The neutral theory and natural selection in the HLA region.

Based on available DNA sequence data in the HLA region of 4 Mb, we review the degree of polymorphism at 39 loci of which most are involved in the immune system. The extent of nucleotide differences per silent site differs greatly from locus to locus. It is exceptionally high at classical MHC loci, intermediate at six MHC-related pseudogenes as well as at some loci in class I and II regions, and low in the class III region. Different exons of individual MHC loci show also different degrees of silent polymorphism; high in the exons encoding for the peptide binding region (PBR) and low in the exons encoding for trans-membranes and cytoplasmic tails. The degree of polymorphism within MHC allelic lineages is not much smaller than that between allelic lineages, contrary to the expectation where intra-allelic sequence exchanges are restricted. The observation that many allelic lineages at the HLA-DRB1 locus are combinations of distinct motifs in the beta pleated sheet and alpha helix of PBR indicates that sequence exchanges occur even within exon 2. Semi-quantitative analysis is presented about the rate of sequence exchanges between selected and linked neutral regions, although more sequence information is necessary to make definite conclusions. The extraordinary MHC polymorphism is viewed from the dual function of MHC molecules that controls the acquired immune system.