Long-range regulatory effects of Neandertal DNA in modern humans

Abstract

AbstractThe admixture between modern humans and Neandertals has resulted in ∼2% of the genomes of present-day non-Africans still being composed of Neandertal DNA. Association studies have shown that introgressed DNA still significantly influences skin and hair traits, immunity and behavioral phenotypes in people today. Several of the phenotype-associated archaic variants had links to regulatory effects as well. In general, analyses of allele-specific expression, regulatory sequence composition and cis-eQTL have demonstrated a significant contribution of this introgressed DNA to the transcriptomic landscape in people today. However, little is known about the impact of Neandertal DNA on trans-eQTLs - long-range regulatory effects that have been shown to explain ∼20% of expression variation.Here we used blood eQTL results from >30,000 individuals from eQTLGen Consortium. The cohort size allowed for a robust identification of trans-eQTLs and in addition enabled quantifying the role of transcription factors (TF) in mediating long-range regulatory effects. In our study we used this information to (i) annotate trans-eQTLs that are linked to Neandertal variants and (ii) predict long-range regulatory effects that are induced by Neandertal DNA by screening for the predicted target genes of TFs that are cis-eQTLs linked to Neandertal variants. We show that both trans-eQTL-associated Neandertal variants and those predicted to have long-range regulatory effects affect genes in genomic regions devoid of Neandertal DNA. In addition, both types of variants included candidates for local adaptation and show associations with autoimmune disorders, a severe Covid-19 phenotype, blood cell type composition and anthropometric measures.Our results suggest that the regulatory reach of Neandertal DNA goes beyond the 40% of genomic sequence that it still covers in present-day non-Africans and that via this mechanism Neandertal DNA additionally influences the phenotypic variation in people today.