Many modern human genomes retain DNA inherited from interbreeding with archaic hominins, such as Neanderthals, yet the influence of this admixture on human traits is largely unknown. We analyzed the contribution of common Neanderthal variants to over 1,000 electronic health record (EHR)-derived phenotypes in ~28,000 adults of European ancestry. We discovered and replicated associations of Neanderthal alleles with neurological, psychiatric, immunological, and dermatological phenotypes. Neanderthal alleles together explain a significant fraction of the variation in risk for depression and skin lesions resulting from sun exposure (actinic keratosis), and individual Neanderthal alleles are significantly associated with specific human phenotypes, including hypercoagulation and tobacco use. Our results establish that archaic admixture influences disease risk in modern humans, provide hypotheses about the effects of hundreds of Neanderthal haplotypes and demonstrate the utility of EHR data in evolutionary analyses.

Transposable element (TE)-derived sequences make up approximately half of most mammalian genomes, and many TEs have been co-opted into gene regulatory elements. However, we lack a comprehensive tissue- and genome-wide understanding of how and when TEs gain regulatory activity in their hosts. We evaluated the prevalence of TE-derived DNA in enhancers and promoters across hundreds of human and mouse cell lines and primary tissues. Promoters are significantly depleted of TEs in all tissues compared with their overall prevalence in the genome (P < 0.001); enhancers are also depleted of TEs, though not as strongly as promoters. The degree of enhancer depletion also varies across contexts (1.5-3×), with reproductive and immune cells showing the highest levels of TE regulatory activity in humans. Overall, in spite of the regulatory potential of many TE sequences, they are significantly less active in gene regulation than expected from their prevalence. TE age is predictive of the likelihood of enhancer activity; TEs originating before the divergence of amniotes are 9.2 times more likely to have enhancer activity than TEs that integrated in great apes. Context-specific enhancers are more likely to be TE-derived than enhancers active in multiple tissues, and young TEs are more likely to overlap context-specific enhancers than old TEs (86% vs. 47%). Once TEs obtain enhancer activity in the host, they have similar functional dynamics to one another and non-TE-derived enhancers, likely driven by pleiotropic constraints. However, a few TE families, most notably endogenous retroviruses, have greater regulatory potential. Our observations suggest a model of regulatory co-option in which TE-derived sequences are initially repressed, after which a small fraction obtains context-specific enhancer activity, with further gains subject to pleiotropic constraints.

Neanderthal ancestry remains across modern Eurasian genomes, and introgressed sequences influence diverse phenotypes. Here we demonstrate that introgressed sequences reintroduced thousands of ancestral alleles that were lost in Eurasian populations prior to introgression. Our simulations and variant effect predictions argue that these reintroduced alleles (RAs) are more likely to be tolerated by modern humans than introgressed Neanderthal-derived alleles (NDAs) due to their distinct evolutionary histories. Consistent with this, we show enrichment for RAs and depletion for NDAs on introgressed haplotypes with expression quantitative trait loci (eQTL) and phenotype associations. Analysis of available cross-population eQTLs and massively parallel reporter assay (MPRA) data show that RAs commonly influence gene expression independent of linked NDAs. We further validate these independent effects for one RA in vitro . Finally, we demonstrate that NDAs are depleted for regulatory activity compared to RAs, while RAs have activity levels similar to non-introgressed variants. In summary, our study reveals that Neanderthal introgression reintroduced thousands of lost ancestral variants with gene regulatory activity and that these RAs were more tolerated than NDAs. Thus, RAs and their distinct evolutionary histories must be considered when evaluating the effects of introgression. ONE SENTENCE SUMMARY Neanderthal interbreeding with anatomically modern humans restored thousands of ancient alleles that were previously lost in Eurasian populations.

Although prostate cancer is the leading cause of cancer mortality for African men, the vast majority of known disease associations have been detected in European study cohorts. Furthermore, most genome-wide association studies have used genotyping arrays that are hindered by SNP ascertainment bias. To overcome these disparities in genomic medicine, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a genotyping array that is optimized for African populations. The MADCaP Array contains more than 1.5 million markers and an imputation backbone that successfully tags over 94% of common genetic variants in African populations. This array also has a high density of markers in genomic regions associated with cancer susceptibility, including 8q24. We assessed the effectiveness of the MADCaP Array by genotyping 399 prostate cancer cases and 403 controls from seven urban study sites in sub-Saharan Africa. Samples from Ghana and Nigeria clustered together, whereas samples from Senegal and South Africa yielded distinct ancestry clusters. Using the MADCaP array, we identified cancer-associated loci that have large allele frequency differences across African populations. Polygenic risk scores for prostate cancer were higher in Nigeria than in Senegal. In summary, individual and populationlevel differences in prostate cancer risk were revealed using a novel genotyping array.Significance: This study presents an Africa-specific genotyping array, which enables investigators to identify novel disease associations and to fine-map genetic loci that are associated with prostate and other cancers.

BackgroundRPB1, the largest subunit of RNA polymerase II, contains a highly modifiable C-terminal domain (CTD) that consists of variations of a consensus heptad repeat sequence (Y1S2P3T4S5P6S7). The consensus CTD repeat motif and tandem organization represent the ancestral state of eukaryotic RPB1, but across eukaryotes CTDs show considerable diversity in repeat organization and sequence content. These differences may reflect lineage-specific CTD functions mediated by protein interactions. Mammalian CTDs contain eight non-consensus repeats with a lysine in the seventh position (K7). Posttranslational acetylation of these sites was recently shown to be required for proper polymerase pausing and regulation of two growth factor-regulated genes.ResultsTo investigate the origins and function of RPB1 CTD acetylation (acRPB1), we computationally reconstructed the evolution of the CTD repeat sequence across eukaryotes and analyzed the evolution and function of genes dysregulated when acRPB1 is disrupted. Modeling the evolutionary dynamics of CTD repeat count and sequence content across diverse eukaryotes revealed an expansion of the CTD in the ancestors of Metazoa. The new CTD repeats introduced the potential for acRPB1 due to the appearance of distal repeats with lysine at position seven. This was followed by a further increase in the number of lysine-containing repeats in developmentally complex clades like Deuterostomia. Mouse genes enriched for acRPB1 occupancy at their promoters and genes with significant expression changes when acRPB1 is disrupted are enriched for several functions, such as growth factor response, gene regulation, cellular adhesion, and vascular development. Genes occupied and regulated by acRPB1 show significant enrichment for evolutionary origins in the early history of eukaryotes through early vertebrates.ConclusionsOur combined functional and evolutionary analyses show that RPB1 CTD acetylation was possible in the early history of animals, and that the K7 content of the CTD expanded in specific developmentally complex metazoan lineages. The functional analysis of genes regulated by acRPB1 highlight functions involved in the origin of and diversification of complex Metazoa. This suggests that acRPB1 may have played a role in the success of animals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-015-0327-z) contains supplementary material, which is available to authorized users.