Genetics of Alcohol Sensitivity in Drosophila

描述（由申请人提供）：酗酒是世界范围内许多医疗、社会和经济问题的原因。虽然酒精是最广泛滥用的物质之一，但个体在酒精敏感性和产生酒精依赖的倾向方面差异很大。然而，我们对酒精相关行为变异的遗传机制和环境触发因素的理解还远远不够。困难的是，酒精相关行为是复杂的特征，个体差异可归因于多个相互作用的基因，影响很小，其表达取决于环境因素。该项目的长期目标是阐明一个强大的遗传模型系统——黑腹果蝇（Drosophila melanogaster）中酒精敏感性和耐受性的遗传结构，并利用这些信息深入了解易导致人类酒精依赖的遗传因素。本提案的具体目标是：(1)在更大的分子和表型细节上表征先前确定的影响乙醇中毒效应敏感性和抗性的p元素插入突变，并确定这些基因相互作用的程度；(2)利用系统生物学方法，将全基因组转录分析应用于影响酒精敏感性的p元素插入系和抗性和敏感性的人工选择系，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变异的数量性状位点进行高分辨率的基因组扫描，并确定导致选择品系酒精敏感性差异的位置候选基因；(4)评估在先前特定目标中发现的影响酒精敏感性的候选基因多态性与自然发生的酒精敏感性变异的关联程度。美国大约有1400万人患有酒精中毒。长期酗酒是造成严重伤害或死亡的大量交通事故的原因；神经、胃肠和心血管疾病；以及社会经济问题，包括对养育子女和婚姻稳定产生不利影响的攻击性行为的增加。确定哪些遗传因素影响与酒精有关的行为在人类中是具有挑战性的，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的全面描述将有助于未来的比较基因组方法，我们将这些信息直接纳入人类连锁和关联研究中，以确定导致人类酒精依赖的基因。

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.