Limited selection on Neanderthal DNA in 30,780 recently admixed genomes with African-like ancestry

Following introgression, Neanderthal DNA was initially purged from non-African genomes, but the evolutionary fate of remaining introgressed DNA in recently admixed genomes with African-like genetic ancestry has not been tested at biobank-scale. In these admixed genomes, Neanderthal alleles encountered a novel genetic background, potentially leading to renewed selective pressures. We analyzed 30,780 admixed genomes from the All of Us research program, in which Neanderthal alleles were introduced into an African-like genetic background during the last 15 generations. Observed amounts of Neanderthal DNA approximately match expectations based on ancestry proportions, suggesting neutral evolution. In line with this, simulations under a realistic demographic scenario suggest that strong genome-wide selection of Neanderthal DNA (s ≥ |0.1|) would have led to significant changes in recent ancestry proportions that are not observed in real data. Nevertheless, we identified genomic regions that have significantly less or more Neanderthal ancestry than expected and are associated with spermatogenesis, cell cycle regulation, and neuronal signaling, among other biological processes. We also identified four novel introgression desert-like regions in recently admixed genomes, whose genetic features are compatible with hybrid incompatibilities and intrinsic negative selection. Overall, we find that much of the remaining Neanderthal DNA in human genomes is likely not under strong selection, and complex evolutionary dynamics have shaped introgression landscapes in our species.