Trans-species polymorphism, HLA-disease associations and the evolution of the MHC

Currently, the paradigm is that Major Histocompatibility Complex (MHC) polymorphism is maintained by balancing selection on the immune genes. However, other evolutionary forces besides selection also play a role in the population genetics of this multigene family. van Oosterhout proposed a new theory of MHC evolution called Associative Balancing Complex (ABC) evolution1. This theory incorporates the effects of the evolutionary forces in the entire MHC region (peri-MHC), and it proposes that recessive deleterious mutations can accumulate in the peri-MHC in a process similar to Muller’s ratchet2. These mutations are not easily purged because epistasis and high gene diversity in the MHC reduce the efficacy of natural selection. Because natural selection is less efficient, it could also make the MHC prone to the onslaught of genomic parasites such as retroviruses and transposable elements (TEs). The accumulated genetic load has important consequences for the evolution of this immune gene family, and it can reinforce linkage disequilibria and help to maintain the MHC polymorphism. ABC evolution offers new insights into some of the most puzzling aspects of the MHC, including the occurrence of identical MHC sequences in diverged species (i.e. trans-species polymorphism). It may also explain why the large numbers of disease-associated mutations are not removed by natural selection, and why the genes that protect vertebrates against infectious diseases are associated to such a wide variety of genetic disorders.