Temporally Dynamic Waves of Selection on Archaic Variation in Peruvians

Abstract

Introgression introduced deeply diverged archaic variation into modern human populations and contributed to local adaptation. In Indigenous American populations, however, the landscape of adaptive introgression remains poorly resolved. Genome-wide scans have reported numerous candidate loci, but complex demographic histories and recent admixture make genuine signals difficult to distinguish from false positives. Here, we systematically re-evaluated previously reported candidates of adaptive introgression in Peruvians using a multilayered framework and refined more than 150 putative signals to 25 high-confidence candidate loci with concordant evidence of Neanderthal- or Denisovan-like ancestry and positive selection. Using ancestral recombination graph (ARG) approaches, we inferred selection onset windows for 21 loci. These onsets were non-uniformly distributed across Peruvian population history, revealing temporally dynamic selection without robust evidence for a fixed number of discrete waves. Together with pre-Columbian ancient DNA evidence, the inferred histories support the inheritance of the candidate adaptive archaic haplotypes through ancestral Native American populations rather than first introduction through post-Columbian admixture. Functional analyses identified network-level signals consistent with polygenic selection in lipid metabolic and immune-related pathways, elevated regulatory effects predicted across archaic haplotypes, and occasional coding variation of potential functional relevance, including a missense variant at the immune-related gene CXCR4. Our results show that archaic introgressed variation remained evolutionarily important and available to selection long after introgression, providing a reservoir of genetic variation that could be repeatedly recruited by selection at different points in American population history.