TheMUC19gene in Denisovans, Neanderthals, and Modern Humans: An Evolutionary History of Recurrent Introgression and Natural Selection

Abstract

AbstractAll humans carry a small fraction of archaic ancestry across the genome, the legacy of gene flow from Neanderthals, Denisovans, and other hominids into the ancestors of modern humans. While the effects of Neanderthal ancestry on human fitness and health have been explored more thoroughly, there are fewer examples of adaptive introgression of Denisovan variants. Here, we study the geneMUC19, for which some modern humans carry aDenisovan-likehaplotype.MUC19is a mucin, a glycoprotein that forms gels with various biological functions, from lubrication to immunity. We find the diagnostic variants for theDenisovan-like MUC19haplotype at high frequencies in admixed Latin American individuals among global population, and at highest frequency in 23 ancient Indigenous American individuals, all predating population admixture with Europeans and Africans. We find that some Neanderthals––Vindija and Chagyrskaya––carry theDenisovan-like MUC19haplotype, and that it was likely introgressed into human populations through Neanderthal introgression rather than Denisovan introgression. Finally, we find that theDenisovan-like MUC19haplotype carries a higher copy number of a 30 base-pair variable number tandem repeat relative to theHuman-likehaplotype, and that copy numbers of this repeat are exceedingly high in American populations. Our results suggest that theDenisovan-like MUC19haplotype served as the raw genetic material for positive selection as American populations adapted to novel environments during their movement from Beringia into North and then South America.