Fig. 6.18 Human MHC genes are highly polymorphic. With the notable exception of the DRα locus, which is functionally monomorphic, each gene locus has many alleles. The number of functional proteins encoded is less than the total number of alleles. Shown in this figure as the heights of the bars are the number of different HLA proteins assigned by the WHO Nomenclature Committee for Factors of the HLA System as of January 2010.
6-11 The protein products of MHC class I and class II genes are highly polymorphic.
Because of the polygeny of the MHC, every person expresses at least three different MHC class I molecules and three (or sometimes four) MHC class II molecules on his or her cells. In fact, the number of different MHC molecules expressed by most people is greater because of the extreme polymorphism of the MHC (Fig. 6.18).
The term polymorphism comes from the Greek poly, meaning many, and morphe, meaning shape or structure. As used here, it means within-species variation at a gene locus, and thus in the gene’s protein product; the variant genes that can occupy the locus are termed alleles. For several MHC class I and class II genes, there are more than 1000 alleles in the human population, far more than the number of alleles for other genes found within the MHC region. Each MHC class I and class II allele is relatively frequent in the population, so there is only a small chance that the corresponding gene loci on both homologous chromosomes of an individual will have the same allele; most individuals will be heterozygous for the genes encoding MHC class I and class II molecules. The particular combination of MHC alleles found on a single chromosome is known as an MHC haplotype. Expression of MHC alleles is codominant, meaning that the protein products of both of the alleles at a locus are expressed equally in the cell, and both gene products can present antigens to T cells. The number of MHC alleles discovered that do not code for a functional protein is remarkably small. The extensive polymorphism at each locus thus has the potential to double the number of different MHC molecules expressed in an individual and thereby increase the diversity already available through polygeny (Fig. 6.19).
Because most individuals are heterozygous, most matings will produce offspring that receive one of four possible combinations of the parental MHC haplotypes. Thus siblings are also likely to differ in the MHC alleles they express, there being one chance in four that an individual will share both haplotypes with a sibling. One consequence of this is the difficulty of finding suitable donors for tissue transplantation, even among siblings.
All MHC class I and II proteins are polymorphic to a greater or lesser extent, with the exception of the DRα chain and its mouse homolog Eα. These chains do not vary in sequence between different individuals and are said to be monomorphic. This might indicate a functional constraint that prevents variation in the DRαand Eα proteins, but no such special function has been found.
Fig. 6.19 Polymorphism and polygeny both contribute to the diversity of MHC molecules expressed by an individual.
Many mice, both domestic and wild, have a mutation in the Eα gene that prevents synthesis of the Eα protein. They thus lack cell-surface H-2E molecules, so if H2-E does have a special function it is unlikely to be essential.
MHC polymorphisms at individual MHC genes seem to have been strongly selected by evolutionary pressures. Several genetic mechanisms contribute to the generation of new alleles. Some new alleles arise by point mutations and others by gene conversion, a process in which a sequence in one gene is replaced, in part, by sequences from a different gene (Fig. 6.20). The effects of selective pressure in favor of polymorphism can be seen clearly in the pattern of point mutations in the MHC genes. Point mutations can be classified as replacement substitutions, which change an amino acid, or silent substitutions, which simply change the codon but leave the amino acid the same. Replacement substitutions occur within the MHC at a higher frequency relative to silent substitutions than would be expected, providing evidence that polymorphism has been actively selected for in the evolution of the MHC.
influencing both peptide binding and the contacts between