Contrasting selective pressures shape human pepsinogen A gene copy-number variation across Eurasia

Abstract

Diet has repeatedly shaped human genomes, yet adaptation of protein digestion remains poorly understood. Using 1,348 haplotype-resolved assemblies, we reconstructed the structural evolution of the human pepsinogen A (PGA) locus and found a west-to-east increase in copy-number across Eurasia that tracked regional reliance on plant-derived protein. Modern and ancient genomes further revealed a recent selective sweep in the East but signatures of balancing selection in the West. We traced this divergence primarily to expansion of PGA34A, the most proteolytically active paralog in vitro, and showed that recurrent nonallelic homologous recombination continually generated structural diversity in this locus. Independent PGA expansions were also enriched in plant-dominant mammals. These findings link paralog-specific dosage variation in protein digestion to dietary adaptation across human populations and diverse mammalian lineages.