Allelic Variability and Tests for Signatures of Natural Selection at the Human ALDH2 Locus

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The enzyme produced by the human ALDH2 gene is important in normal alcohol and drug metabolism via its role in the oxidation of aldehydes. There is a deficiency variant of the gene, ALDH2-2, that is common in people from East Asia but absent in other people. People who carry of the ALDH2-2 allele tend to abstain from drinking because acetaldehyde in their blood builds up to unpleasant and noxious levels. It is possible that natural selection has favored the ALDH2-2 variant, at least in the parts of Asia where it occurs. However, the benefit of abstaining from alcohol to people who carry ALDH2-2 might be offset by the fact that acetaldehyde is cytotoxic and mutagenic, and may exacerbate liver disease and throat cancer. Natural selection will act on the balance between positive and negative effects of ALDH2-2. This research tests the hypothesis that natural selection has influenced variation at the human ALDH2 gene locus. It is important to identify genetic loci that are under natural selection because they are likely to demonstrate adaptations to specific environments and to influence health and reproduction.Molecular signatures of natural selection will be identified by analyzing DNA sequences within and between regions of the human genome, within and between human populations, and between species. The analysis is based on first principles of neutral molecular evolution applied to the complex geography of our species. In accordance with the specific aims, the project will sequence DNA at the ALDH2 locus in humans and chimpanzees. For some samples, DNA will also be sequenced at the ALDH1A1 locus. The specific aims also include developing and refining an original statistical method for comparing genetic differences within and between populations. This project utilizes recent advances in genome science and the completed human DNA sequence. It would have been impossible to conduct even a decade ago.The project's impact on the scientific community has several dimensions. It has a training component that spans undergraduate, graduate, and postdoctoral levels. Intellectual contributions will be made through the fusion of talents of graduate and postdoctoral trainees with those of undergraduates drawn from the Summer Research Opportunities Program for underrepresented minority students. The principal investigator will incorporate the results of this research into a lecture on human genetic diversity that will be given as part of the University of Michigan Life Sciences Values Program public outreach series. Furthermore, the project will collect a large body of DNA sequence data for several populations. These data will be deposited in GenBank and will provide a resource for other genetic researchers.