The seven human Alcohol dehydrogenase (ADH) genes code for a family of enzymes that catalyze the reversible oxidation of alcohols to aldehydes. The three Class I ADH genes (ADH1A, ADH1B, ADH1C) share 95% sequence identity and are believed to play a major role in ethanol metabolism. Variants of different Class I ADH genes are associated with a protective effect against alcoholism. We have typed nine Class I ADH SNPs (ADH1C EcoR I, HaeIII, Arg271Gln, Ile349Val, Pro351Thr, ADH1B Arg47His, RsaI, Arg369Cys, ADH1A BccI) spanning > 68kb of the > 77kb Class I cluster, in samples of 38 populations. Most of the haplotypes that are common in Sub-Saharan Africa can be accounted for by a simple multibranched tree of nucleotide substitutions starting from the rare ancestral haplotype. The most common haplotype in the world differs from the ancestral haplotype by two nucleotide substitutions; the intermediate differing from the ancestor at only one of those sites is rare but present in African populations. The second most common haplotype differs from the most common haplotype at two additional changes; again, the intermediate differing at only one of those sites is found only in Africa. Thus, the haplotype frequencies suggest that most haplotypes were generated in Africa before modern humans migrated out of Africa. The haplotype that harbors a functional substitution associated with protection against alcoholism (ADH1B*47His) is seen exclusively and at high frequency (>60%) in East Asia and appears to be a crossover product involving two haplotypes common in Western Asia. This crossover haplotype is not found in indigenous Africans suggesting it arose from a recombination event among modern humans who had already left Africa. Regionally restricted functional variants also exist in Africa and the Americas suggesting selection is operating on these genes probably related to adaptation in each geographical region.
Department, Program, or Center
Thomas H. Gosnell School of Life Sciences (COS)
American Journal of Human Genetics 73N5 Supp (2003) 1315
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