Evolution of class II genes: Role of selection in both the maintenance of polymorphism and the retention of non-expressed alleles

Abstract

Our studies of the origins of the nonfunctional Eα and Eβ genes and their associated Aα genes have provided a unique view of the factors affecting the evolution of these genes and their haplotypes. The set of three haplotypes originating inM. m. domesticus andM. m. castaneus carrying Eβ genes with the identical Eβ02 mutation allows a direct comparison between the rates of divergence of the non-expressed (Eβ) genes and the linked expressed (Aα) genes. The near-identity of the three Eβ02 genes and the divergence of the Aα1 domains provides strong evidence that selection acting on functional class II proteins is a major driving force in the accumulation and maintenance of MHC polymorphism. The basis for the retention of null Eα and Eβ genes at high frequencies as balanced polymorphisms in mouse populations remains difficult to understand, given the expectation that E− phenotypes should result in reduced immune response potential. However, the high frequencies of E0 haplotypes and the maintenance of specific mutant Eα and Eβ genes since their origin prior to the divergence ofM. m. domesticus fromM. m. castaneus andbactrianus suggest that these nonfunctional alleles are being actively maintained. It may be that in some pathogenic environments the expression of EαEβ proteins is selected against, due to E-associated immune-mediated pathology or reductions in the functional T-cell repertoire.