Selection against archaic hominin genetic variation in regulatory regions

Traces of Neandertal and Denisovan DNA persist in the modern human gene pool, but have been systematically purged by natural selection from genes and other functionally important regions. This implies that many archaic alleles harmed the fitness of hybrid individuals, but the nature of this harm is poorly understood. Here, we show that enhancers contain less Neandertal and Denisovan variation than expected given the background selection they experience, suggesting that selection acted to purge these regions of archaic alleles that disrupted their gene regulatory functions. We infer that selection acted mainly on young archaic variation that arose in Neandertals or Denisovans shortly before their contact with humans; enhancers are not depleted of older variants found in both archaic species. Some types of enhancer appear to have tolerated introgression better than others; compared with tissue-specific enhancers, pleiotropic enhancers show stronger depletion of archaic single-nucleotide polymorphisms. To some extent, evolutionary constraint is predictive of introgression depletion, but certain tissues’ enhancers are more depleted of Neandertal and Denisovan alleles than expected given their comparative tolerance to new mutations. Foetal brain and muscle are the tissues whose enhancers show the strongest depletion of archaic alleles, but only brain enhancers show evidence of unusually stringent purifying selection. We conclude that epistatic incompatibilities between human and archaic alleles are needed to explain the degree of archaic variant depletion from foetal muscle enhancers, perhaps due to divergent selection for higher muscle mass in archaic hominins compared with humans. This study reports the depletion of young Neandertal and Denisovan introgressed SNPs from gene regulatory enhancers in modern human genomes, as well as an association of enhancer pleiotropy with both the magnitude of archaic SNP depletion and the degree of intolerance to new mutations.