archaic haplotypes either span or are proximal to seven genes involved in skin traits and 31 genes involved in immunity, with significant Gene Ontology (GO) enrichments for defense response (Benjamini and Hochberg corrected p = 8 × 10−4) and cytokine receptor activity (Benjamini and Hochberg corrected p = 3.64 × 10−6), among others (Table S2). We estimate the strength of selection acting on these loci to be ∼10−3, which is an order of magnitude lower than selection coefficients associated with strong recent selective sweeps, such as loci that confer lactase persistence and malaria resistance [19Vitti J.J. Grossman S.R. Sabeti P.C. Detecting natural selection in genomic data.Annu. Rev. Genet. 2013; 47: 97-120Crossref PubMed Scopus (377) Google Scholar, 20Fu W. Akey J.M. Selection and adaptation in the human genome.Annu. Rev. Genomics Hum. Genet. 2013; 14: 467-489Crossref PubMed Scopus (90) Google Scholar] (Figure S1C). Interestingly, 107 of the 126 distinct regions are at high frequency in only one population (Figure 1C). For instance, 66% and 58% of archaic haplotypes are population specific in Europeans and South Asians, respectively, whereas 84% and 86% of haplotypes are population specific in East Asians and Melanesians. These data are consistent with additional distinct pulses of introgression into East Asians and Melanesians [5Vernot B. Tucci S. Kelso J. Schraiber J.G. Wolf A.B. Gittelman R.M. Dannemann M. Grote S. McCoy R.C. Norton H. et al.Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.Science. 2016; 352: 235-239Crossref PubMed Scopus (250) Google Scholar] (Figure 1C). We next analyzed the number of high-frequency archaic haplotypes that were inherited from Neanderthals or Denisovans. As described in Vernot et al. [5Vernot B. Tucci S. Kelso J. Schraiber J.G. Wolf A.B. Gittelman R.M. Dannemann M. Grote S. McCoy R.C. Norton H. et al.Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.Science. 2016; 352: 235-239Crossref PubMed Scopus (250) Google Scholar] some archaic haplotypes exhibit high sequence similarity to both the Neanderthal and Denisovan reference genomes and thus cannot be confidently labeled; we refer to these haplotypes as ambiguous. As expected, all high-frequency archaic haplotypes in Europeans, East Asians, and South Asians are of Neanderthal origin. Strikingly, however, 59% of high-frequency haplotypes in Melanesians are inherited solely from Neanderthals, despite the fact that these individuals have considerably more Denisovan compared to Neanderthal ancestry [5Vernot B. Tucci S. Kelso J. Schraiber J.G. Wolf A.B. Gittelman R.M. Dannemann M. Grote S. McCoy R.C. Norton H. et al.Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.Science. 2016; 352: 235-239Crossref PubMed Scopus (250) Google Scholar] (Figure 1C). We also identified five regions segregating both Neanderthal and Denisovan sequences (Figure S2; Table S1), including archaic haplotypes that are mostly Denisovan and span TNFAIP3 (Figures 2A and 2B ), a ubiquitin-editing enzyme involved in the attenuation of cytokine-induced innate immune responses [22Heyninck K. De Valck D. Vanden Berghe W. Van Criekinge W. Contreras R. Fiers W. Haegeman G. Beyaert R. The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN.J. Cell Biol. 1999; 145: 1471-1482Crossref PubMed Scopus (253) Google Scholar]. To better understand the phenotypic consequences of high-frequency archaic haplotypes, we analyzed previously published genome-wide association study (GWAS) results [23Li M.J. Liu Z. Wang P. Wong M.P. Nelson M.R. Kocher J.-P.A. Yeager M. Sham P.C. Chanock S.J. Xia Z. Wang J. GWASdb v2: an update database for human genetic variants identified by genome-wide association studies.Nucleic Acids Res. 2016; 44: D869-D876Crossref PubMed Scopus (121) Google Scholar]. We found that ten haplotypes are associated with 17 traits, including breast and nasopharyngeal carcinoma, bone abnormalities (Paget’s disease), celiac disease, rheumatoid arthritis, optic disk size, and atopic dermatitis (Table S1). The median length of putative adaptively introgressed haplotypes is 81 kb. Thus, compared to analyses of recent selective sweeps that typically identify large genomic regions, adaptively introgressed sequences often result in single gene resolution [9Vattathil S. Akey J.M. Small Amounts of Archaic Admixture Provide Big Insights into Human History.Cell. 2015; 163: 281-284Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. 