As described in more detail later, the loci constituting the MHC are highly polymorphic; that is, many alternative forms of the gene, or alleles, exist at each locus among the population. The genes of the MHC loci lie close together; for example, the recombination frequency within the H-2 complex (i.e., the frequency of chromosome crossover events during mitosis, indicative of the distance between given gene segments) is only 0.5%—crossover occurs only once in every 200 mitotic cycles. For this reason, most individuals inherit the alleles encoded by these closely linked loci as two sets, one from each parent. Each set of alleles is referred to as a haplo-type. An individual inherits one haplotype from the mother and one haplotype from the father. In outbred populations, the offspring are generally heterozygous at many loci and will express both maternal and paternal MHC alleles. The alleles are codominantly expressed; that is, both maternal and paternal gene products are expressed in the same cells. If mice are inbred (that is, have identical alleles at all loci), each H-2 locus will be homozygous because the maternal and paternal haplotypes are identical, and all offspring therefore express identical haplotypes.
Certain inbred mouse strains have been designated as prototype strains, and the MHC haplotype expressed by these strains is designated by an arbitrary italic superscript (e.g., H-2a, H-2b). These designations refer to the entire set of inherited H-2 alleles within a strain without having to list each allele individually (Table 7-1). Different inbred strains may have the same set of alleles, that is the same MHC hap-lotype, as the prototype strain. For example, the CBA, AKR, and C3H strains all have the same
The three strains differ, however, in genes outside the H-2 complex.
If two mice from inbred strains having different MHC haplotypes are bred to one another, the F1 generation inherits haplotypes from both parental strains and therefore ex presses both parental alleles at each MHC locus. For example, if an H-2b strain is crossed with an H-2k, then the F 1 inherits both parental sets of alleles and is said to be H-2b/k (Figure 7-2a). Because such an F1 expresses the MHC proteins of both parental strains on its cells, it is histocompatible with both strains and able to accept grafts from either parental strain (see example in Figure 7-2b). However, neither of the inbred parental strains can accept a graft from the F1 mice because half of the MHC molecules will be foreign to the parent.
The inheritance of HLA haplotypes from heterozygous human parents is illustrated in Figure 7-2c. In an outbred population, each individual is generally heterozygous at each locus. The human HLA complex is highly polymorphic and multiple alleles of each class I and class II gene exist. However, as with mice, the human MHC loci are closely linked and usually inherited as a haplotype. When the father and mother have different haplotypes, as in the example shown (Figure 7-2c) there is a one-in-four chance that siblings will inherit the same paternal and maternal haplotypes and therefore be histocompatible with each other; none of the offspring will be histocompatible with the parents.
Although the rate of recombination by crossover is low within the HLA, it still contributes significantly to the diversity of the loci in human populations. Genetic recombination generates new allelic combinations (Figure 7-2d), and the high number of intervening generations since the appearance of humans as a species has allowed extensive recombination, so that it is rare for any two unrelated individuals to have identical sets of HLA genes.
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