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. Introgressed Neandertal DNA has been demonstrated to significantly affect the transcriptomic landscape in people today and via this molecular mechanism influence phenotype variation as well. However, little is known about how much of that regulatory 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 in GTEx being of Neandertal ancestry and predicted long-range Neandertal DNA-induced regulatory effects by screening for the predicted target genes of those TFs. We show that the TFs form a significantly connected protein–protein interaction network. Among them are JUN and PRDM5, two brain-expressed TFs that have their predicted target genes enriched in regions devoid of Neandertal DNA. Archaic cis-eQTLs for the 60 TFs include multiple candidates for local adaptation, some of which show significant allele frequency increases over the last ∼10,000 years. A large proportion of the cis-eQTL-associated archaic SNPs have additional associations with various immune traits, schizophrenia, blood cell type composition and anthropometric measures. Finally, we demonstrate that our results are consistent with those of Neandertal DNA-associated empirical trans-eQTLs. Our results suggest that Neandertal DNA significantly influences regulatory networks, that its regulatory reach goes beyond the 40% of genomic sequence it still covers in present-day non-Africans and that via the investigated mechanism Neandertal DNA influences the phenotypic variation in people today.