59% of loci overlap protein-coding genes, and there are 49 protein-coding variants in 36 distinct genes. However, 80% of high frequency haplotypes contain no protein-coding variants, indicating that regulatory evolution is the prominent mechanism through which adaptively introgressed sequences act. Given the likelihood that many high frequency archaic haplotypes influence patterns of gene expression, we leveraged extensive RNA-sequencing data from the GTEx [24GTEx ConsortiumHuman genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans.Science. 2015; 348: 648-660Crossref PubMed Scopus (3074) Google Scholar] and Geuvadis [25Lappalainen T. Sammeth M. Friedländer M.R. ’t Hoen P.A.C. Monlong J. Rivas M.A. Gonzàlez-Porta M. Kurbatova N. Griebel T. Ferreira P.G. et al.Geuvadis ConsortiumTranscriptome and genome sequencing uncovers functional variation in humans.Nature. 2013; 501: 506-511Crossref PubMed Scopus (1212) Google Scholar] projects to identify expression quantitative trait loci (eQTLs; see the Supplemental Experimental Procedures). Of the 48 high-frequency introgressed haplotypes that could be tested, 13 act as eQTLs to 34 different genes across multiple tissues (permutation FDR = 0.05; Figure 1A). Notably, the highest-frequency introgressed haplotype in East Asians (62%) encompasses a 29.7 kb region of the OCA2 gene (Figure 2C) and is also found at appreciable frequencies in South Asians (29%), Europeans (20%), and Melanesians (35%). OCA2 encodes a transmembrane protein involved in iris, skin, and hair pigmentation [26Sulem P. Gudbjartsson D.F. Stacey S.N. Helgason A. Rafnar T. Magnusson K.P. Manolescu A. Karason A. Palsson A. Thorleifsson G. et al.Genetic determinants of hair, eye and skin pigmentation in Europeans.Nat. Genet. 2007; 39: 1443-1452Crossref PubMed Scopus (534) Google Scholar], and both coding and non-coding variants are under strong selection in Europeans and East Asians [27Donnelly M.P. Paschou P. Grigorenko E. Gurwitz D. Barta C. Lu R.-B. Zhukova O.V. Kim J.J. Siniscalco M. New M. et al.A global view of the OCA2-HERC2 region and pigmentation.Hum. Genet. 2012; 131: 683-696Crossref PubMed Scopus (87) Google Scholar]. The introgressed haplotype contains an average of 10.6 differences with Neanderthals (Figure 2D). In contrast, African haplotypes contain an average of 74.3 differences, with the exception of four haplotypes that appear to be introgressed, most likely a result of recent gene flow [28Sikora M. Carpenter M.L. Moreno-Estrada A. Henn B.M. Underhill P.A. Sánchez-Quinto F. Zara I. Pitzalis M. Sidore C. Busonero F. et al.Population genomic analysis of ancient and modern genomes yields new insights into the genetic ancestry of the Tyrolean Iceman and the genetic structure of Europe.PLoS Genet. 2014; 10: e1004353Crossref PubMed Scopus (64) Google Scholar] (Figure 2D). We used a coalescent framework to calculate the probability that a haplotype of this length and divergence from Neanderthals is caused by incomplete lineage sorting as opposed to introgression (Supplemental Experimental Procedures) and across a wide range of parameters can robustly reject the hypothesis of incomplete lineage sorting (ILS; p < 0.003). The introgressed haplotype does not overlap, nor is it in linkage disequilibrium (LD; maximum r2 < 0.03), with variants that have previously been inferred to be targets of positive selection or are most strongly associated with pigmentation traits (Figure 2C). However, it does contain a variant that is associated with blue versus brown eyes in Europeans (p = 4 × 10−10) [29Sulem P. Gudbjartsson D.F. Stacey S.N. Helgason A. Rafnar T. Jakobsdottir M. Steinberg S. Gudjonsson S.A. Palsson A. Thorleifsson G. et al.Two newly identified genetic determinants of pigmentation in Europeans.Nat. Genet. 