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

由人类ALDH2基因产生的酶通过其在醛氧化中的作用在正常的酒精和药物代谢中起重要作用。该基因有一种缺陷变体ALDH2-2，在东亚人群中很常见，但在其他人群中没有。携带ALDH2-2等位基因的人往往不喝酒，因为他们血液中的乙醛会累积到令人不快和有害的水平。有可能是自然选择倾向于ALDH2-2变体，至少在它出现的亚洲部分地区是这样。然而，对于携带ALDH2-2的人来说，戒酒的好处可能会被乙醛具有细胞毒性和诱变性这一事实所抵消，乙醛可能会加剧肝脏疾病和喉癌。自然选择将在ALDH2-2的正负作用之间取得平衡。本研究验证了自然选择影响人类ALDH2基因位点变异的假设。确定自然选择下的基因位点是很重要的，因为它们很可能表现出对特定环境的适应，并影响健康和生殖。自然选择的分子特征将通过分析人类基因组区域内部和区域之间、人群内部和人群之间以及物种之间的DNA序列来确定。这种分析是基于中性分子进化的第一原理，应用于我们物种的复杂地理。根据具体目标，该项目将对人类和黑猩猩的ALDH2位点进行DNA测序。对于一些样本，DNA也将在ALDH1A1位点测序。具体目标还包括发展和改进一种原始的统计方法，用于比较种群内部和种群之间的遗传差异。该项目利用了基因组科学的最新进展和已完成的人类DNA序列。这在十年前是不可能进行的。该项目对科学界的影响有几个方面。它有一个涵盖本科生、研究生和博士后水平的培训部分。通过融合研究生和博士后学员的才能，以及从少数族裔学生暑期研究机会项目中抽取的本科生的才能，将做出智力贡献。首席研究员将把这项研究的结果纳入一个关于人类遗传多样性的讲座中，该讲座将作为密歇根大学生命科学价值计划公众推广系列的一部分。此外，该项目将收集多个种群的大量DNA序列数据。这些数据将被存入基因库，并将为其他遗传研究人员提供资源。

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.