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Significance The major histocompatibility complex (MHC), in particular, the human leukocyte antigen (HLA) loci encode key components of the immune system and include some of the most diverse genes in the human genome. Evolution of the HLA loci is generally thought to be driven by selection for increased diversity, i.e., against common haplotypes (negative frequency-dependent selection). Here, we compare the haplotype frequency and homozygosity distributions from the extensive National Marrow Donor Program registry to the predictions of different models of evolution and show that the data are best compatible with multiplicative fitness and rapid fitness decay of haplotypes in some populations. Selection against common haplotypes is not supported. The data cannot be explained by mating preferences or population substructure either.

Multiplicative fitness, rapid haplotype discovery, and fitness decay explain evolution of human MHC