the evolution of modern humans. This claim has been erroneously founded on the inference that the mitochondrial DNA polymorphisms of modern humans can be traced to a single woman who lived some 200,000 years ago (Cann et al., 1987; Stoneking et al., 1990; Vigilant et al., 1991). As we shall show, DNA polymorphisms in the major histocompatibility complex (MHC) of humans and other primates manifest that no severe population bottleneck has occurred in human evolution.
The MHC is an array of genetic loci that specify molecules with a major role in tissue compatibility and defense against foreign substances. The MHC is present in all mammals, birds, amphibians, and fishes, and it may in fact exist in all vertebrates (Klein, 1986; Bjorkman and Parham, 1990). MHC molecules present on the surfaces of certain cells bind fragments of proteins (antigens) and present them to thymus-derived lymphocytes (T cells) expressing T-cell receptors on their surfaces. The clone of T lymphocytes bearing receptors that match a particular combination of protein fragment and MHC molecule is stimulated, by the contact with the antigen-presenting cells, to proliferate and to initiate the specific arm of the immune response, including the secretion of specific antibodies. The MHC molecules thus protect against pathogens and parasites in general.
The recognition of protein fragments is mediated by a specialized groove on the surface of the MHC molecule, the so-called peptide-binding region (PBR) composed of some 50 amino acid residues (Bjorkman et al., 1987a, b; Brown et al., 1993). The composition of the amino acids in the PBR varies from one MHC molecule to another, and it is primarily this variation that is responsible for the tremendous polymorphism characteristic of the MHC molecules and their encoding genes. In people, as well as in some mammalian species (e.g., the house mouse), scores of alleles may exist at any one of several MHC loci, and some of the allelic pairs may differ by more than 100 nucleotide substitutions (Klein and Figueroa, 1986; Marsh and Bodmer, 1991, 1993; Bontrop, 1994).
The human MHC, also referred to as the human leukocyte antigen (HLA ) complex, consists of about 100 genes located on chromosome 6, extending over a DNA region that is four million nucleotide pairs in length. The MHC genes fall into two distinct classes, I and II, separated by a set of genes with functions mostly unrelated to the immune response (Figure 1).
The origins of the MHC polymorphisms have been studied extensively in rodents (Arden and Klein, 1982; Figueroa et al., 1988; McCon-