Long-range regulatory effects of Neandertal DNA in modern humans

Abstract

11 The admixture between modern humans and Neandertals has resulted in ~2% of the 12 genomes of present-day non-Africans still being composed of Neandertal DNA. Association 13 studies have shown that introgressed DNA still significantly influences skin and hair traits, 14 immunity and behavioral phenotypes in people today. Several of the phenotype-associated 15 archaic variants had links to regulatory effects as well. In general, analyses of allele-specific 16 expression, regulatory sequence composition and cis-eQTL have demonstrated a significant 17 contribution of this introgressed DNA to the transcriptomic landscape in people today. However, 18 little is known about the impact of Neandertal DNA on trans-eQTLs - long-range regulatory 19 effects that have been shown to explain ~20% of expression variation. 20 Here we used blood eQTL results from >30,000 individuals from eQTLGen Consortium. 21 The cohort size allowed for a robust identification of trans-eQTLs and in addition enabled 22 quantifying the role of transcription factors (TF) in mediating long-range regulatory effects. In our 23 study we used this information to (i) annotate trans-eQTLs that are linked to Neandertal variants 24 and (ii) predict long-range regulatory effects that are induced by Neandertal DNA by screening 25 for the predicted target genes of TFs that are cis-eQTLs linked to Neandertal variants. We show 26 that both trans-eQTL-associated Neandertal variants and those predicted to have long-range 27 regulatory effects affect genes in genomic regions devoid of Neandertal DNA. In addition, both 28 types of variants included candidates for local adaptation and show associations with 29 autoimmune disorders, a severe Covid-19 phenotype, blood cell type composition and 30 anthropometric measures. 31 Our results suggest that the regulatory reach of Neandertal DNA goes beyond the 40% 32 of genomic sequence that it still covers in present-day non-Africans and that via this mechanism 33 Neandertal DNA additionally influences the phenotypic variation in people today. bioRxiv preprint doi: https://doi.org/10.1101/2021.10.20.464628; this version posted October 21, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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-ND 4.0 International license. 34