Genetics of Alcohol Sensitivity in Drosophila

酗酒是世界范围内许多医疗、社会和经济问题的原因。而酒精是其中之一 在最广泛滥用的物质中，不同的人在酒精敏感性和 形成酒精依赖。然而，我们对遗传机制和 导致酒精相关行为变化的环境因素远未完成。这个 困难的出现是因为酒精相关的行为是复杂的特征，而且个体差异是可归因于 对于多个相互作用、影响较小的基因，其表达依赖于环境因素。 这个项目的长期目标是阐明酒精敏感性和耐受性的遗传结构。 在一个强大的遗传模型系统中，黑腹果蝇，并利用这些信息来获得洞察力 容易导致人们产生酒精依赖的遗传因素。具体的 这项建议的目的是：(1)表征预先发现的影响 在更大的分子和表型细节上对乙醇的醉人效应的敏感性和抵抗力，以及 以确定这些基因在多大程度上相互作用；(2)使用系统生物学方法，其中 基因组转录图谱应用于影响酒精敏感性和抗性的P-元件插入系 和敏感的人工选择系，以识别影响酒精敏感性的共调控遗传网络； (3)进行高分辨率基因组扫描，寻找影响自然发生的变异的数量性状基因座 酒精敏感度提高和降低的品系之间的酒精敏感度，并识别 导致选择系酒精敏感性差异的位置候选基因；和(4) 评估在候选基因中发现的影响酒精敏感性的多态程度 以前的特定目标与酒精敏感度的自然变化有关。 在美国，大约有1400万人患有酒精中毒。长期酗酒是 对导致重伤或死亡的大量交通事故负责；神经学， 胃肠和心血管疾病；以及社会经济问题，包括攻击性增加 对养育子女和婚姻稳定产生不利影响的行为。确定哪些遗传因素会影响 与酒精相关的行为在人类中具有挑战性，但在模式生物中可以更容易地解决。 全面描述果蝇对酒精敏感的遗传基础将有助于 未来的比较基因组学方法，在这种方法中，我们直接将这一信息合并到人类连锁中，并 协会研究确定人类发展成酒精依赖的易感性基因 人口。

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 usethis 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 increasedaggressive 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.