Functional archaic DNA regulates molecular variation and is associated with disease risk across global populations

Abstract

23 24 The human genome contains many remnants of its evolutionary history, including a large 25 number of evolutionarily volatile loci which have been introduced since our divergence from 26 primates. One particularly intriguing source of novel DNA sequences is introgression events 27 with archaic species which co-existed with modern humans. Both Neanderthals, who were 28 common in Europe, and Denisovans, who have been observed only in Asia, have contributed 29 genetic variants to the modern human genome but the functional consequences of these 30 introgressed variants have yet to be investigated systematically. In this work, we show that 31 Neanderthal and Denisovan DNA is most enriched for genetic variants which regulate gene 32 expression in Europe and East Asia respectively, i.e. the populations in which the introgression 33 event(s) most contributed to contemporary genetic variation. Neanderthal eQTLs, in 34 particular, frequently upregulate gene expression. Archaic eQTLs from these two species 35 regulate target genes with similar molecular functions which are distinct in each 36 contemporary population, with the only common enrichment being for Neanderthal eQTLs 37 to regulate taste receptor genes in both Europe and East Asia. We observed a correlated 38 pattern of enrichment and depletion of medical phenotypes across Neanderthal and 39 Denisovan eQTLs, including a shared enrichment for CNVs associated with developmental 40 delay. Our results demonstrate the role of functional archaic DNA in regulating molecular 41 phenotypes and disease risk across global populations and confirm the relevance of recently 42 acquired DNA to contemporary human genetic variation. 43 44 Author Summary 2 bioRxiv preprint doi: https://doi.org/10.1101/2023.04.26.538367; this version posted April 26, 2023. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. 45 46 Modern humans co-existed and interbred with two archaic human species (Neanderthals and 47 Denisovans). The results of these events can still be detected as introgressed, archaic DNA 48 sequences within the modern human genome. Here, we surveyed the contribution of 49 functional archaic DNA across European and Asian populations by assessing their contribution 50 to genetic variants which regulate gene expression in these two populations. We found that 51 both species make a disproportionate functional contribution to the population with which 52 they shared the most overlap (i.e. Neanderthals in Europe and Denisovans in East Asia). 53 Although only Neanderthal DNA drives a higher level of gene expression compared to modern 54 genetic variants, the DNA from both archaic species frequently regulates genes involved in 55 many different biological processes and risk of disease, including a shared contribution to 56 developmental delay. These results confirm the relevance of our recent evolutionary past in 57 generating functional variation across global populations and the importance these recently 58 introduced genetic sequences play in regulating current biological variation, such as disease 59 risk. 60 61