Speculation on the evolution of insulin-dependent diabetes genes.

A hypothesis about the evolution of insulin-dependent diabetes mellitus (IDDM)-susceptibility alleles is proposed. IDDM is known to be associated with two HLA-DR alleles, DR3 and DR4. DR3 is associated with IDDM in all ethnoracial groups including populations in which IDDM is rare, such as African and Asian populations, as well as whites in whom IDDM is common. However, in general, DR4 is associated with IDDM only in populations with white ancestry with high rates of IDDM. IDDM in American blacks illustrates the evolutionary patterns of the two diabetes alleles. The frequency of IDDM in American blacks relative to that in American whites (20% to 30%) approximates the frequency of the American black gene pool that is white-derived (also 20% to 30%), and DR4 is associated with IDDM in American blacks but not in African blacks. These data are consistent with the infusion of a dominant white-derived DR4-associated diabetes allele into the black gene pool. Recent studies of mitochondrial DNA suggest that modern humans evolved in Africa 200,000 to 300,000 years ago and that repeated migrations populated the world. The DR-population:IDDM-frequency relationships suggest that the DR3-associated diabetes allele evolved early (greater than or equal to 100,000 years ago) in Africa, whereas the DR4-associated diabetes allele evolved later (less than 15,000 years ago) in northern Europe. Recent data from studies of IDDM in families and populations which suggest that the DR4-associated allele has dominant characteristics and the DR3-associated allele has recessivelike characteristics fit into this hypothesis.