Archaic introgression contributed to shape the adaptive modulation of angiogenesis and nitric oxide induction in human high-altitude populations from the Himalayas

It is well established that severalHomo sapienspopulations experienced admixture with extinct human species during their evolutionary history. Sometimes, such a gene flow could have played a role in modulating their capability to cope with a variety of selective pressures, thus resulting in archaic adaptive introgression events. A paradigmatic example of this evolutionary mechanism is offered by theEPAS1gene, whose most frequent haplotype in Himalayan highlanders was proved to reduce their susceptibility to chronic mountain sickness and to be introduced in the gene pool of their ancestors by admixture with Denisovans. In this study, we aimed at further expanding the investigation of the impact of archaic introgression on more complex adaptive responses to hypobaric hypoxia evolved by populations of Tibetan and Sherpa ancestry, which have been plausibly mediated by soft selective sweeps and/or polygenic adaptations rather than by hard selective sweeps. For this purpose, we used a combination of composite-likelihood and gene network-based methods to detect adaptive loci in introgressed chromosomal segments from Tibetan whole genome sequence data and to shortlist those enriched for Denisovan-like derived alleles that participate to the same functional pathways. According to this approach, we identified multiple genes putatively involved in archaic introgression events and that, especially as regardsEP300andNOS2, have plausibly contributed to shape the adaptive modulation of angiogenesis and nitric oxide induction in high-altitude Himalayan peoples. These findings provided unprecedented evidence about the complexity of the adaptive phenotype evolved by these human groups to cope with challenges imposed by hypobaric hypoxia, offering new insights into the tangled interplay of genetic determinants that mediates the physiological adjustments crucial for human adaptation to the high-altitude environment.