The MHC, Disease and Selection

Given large sample sizes, whole genome screens are now able to identify even quite modest contributions of common human genetic variation to disease. These approaches, made possible by the development of high-throughput, dense SNP genotyping, find few associations stronger than those for the human MHC, in multigenic autoimmune conditions. They confirm earlier findings that the major variants affecting susceptibility and resistance to autoimmunity relate to MHC class I and class II genes. It is generally assumed, although there are few good examples, that selection for resistance to infection drives evolution of MHC variation. Many MHC-associated diseases may be the price paid for an effective immune response. Interestingly, the MHC appears to influence susceptibility to conditions unrelated to immunity, including some neuropathologies. The infectious history of the individual, conditioned by their MHC, may exert an indirect effect on these diseases, although there are hints of more direct involvement of MHC molecules in neuronal systems. Here I survey the variety of conditions associated with the MHC in relation to ideas that selection through disease resistance is dependent upon MHC variation, not only at the level of the individual, but also at the level of the population.