NATURAL SELECTION AND THE EVOLUTIONARY HISTORY OF MAJOR HISTOCOMPATIBILITY COMPLEX LOCI

Austin L. Hughes and Meredith Yeager

Department of Biology and Institute of Molecular Evolutionary Genetics, The Pennsylvania State University, University Park PA 16802 USA

Received 5/11/98 Accepted 5/22/98

4. Duplication of Loci

It is by now well established that gene duplication plays a major role in the adaptive evolution of organisms (27,28), and patterns of gene duplication have been reconstructed for a number of multi-gene families of eukaryotic organisms. In the case of the MHC, an ancestral gene duplication early in vertebrate history gave rise to the class I and class II MHC loci. This event must have also included rearrangement of exons, since class I and class II molecules have different structures (29). In mammals, phylogenetic analyses have revealed different patterns of gene duplication in class I and class II (30,31). In the class I MHC of mammals, duplication and deletion of genes has occurred frequently so that orthologous relationships do not exist between class I loci of mammals of different orders (30). The process of duplication and deletion of loci occurs more slowly in the class II MHC. Orthologous relationships do occur between class II loci of mammals belonging to different eutherian (placental) orders (31). However, no orthologous relationships are known between class II MHC loci in different classes of vertebrates.

The class I MHC of mammals includes a number of different loci differing in expression and function. The class Ia loci or classical class I loci are typically highly polymorphic; they are expressed in all nucleated somatic cells and function to present peptides to cytotoxic T cells ( 11). The class Ia loci are characterized by an enhanced rate of nonsynonymous nucleotide substitution in the PBR codons, indicating that polymorphism at these loci is selectively maintained. In addition, there are certain loci expressed at lower levels, which also show relatively low levels of polymorphism; these are known as class Ib or nonclassical class I loci (32). The function of class Ib loci is not clearly understood, although at least some of them have been shown to bind peptides (33). The class Ib loci do not have an enhanced rate of nonsynonymous substitution in the PBR codons; thus what little polymorphism is seen at these loci appears to be neutral polymorphism (30).

From an evolutionary point of view, the most remarkable feature of class Ib loci is that they do not show orthologous relationships between mammals of different orders. Thus these loci have arisen independently in different mammalian lineages (30). Class Ib loci have evidently evolved as a result of duplication of class Ia loci follwed by a change in expression pattern due to mutation in the promoter region (30). The class Ia and class Ib genes thus do not represent mutually exclusive groups over evolutionary time. Dramatic evidence for this is the fact that the class Ia genes of New World primates are homologous to the human class Ib locus HLA-G (34,35). This locus was evidently present in the common ancestor of New World monkeys and Old World monkeys, apes, and hominids, but in the former it has been duplicated to form separate class Ia loci. In spite of the independent origin of class Ib loci in different mammals, there is evidence that they can evolve similar functions convergently. For example the class Ib HLA-E molecule of humans and other primates has convergently evolved features of the PBR that are similar to those of the mouse class Ib molecule H2-Qa-1a (36), and there is evidence that these molecules may bind similar peptides (37).