Ó³»­´«Ã½

The specific mechanisms through which human biology and disease susceptibility evolved with major shifts in West Eurasian environments and societies over the last 10,000 years()-particularly rising infectious burden()-remain poorly characterized, despite ancient DNA studies() identifying hundreds of candidate loci under positive selection(). Here, we identify specific immune diseases/traits, genes/variants, pathways, and tissues/cell types impacted by natural selection by systematically integrating variant-level selection statistics with genome-wide association study (GWAS), quantitative trait locus (QTL), and molecular bulk/single-cell and gene pathway data. Genome-wide, positively-selected alleles are associated with reduced susceptibility to infectious diseases like tuberculosis (TB), influenza, and intestinal infections; consistent with selection-signal enrichments in immune cells within barrier tissues such as the respiratory tract and gut mucosa. In contrast, positively-selected alleles increase risk of intestinal inflammatory disease and autoimmune hypothyroidism, supportive of a tradeoff between infection and immune-mediated pathology, and consistent with adaptive alleles being QTLs for genes upregulating inflammation and other host-defense pathways. We reveal many novel adaptive loci with convergent signals from selection, infectious disease GWAS and immune-gene QTLs (including at for intestinal infections; at for TB; and at , an antimicrobial enzyme), fine-mapping selection onto likely causal variants. Surprisingly, adaptive alleles had a protective effect on allergic conditions like asthma and dermatitis, challenging a common view that these conditions arose through evolutionary mismatch of present-day hygienic contexts relative to past, pathogen-rich environments().