Metabolic Control and Molecular Adaptation in Drosophila

描述(申请人提供)：生物学中的一个基本问题是如何 自然选择塑造了导致新陈代谢的遗传变异 个体间的差异。几十年前，很明显，许多人 在许多生物体中，代谢酶对分子变异起着隔离作用 包括人类。这项研究提出的长期目标将审查 在多大程度上代谢变异与分子变异有关。 普遍的中枢代谢途径的酶。它将研究这些 果蝇--黑腹果蝇--的机制 今年对整个基因组进行了测序。新陈代谢中的遗传性疾病 从糖尿病到肥胖症，这是一个主要的健康问题。这些障碍中的许多都有 它们在被调查的基因中的原因。特定的科学 目标有几个。(1)确定哪些酶、基因和途径是 对自然选择的反应。这将涉及对一组基因进行测序。 参与脂肪生成、糖酵解、糖异生、NADH/NAD穿梭， 和谷氨酸代谢。根据DNA模式和推断的蛋白质序列 与纬度相关的变化和地理模式，它将是 确定步骤响应自然选择来调节哪些途径 代谢池和适应乙醇丰富的利基市场。(2)研究泛函 与通路步骤相关的差异似乎携带着遗传变异 与地理变化的模式有关。(3)试验性 将进行操作，以评估个人在多大程度上 步骤或酶可以调节代谢池和途径通量。(4) 与纬度变化相关的近端选择性原因将是 调查过了。这些可能涉及对北方延缓衰老的选择 区域，以及相关的代谢池重新分配远离 繁殖。这将集中在女性的二分变异上 生殖滞育及其相关表型，如耐饥性。 研究将开始确定导致这种变异的基因。 对新陈代谢途径有连锁影响的一系列特征。

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.