Contrasting evolutionary histories among tightly linked HLA loci

Genes comprising the major histocompatibility complex (MHC) play a central role in governing the immune response of vertebrates. A great deal of information has been revealed on the molecular biology and physiology of these loci, but three features-the high polymorphism, tight linkage among the loci, and the nonrandom association of alleles-make the system of particular interest from the perspective of population genetics. Information on the dynamic evolutionary forces that have acted on a locus can be inferred from the number and distribution of alleles that it carries. Ten loci from the HLA region of the human MHC, each sampled from several different populations, have been examined for departures from the expected value of homozygosity under the condition of selective neutrality. The homozygosities of five class I and II loci that code for membrane glycoproteins, HLA-A, -B, -C, -DR, and -DQ, and of glyoxylase I (GLO) were significantly less than the neutrality expectations. This suggests the presence of some form of balancing selection. In spite of being closely linked, in fact, located between the class I and class II histocompatibility loci, the homozygosities of the four class III or complement loci C2, Bf, C4A, and C4B, which are detected by electrophoresis, were indistinguishable from, or exceeded, that expected under neutrality. Although this conforms to the suggestion that, in general, electrophoretic variants are neutral, because of the tight linkage to loci demonstrating a history of selection, it is possible that the mechanism for generating variation in the class III loci may be different from that of the class I and class II loci.