The genetics of the Drosophila IIS pathway response to changing nutrition

描述(申请人提供)：现代人经历了饮食和活动水平的变化，导致代谢紊乱的增加。已知IIS途径影响生长、新陈代谢和寿命的许多方面，但对该途径站立变异的遗传基础知之甚少。该项目的目标是研究胰岛素/胰岛素样信号通路(IIS)中自然遗传变异的遗传基础。该项目将利用一种新开发的资源进行复杂性状的遗传分析，即果蝇合成种群资源(DSPR)。将测量IIS途径中每个基因在三种不同营养条件下的基因表达水平，并对影响这些基因表达水平的QTL进行定位。该项目将确定IIS中自然遗传变异的来源，并确定遗传变异是否与该途径中编码主要蛋白质的基因共存。影响基因表达的基因将在多种营养环境中被识别，从而有可能确定在不同环境中控制IIS途径的是相同的还是不同的变体。此外，该项目将解决是否相同的“主基因”控制IIS途径的几个组成部分。该项目还将使用系统生物学方法回答有关IIS途径组件之间相互作用的性质的广泛问题。通过使用DSPR，该项目将能够将影响IIS途径的QTL定位到1-2厘米，估计这些QTL的影响和频率，并确定潜在的致病部位。IIS通路在果蝇和人类之间高度保守，因此，识别果蝇中控制IIS信号转导的基因可能直接识别药物干预的靶点，特别是如果识别出“主控基因”。最终，这个项目将描述中央内分泌途径的遗传基础，这对我们理解新陈代谢和资源的内部分配具有直接意义。

DESCRIPTION (provided by applicant): Modern human populations have experienced changes in diet and activity levels, leading to an increase in metabolic disorders. The IIS pathway is known to influence many aspects of growth, metabolism, and longevity but little is known about the genetic basis of standing variation in the pathway. The goal of this project is to examine the genetic basis of natural genetic variation in the insulin/insulin-like signaling (IIS) pathway. The project will utilize a newly developed resource for the genetic analysis of complex traits, the Drosophila Synthetic Population Resource (DSPR). Gene expression levels for every gene in the IIS pathway will be measured in three different nutritional conditions and QTL influencing these gene expression levels will be mapped. The project will identify the source of natural genetic variation in IIS and determine if genetic variants co-localize with the genes encoding major proteins in the pathway. Genes influencing gene expression will be identified in multiple nutritional environments, making it possible to determine if the same or different variants control the IIS pathway in different environments. In addition, the project will address whether the same "master genes" control several components of the IIS pathway. The project will also answer broad questions about the nature of the interactions between components of the IIS pathway using systems biology approaches. By using the DSPR, this project will be able to map QTL influencing the IIS pathway to 1-2 centiMorgans, estimate both the effect and frequency of those QTL and identify potentially causative sites. The IIS pathway is highly conserved between Drosophila melanogaster and humans and therefore, identifying the genes controlling IIS signaling in Drosophila may directly identify targets for pharmacological intervention, particularly if "master genes" are identified. Ultimately, this project will characteize the genetic basis of a central endocrine pathway that has direct implications for our understanding of metabolism and the internal allocation of resources.