Evidence of positive selection on a class I ADH locus
Evidence of positive selection on a class I ADH locus
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DOI：
10.1086/512485
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发表时间：
2007-03-01
影响因子：
9.8
通讯作者：
Kidd, Kenneth K.
中科院分区：
文献类型：
--
作者：
Han, Yi;Gu, Sheng;Kidd, Kenneth K.
乙醇脱氢酶 (ADH) 家族酶催化乙醇可逆氧化为乙醛。 4q21 上一段类似 370 kb 的片段中存在 7 个 ADH 基因。具有 95% 序列同一性的三个 I 类 ADH 基因的产物被认为在乙醇代谢的第一步中发挥着主要作用。由于普遍认为东亚人群中的 ADH1B*47His 等位基因发生了选择，但缺乏直接的生物学或统计证据，因此我们使用基因组数据来检验这一假设。数据由 42 个人群的全球抽样中 ADH 簇中的 54 个单核苷酸多态性 (SNP) 组成。 F-st 统计和远程单倍型（LRH）测试都提供了几个东亚人群选择的积极证据。 ADH1B Arg47His 功能多态性在 ADH 簇中的 54 个 SNP 中具有最高的 F-st，并且显着高于在相同的 42 个群体样本中测试的 382 个可能中性位点的平均 F-st。使用包括该位点在内的核心并在两侧延伸的 LRH 测试也提供了一些东亚人群对携带 ADH1B*47His 等位基因的特定单倍型的正选择的重要证据。有趣的是，这种单倍型仅在一些东亚人群中出现频率很高，而特定等位基因也存在于其他东亚人群以及近东和欧洲，但没有显示使用 LRH 测试进行选择的证据。尽管 ADH1B*47His 等位基因传达了经过充分证实的针对酗酒的保护作用，但现代表型表现并不容易转化为积极的选择力，并且该选择力的性质在过去和/或现在仍然是推测性的。
The alcohol dehydrogenase (ADH) family of enzymes catalyzes the reversible oxidation of alcohol to acetaldehyde. Seven ADH genes exist in a segment of similar to 370 kb on 4q21. Products of the three class I ADH genes that share 95% sequence identity are believed to play the major role in the first step of ethanol metabolism. Because the common belief that selection has operated at the ADH1B*47His allele in East Asian populations lacks direct biological or statistical evidence, we used genomic data to test the hypothesis. Data consisted of 54 single-nucleotide polymorphisms ( SNPs) across the ADH clusters in a global sampling of 42 populations. Both the F-st statistic and the long-range haplotype (LRH) test provided positive evidence of selection in several East Asian populations. The ADH1B Arg47His functional polymorphism has the highest F-st of the 54 SNPs in the ADH cluster, and it is significantly above the mean F-st of 382 presumably neutral sites tested on the same 42 population samples. The LRH test that uses cores including that site and extending on both sides also gives significant evidence of positive selection in some East Asian populations for a specific haplotype carrying the ADH1B*47His allele. Interestingly, this haplotype is present at a high frequency in only some East Asian populations, whereas the specific allele also exists in other East Asian populations and in the Near East and Europe but does not show evidence of selection with use of the LRH test. Although the ADH1B*47His allele conveys a well-confirmed protection against alcoholism, that modern phenotypic manifestation does not easily translate into a positive selective force, and the nature of that selective force, in the past and/or currently, remains speculative.