Gutierrez, S.; Allemon, A.; Meyer, E.; Zhang, X.

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.