Long-range regulatory effects of Neandertal DNA in modern humans

The admixture between modern humans and Neandertals has resulted in ∼2% of the genomes of present-day non-Africans being composed of Neandertal DNA. Association studies have shown that introgressed DNA significantly influences phenotypic variation in people today and that several of the phenotype-associated archaic variants had links to expression regulation as well. In general, introgressed DNA has been demonstrated to significantly affect the transcriptomic landscape in people today. However, little is known about how much of that impact is mediated through long-range regulatory effects that have been shown to explain ∼20% of expression variation.

Here we identified 60 transcription factors (TFs) with their top cis-eQTL SNP being of Neandertal ancestry in GTEx and predicted long-range Neandertal DNA-induced regulatory effects by screening for the predicted target genes of those TFs. We show that genes in regions devoid of Neandertal DNA are enriched among the target genes of some of these TFs. Furthermore, archaic cis-eQTLs for these TFs included multiple candidates for local adaptation and have associations with various immune traits, schizophrenia, blood cell type composition and anthropometric measures. Finally, we show that our results can be replicated in empirical trans-eQTLs with Neandertal variants.

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.