2008; 40: 835-837Crossref PubMed Scopus (278) Google Scholar] (Figure 2C). Finally, although there are no coding variants on the Neanderthal haplotype, 25 introgressed variants overlap regulatory elements active in melanocytes (Figure 2C). Thus, these data are consistent with the hypothesis of recurrent positive selection acting on multiple variants of OCA2, some of which arose in modern humans and some that were inherited through hybridization with Neanderthals. Our eQTL analyses provide significant new insights into both novel and previously hypothesized targets of adaptive introgression. For instance, Mendez et al. [30Mendez F.L. Watkins J.C. Hammer M.F. Neandertal origin of genetic variation at the cluster of OAS immunity genes.Mol. Biol. Evol. 2013; 30: 798-801Crossref PubMed Scopus (66) Google Scholar] proposed that a Neanderthal haplotype encompassing the genes OAS1, OAS2, and OAS3, which encode for antiviral proteins [31Hornung V. Hartmann R. Ablasser A. Hopfner K.-P. OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids.Nat. Rev. Immunol. 2014; 14: 521-528Crossref PubMed Scopus (181) Google Scholar], was driven to high frequency by positive selection. Although this haplotype is only an outlier in Europeans, it is also found at appreciable frequencies in other populations (17%, 13%, and 13% in East Asians, Melanesians, and South Asians, respectively). This introgressed haplotype is strongly associated with expression of all three OAS genes across various tissues (Figure 3). When looking at expression aggregated across isoforms, the eQTL is specific to OAS2 and OAS3 in transformed fibroblasts and OAS1 and OAS3 in transformed lymphoblast cell lines (LCLs), with individuals containing the introgressed allele show lower expression in all cases (Figure 3). Further analyses of exon-level expression suggests the Neanderthal haplotype results in differential splicing of OAS1 and OAS2 (Figure S3). In particular, the introgressed haplotype contains a 3′ splice variant between exons 6 and 7 of OAS1, leading to the production of a higher-activity isoform of OAS1 [32Bonnevie-Nielsen V. Field L.L. Lu S. Zheng D.-J. Li M. Martensen P.M. Nielsen T.B. Beck-Nielsen H. Lau Y.L. Pociot F. Variation in antiviral 2′,5′-oligoadenylate synthetase (2′ 5′AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene.Am. J. Hum. Genet. 2005; 76: 623-633Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar]. It is important to note that the introgressed haplotype also harbors protein-coding variants that could be targets of selection (Table S3). Our eQTL analyses reveal novel insights into the recently discovered TLR1/6/10 haplotype [11Dannemann M. Andrés A.M. Kelso J. Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors.Am. J. Hum. Genet. 2016; 98: 22-33Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar, 33Deschamps M. Laval G. Fagny M. Itan Y. Abel L. Casanova J.L. Patin E. Quintana-Murci L. Genomic Signatures of selective pressures and introgression from archaic hominins at human innate immunity genes.Am. J. Hum. Genet. 2016; 98: 5-21Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar] inherited from Neanderthals, which is at high frequency (39%) in East Asians and intermediate frequency in other populations (22%, 6%, and 17% in Europeans, Melanesians, and South Asians, respectively; Figure 4A). Toll-like receptors play a key role in the innate immune system, and TLR1 and TLR6 are well-characterized non-viral receptors [34Kawai T. Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.Nat. Immunol. 2010; 11: 373-384Crossref PubMed Scopus (6189) Google Scholar], whereas TLR10 has only recently been identified as a possible receptor for influenza [35Lee S.M.Y. Kok K.-H. Jaume M. Cheung T.K.W. Yip T.-F. Lai J.C.C. Guan Y. Webster R.G. Jin D.Y. Peiris J.S. Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection.Proc. Natl. Acad. Sci. USA. 2014; 111: 3793-3798Crossref PubMed Scopus (115) Google Scholar] and other pathogens [36Nagashima H. Iwatani S. Cruz M. Jiménez Abreu J.A. Uchida T. Mahachai V. Vilaichone R.K. Graham D.Y. Yamaoka Y. Toll-like receptor 10 in Helicobacter pylori infection.J. Infect. Dis. 2015; 212: 1666-1676Crossref PubMed Scopus (61) Google Scholar]. The introgressed haplotype contains 25 variants that have been associated with several immune traits, including Helicobacter pylori status [37Mayerle J. den Hoed C.M. Schurmann C. Stolk L. Homuth G. Peters M.J. Capelle L.G. Zimmermann K. Rivadeneira F. Gruska S. et al.Identification of genetic loci associated with Helicobacter pylori serologic status.JAMA. 2013; 309: 1912-1920Crossref PubMed Scopus (119) Google Scholar], allergy burden [38Hinds D.A. McMahon G. Kiefer A.K. Do C.B. Eriksson N. Evans D.M. St Pourcain B. Ring S.M. Mountain J.L. Francke U. et al.A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci.Nat. Genet. 