Genetics of Alcohol Sensitivity in Drosophila

描述(申请人提供)：酗酒是世界范围内许多医疗、社会和经济问题的原因。虽然酒精是被滥用最广泛的物质之一，但每个人对酒精的敏感性和对酒精依赖的倾向差异很大。然而，我们对导致酒精相关行为变化的遗传机制和环境触发因素的了解还远未完成。困难的出现是因为与酒精相关的行为是复杂的特征，个体差异可归因于多个影响较小的相互作用基因，其表达取决于环境因素。该项目的长期目标是在一个强大的遗传模型系统--黑腹果蝇中阐明酒精敏感性和耐受性的遗传结构，并利用这些信息来洞察容易导致人类酒精依赖发展的遗传因素。这一建议的具体目的是：(1)以更多的分子和表型细节表征先前发现的影响对酒精毒性效应的敏感性和抗性的P-元件插入突变，并确定这些基因在多大程度上相互作用；(2)使用系统生物学的方法，将全基因组转录图谱应用于影响酒精敏感性的P元件插入系和抗性和敏感的人工选择系，以确定影响酒精敏感性的共调控遗传网络；(3)对影响酒精敏感性自然发生变异的数量性状基因座进行高分辨率基因组扫描，这些数量性状基因座在为酒精敏感性增加和降低而被选择的品系之间进行选择，并识别导致在选择品系中酒精敏感性差异的位置候选基因；以及(4)评估在先前的特定目的中发现的影响酒精敏感性的候选基因的多态与酒精敏感性自然发生变化的关联程度。在美国，大约有1400万人患有酒精中毒。长期酗酒造成大量交通事故，导致严重受伤或死亡；神经、胃肠和心血管疾病；以及社会经济问题，包括攻击性行为增加，对育儿和婚姻稳定产生不利影响。在人类中，确定哪些遗传因素影响与酒精相关的行为是具有挑战性的，但在模式生物中可以更容易地解决。对果蝇酒精敏感性的遗传基础进行全面描述将有助于未来的比较基因组学方法，即我们将这些信息直接纳入人类连锁和关联研究，以确定在人类群体中容易发生酒精依赖的基因。

DESCRIPTION (provided by applicant): Alcoholism is the cause of many medical, social and economic problems worldwide. Whereas alcohol is one of the most widely abused substances, individuals vary greatly in alcohol sensitivity and propensity for developing alcohol dependence. However, our understanding of the genetic mechanisms and the environmental triggers responsible for this variation in alcohol-related behavior is far from complete. The difficulty arises because alcohol-related behaviors are complex traits, and individual variation is attributable to multiple interacting genes with small effects, the expression of which depends on environmental factors. The long-term goal of this project is to elucidate the genetic architecture of alcohol sensitivity and tolerance in a powerful genetic model system, Drosophila melanogaster, and to use this information to gain insights into the genetic factors that predispose to the development of alcohol dependence in people. The Specific Aims of this proposal are: (1) to characterize prevously identified P-element insertional mutations affecting sensitivity and resistance to the intoxicating effects of ethanol in greater molecular and phenotypic detail, and to determine to what extent these genes interact; (2) to use a systems biology approach, in which whole genome transcriptional profiling is applied to P-element insert lines affecting alcohol sensitivity and resistant and sensitive artificial selection lines, to identify co-regulated genetic networks affecting alcohol sensitivity; (3) to perform a high resolution genome scan for quantitative trait loci affecting naturally occurring variation in alcohol sensitivity between lines selected for increased and decreased alcohol sensitivity, and identify positional candidate genes that contribute to differences in alcohol sensitivity in the selection lines; and (4) to assess the extent to which polymorphisms in candidate genes affecting alcohol sensitivity discovered in the previous specific aims are associated with naturally occurring variation in alcohol sensitivity. Approximately 14 million people in the United States suffer from alcoholism. Chronic alcohol abuse is responsible for a vast number of traffic accidents that result in serious injury or death; neurological, gastrointestinal and cardiovascular disorders; and socio-economic problems, including increased aggressive behavior with adverse impacts on parenting and marital stability. Determining what genetic factors affect alcohol-related behavior is challenging in humans, but can be addressed more readily in model organisms. Achieving a comprehensive description of the genetic basis of alcohol sensitivity in Drosophila will facilitate a future comparative genomic approach in which we directly incorporate this information in human linkage and association studies to identify genes that confer liability for development of alcohol dependence in human populations.