DETECTING BALANCED SELECTION WITH DNA SEQUENCE VARIATION

这项提议的长期目标是使用DNA序列数据来 检验一种假说，酶的多态与特定的 氨基酸的取代，都受到选择的影响。 具体地说，这项研究将检查DNA序列多态的模式 葡萄糖-6-磷酸脱氢酶(G6PD)和甘油-6-磷酸脱氢酶(G6PD) 果蝇体内的3-磷酸脱氢酶(GPDH)。这些基因座 一直是相当多的功能性生化和 几十年来的群体遗传学研究，这两个基因座都具有简单的 等位基因多态。这两种病毒的初级DNA序列都已公布 基因。建议对特定区域进行测序，每个拷贝40个 基因样本来自北美和欧洲。对这么大的数字进行排序 通过使用聚合酶链式反应(PCR)将促进基因的分析 从基因组DNA制剂中扩增靶序列。这 基本方法论已被PI成功地获取 已经被用来对G6PD基因的两个拷贝进行测序。十 同样的基因区域的拷贝也将在果蝇中被测序 人形动物。该物种没有这两个基因的等位酶多态。 精神错乱。根据最新的群体遗传学理论进行的统计检验 将用来对比多态和序列的模式 物种间的分化。这些测试的结果将决定是否 在与基因相关的区域发现了过多的DNA多态 等位酶基因多态的氨基酸替换。 如果出现以下情况，预计DNA序列多态水平将显著提高 等位基因的多态通过平衡选择来维持。 这项研究之所以重要，是因为有相当规模的项目正在进行或正在拟议中， 系统地绘制和测序几个物种的大部分基因组 包括人类在内的物种。DNA序列数据量预计将达到 在接下来的十年里呈指数级增长。一个肯定会出现的特征 从这些研究中将发现DNA序列水平上的异质性 基因组各区域间的多态现象。的一项重要任务 理论和实验种群遗传学将解释这一点 中性理论和自然选择背景下的异质性。这 Proposal指的是研究这种情况的一个潜在特征或原因的计划 变种。

The long-term objective of this proposal is to use DNA sequence data to examine the hypothesis that enzyme polymorphisms, associated with specific amino acid substitutions, are under the influence of selection. Specifically, the study will examine patterns of DNA sequence polymorphism at two enzyme loci, glucose-6-phosphate dehydrogenase (G6PD) and glycerol- 3-phosphate dehydrogenase (GPDH), in Drosophila melanogaster. These loci have been the targets of a significant number of functional biochemical and population genetic studies for decades, and both loci posses simple allozyme polymorphisms. Primary DNA sequences have been published for both genes. It is proposed to sequence specific regions in 40 copies of each gene sampled from North America and Europe. Sequencing this large number of genes will be facilitated by using the polymerase chain reaction (PCR) to amplify targeted sequences from genomic DNA preparations. This essential methodology has been successfully acquired by the PI's laboratory, and has been used to sequence two copies of the G6PD gene. Ten copies of the same gene regions will also be sequenced in Drosophila simulans. This species possesses no allozyme polymorphisms for these two loci. Statistical tests formulated from recent population genetic theory will be applied to contrast the patterns of polymorphism and sequence divergence between species. The results of these tests will determine if excessive levels of DNA polymorphism are found in the regions linked to the amino acid substitutions responsible for the allozyme polymorphisms. Significantly increased levels of DNA sequence polymorphism are expected if the allozyme polymorphisms are maintained by balancing selection. This study is important because sizable programs are underway, or proposed, to systematically map and sequence large parts of the genomes of several species including man. The quantity of DNA sequence data is expected to increase exponentially in the next decade. One feature certain to emerge from those studies will be heterogeneity in levels of DNA sequence polymorphism across regions of the genome. An important task of theoretical and experimental population genetics will be to interpret this heterogeneity in the context of neutral theory and natural selection. This proposal is a plan to examine one potential feature or cause of this variation.