A global analysis of population differentiation at the MHC genes across tetrapods

The major histocompatibility complex (MHC) genes are central to pathogen recognition by the adaptive immune system of jawed vertebrates, with MHC class I and II primarily mediating responses to intra- and extracellular pathogens, respectively. Here, we tested the hypothesis that MHC class 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 ~120 tetrapod species. Phylogenetically informed analyses revealed consistently stronger differentiation at MHC class II than at class 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 differences in dispersal capacity. We further show 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 global patterns of immunogenetic differentiation and advance the mechanistic understanding of how extraordinary MHC variation is structured across space.