A global analysis of population differentiation at the major histocompatibility complex genes across tetrapods

Major histocompatibility complex (MHC) genes are central to pathogen recognition by the adaptive immune system of jawed vertebrates, with MHC classes I and II (henceforth referred to as MHC-I and MHC-II, respectively) primarily mediating responses to intracellular and extracellular pathogens, respectively. Here, we tested the hypothesis that MHC-II genes show stronger population differentiation, reflecting spatially heterogeneous selection by extracellular pathogens. We compiled a global dataset comprising >3500 pairwise estimates of MHC differentiation across approximately 120 tetrapod species. Phylogenetically informed analyses revealed consistently stronger differentiation at MHC-II than at MHC-I genes, supporting stronger local adaptation to spatially variable selection by extracellular pathogens. Isolation by distance contributed broadly to MHC differentiation, indicating that balancing selection is insufficient to homogenize MHC variation over large geographical scales. Differentiation varied markedly among tetrapod lineages, reflecting the differences in dispersal capacity. We further showed that differentiation was modulated by the genomic architecture of the MHC region, and our theoretical simulations demonstrated that variation in MHC gene copy number can have contrasting effects on population differentiation, depending on the strength of balancing selection acting on each MHC class. Together, these findings elucidate the global patterns of immunogenetic differentiation and advance the mechanistic understanding of how extraordinary MHC variation is structured across space.