DETECTING BALANCED SELECTION WITH DNA SEQUENCE VARIATION

这项提案的长期目标是利用DNA序列数据， 研究假设，酶的多态性，与特定的 氨基酸取代，都受到选择的影响。 具体来说，该研究将检查DNA序列多态性的模式 在两个酶位点，葡萄糖-6-磷酸脱氢酶（G6 PD）和甘油- 3-磷酸脱氢酶（GPDH），在果蝇。 这些基因座 已经成为大量功能性生物化学的目标， 几十年的群体遗传学研究，这两个位点都很简单， 等位酶多态性 已公布了这两种病毒的主要DNA序列。 基因. 建议对每个40个拷贝中的特定区域进行测序， 从北美和欧洲取样的基因。 对这个大数字进行排序 将通过使用聚合酶链反应（PCR） 从基因组DNA制备物中扩增靶序列。 这 PI成功地获得了基本方法， 实验室，并已用于测序两个拷贝的G6 PD基因。 十 同样的基因区域的拷贝也将在果蝇中进行测序 simulans。 这两个等位酶在该物种中均不存在多态性 的位点 根据最近的群体遗传理论制定的统计检验 将应用于对比多态性和序列的模式 物种之间的差异。 这些测试的结果将决定 DNA多态性的过度水平被发现在区域相关的 负责等位酶多态性的氨基酸取代。 DNA序列多态性水平显著增加，如果 通过平衡选择保持等位酶多态性。 这项研究很重要，因为大规模的项目正在进行中，或提出， 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序列数据的数量预计将 在未来十年呈指数级增长。 其中一个特征 DNA序列水平的异质性 基因组的多态性。 的重要任务 理论和实验群体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 建议是一个计划，以检查一个潜在的特点或原因，这是 变化量

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.