On the origin and maintenance of variation of the Major Histocompatibility Complex

The Major Histocompatibility Complex (MHC), in humans called the Human Leukocyte Antigen (HLA), is a gene cluster present in every vertebrate organism. This gene cluster plays an important role in the establishment of immune reactions. To highlight the structure and function of this cluster, the HLA will serve as a role model. HLA molecules are responsible for self-nonself discrimination, so highly specialized in pathogen recognition. The HLA cluster encoding the HLA molecules is the most variable region of all autosomal chromosomes. On the origin and the maintenance of this extraordinary variation is no consensus in the scientific community. This variation has also been observed in small populations, raising questions. It has been opted the cluster is under overdominant selection, negative frequency dependent selection or selection varying in time and space. Behavior like non-random mating and migration could also be (important) factors. However, it seems that most of these hypotheses have missed a crucial selection force recognized by Cock van Oosterhout, which I will address in this paper. Over 100 diseases are associated with the HLA. These genetic disorders are often the result of deleterious mutation in the intergenic region of the cluster. These mutations are not efficiently removed by purifying selection due to high amounts of linkage disequilibrium of the HLA genes. Because most of the mutations are recessive, they will not be expressed often. Mutations can built up in a process analogous to Muller ratchet and play an important role in selection pressure on the genes in this cluster. Instead of selecting for genes improving pathogen recognition, selection is (also) against these genes if they have a lot of deleterious mutations in their flanking regions.