2013; 45: 907-911Crossref PubMed Scopus (177) Google Scholar], and cellular response to Pam3CSK4 [39Mikacenic C. Reiner A.P. Holden T.D. Nickerson D.A. Wurfel M.M. Variation in the TLR10/TLR1/TLR6 locus is the major genetic determinant of interindividual difference in TLR1/2-mediated responses.Genes Immun. 2013; 14: 52-57Crossref PubMed Scopus (47) Google Scholar] (a TLR1 agonist). Consistent with previous results [11Dannemann M. Andrés A.M. Kelso J. Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors.Am. J. Hum. Genet. 2016; 98: 22-33Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar], the introgressed haplotype results in significantly higher expression (p < 2 × 10−5) of all three genes in transformed LCLs (Figures 4B and S4). However, the Neanderthal haplotype is associated with significantly lower expression of TLR6 (p < 0.019) in transformed fibroblasts and primary B cells from healthy volunteers [40Fairfax B.P. Makino S. Radhakrishnan J. Plant K. Leslie S. Dilthey A. Ellis P. Langford C. Vannberg F.O. Knight J.C. Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles.Nat Genet. 2012; 44: 502-510Crossref PubMed Scopus (331) Google Scholar] (Figure 4B). The differential effect in B cells is particularly interesting because they are closely related to the LCLs, differing only in their lack of viral transformation. Finally, TLR6 expression in other GTEx cell types does not show significant association with the Neanderthal haplotype (data not shown). We hypothesized that the tissue-specific patterns of eQTLs observed for the Neanderthal haplotype reflects differential states of innate immune activation. To test this hypothesis, we measured expression levels in whole-blood samples from healthy volunteers before and after stimulation with lipopolysaccharide (LPS), a TLR4 agonist (see Supplemental Experimental Procedures). Before stimulation, the Neanderthal haplotype showed no association with levels of TLR1, TLR6, or TLR10 expression (p > 0.05; Figures 4C and S4A). However, after stimulation, both TLR10 and TLR6 showed a significant positive association between expression and number of Neanderthal alleles (p = 0.003; Figures 4C and S4A). The effect is modest, but it is most likely attenuated due to the low proportion of immune cells in whole blood. These data are consistent with the hypothesis that the introgressed Neanderthal haplotype influences TLR expression in a context-dependent manner, increasing TLR6 expression specifically in stimulated immune cells (Figure 4B). Fine-scale mapping suggests that the causal regulatory variant, or variants, may fall within the promoter of TLR1 or TLR10 (Figure S4B). In summary, hybridization with Neanderthals and Denisovans provided an important reservoir of advantageous mutations for modern humans that enabled adaptation to emergent selective pressures as they dispersed out of Africa. Our results show that immune and pigmentation traits were frequent substrates of adaptive introgression and that in many cases adaptive archaic haplotypes also contribute to the disease susceptibility in contemporary individuals (Figure 1A; Table S1). Finally, our ability to interpret adaptively introgressed loci was facilitated by large-scale functional genomics and GWAS data [23Li M.J. Liu Z. Wang P. Wong M.P. Nelson M.R. Kocher J.-P.A. Yeager M. Sham P.C. Chanock S.J. Xia Z. Wang J. GWASdb v2: an update database for human genetic variants identified by genome-wide association studies.Nucleic Acids Res. 2016; 44: D869-D876Crossref PubMed Scopus (121) Google Scholar, 24GTEx ConsortiumHuman genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans.Science. 2015; 348: 648-660Crossref PubMed Scopus (3074) Google Scholar, 25Lappalainen T. Sammeth M. Friedländer M.R. ’t Hoen P.A.C. Monlong J. Rivas M.A. Gonzàlez-Porta M. Kurbatova N. Griebel T. Ferreira P.G. et al.Geuvadis ConsortiumTranscriptome and genome sequencing uncovers functional variation in humans.Nature. 2013; 501: 506-511Crossref PubMed Scopus (1212) Google Scholar]. However, many of these datasets were generated in individuals of European ancestry, and thus better geographic representation would accelerate efforts to understand adaptively introgressed loci, and more generally, human genomic diversity." @default.
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