Metabolic Control and Molecular Adaptation in Drosophila

描述（由申请人提供）：生物学中的一个基本问题是如何 自然选择塑造了负责代谢的遗传变异， 个体之间的差异。几十年前，很明显， 在许多生物体中，代谢酶因分子变异而分离 包括人类建议的研究的长远目标，是研究 代谢变异与分子变异相关的程度， 通用中枢代谢途径的酶。它将研究这些 黑腹果蝇（Drosophila melanogaster）是一种模式生物， 整个基因组在今年完成了测序代谢中的遗传性疾病是 从糖尿病到肥胖症的主要健康问题。这些疾病中有许多 他们的原因在正在调查的基因。具体的科学 目标有几个。(1)为了确定哪些酶，基因和途径 对自然选择的反应。这将涉及一组基因测序 参与脂肪生成、糖酵解、脂肪生成、NADH/NAD穿梭， 和谷氨酸代谢。从DNA和蛋白质序列推断 变化和地理模式与纬度，它将是 确定哪些途径步骤响应自然选择来调节 代谢池和适应乙醇丰富的生态位。(2)研究功能性 与途径步骤相关的差异似乎携带着遗传变异 与地理变异模式有关。(3)实验 将进行操作，以评估个人 步骤或酶可以调节代谢库和途径通量。(4)的 与纬度变化相关的近端选择原因将是 研究了这些可能涉及选择延迟衰老在北方 区域，以及相关的代谢池的重新分配， 生殖这将集中在女性的二歧变异 生殖滞育及其相关的表型，如饥饿抗性。 研究将开始，以确定基因的变化，在这方面的责任。 一系列对代谢途径有级联效应的特征。

DESCRIPTION (provided by applicant): A fundamental question in biology is how natural selection shapes the genetic variation responsible for metabolic variation among individuals. Several decades ago it became apparent that many metabolic enzymes are segregating for molecular variation in many organisms including humans. The long range goals of the study proposed will examine the extent to which metabolic variation is associated with molecular variation in the enzymes of universal central metabolic pathways. It will study these mechanisms in the fruit fly Drosophila melanogaster, a model organism for whom the entire genome was sequenced this year. Genetic disorders in metabolism are a major health concern from diabetes to obesity. Many of these disorders have their causes in the genes under investigation. The specific scientific objectives are several. (1) To determine which enzymes, genes and pathways are responding to natural selection. This will involve sequencing a set of genes involved in lipogenesis, glycolysis, gluconeogenesis, the NADH/NAD shuttles, and glutamate metabolism. From patterns of DNA and inferred protein sequence variation and geographic patterns associated with latitude, it will be determined which pathways steps are responding to natural selection to modulate metabolic pools and adapt to ethanol rich niches. (2) To study the functional differences associated with pathway steps seem to be carrying genetic variation associated with patterns of geographic variation. (3) Experimental manipulations will be carried out to evaluate the extent to which individual steps or enzymes can modulate metabolic pools and pathway fluxes. (4) The proximal selective causes associated with latitudinal variation will be investigated. These likely involve selection on delayed senescence in northern regions, as well as associated reallocation of metabolic pools away from reproduction. This will focus on the dichotomous variation of female reproduction diapause and its related phenotypes such as starvation resistance. Studies will begin to identify the genes responsible for the variation in this suite of traits that have cascading effects into the metabolic pathways.