Genetics of Alcohol Sensitivity in Drosophila

酗酒是世界范围内许多医疗、社会和经济问题的根源。酒精是一种 在最广泛滥用的物质中，个体在酒精敏感性和酒精滥用倾向方面差异很大。 发展成酒精依赖然而，我们对遗传机制的理解和 造成这种与酒精有关的行为变化的环境触发因素还远未完成。的 困难在于，与酒精相关的行为是复杂的特征，个体差异是可归因的。 到多个相互作用的基因，其影响很小，其表达取决于环境因素。 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见解， 研究导致人们酒精依赖的遗传因素。具体 该建议的目的是：（1）表征错误鉴定的P元件插入突变， 在更大的分子和表型细节上对乙醇致醉作用的敏感性和抗性，以及 确定这些基因相互作用的程度;（2）使用系统生物学方法，其中整个 基因组转录谱分析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，以确定影响酒精敏感性的共调节遗传网络; (3)进行高分辨率基因组扫描，以获得影响自然发生变异的数量性状基因座， 选择酒精敏感性增加和降低的品系之间的酒精敏感性，并鉴定 有助于选择系中酒精敏感性差异的位置候选基因;和（4） 评估影响酒精敏感性的候选基因的多态性在多大程度上被发现， 先前的特定目标与酒精敏感性的自然发生的变化有关。 在美国，大约有1400万人患有酒精中毒。长期酗酒是 造成大量导致严重伤害或死亡的交通事故;神经系统， 胃肠道和心血管疾病;以及社会经济问题，包括侵袭性疾病增加 对养育子女和婚姻稳定产生不利影响的行为。确定哪些遗传因素影响 酒精相关行为在人类中具有挑战性，但在模式生物中更容易解决。 对果蝇酒精敏感性的遗传基础进行全面的描述，将有助于研究果蝇的酒精敏感性。 未来的比较基因组方法，我们直接将这些信息纳入人类联系， 关联研究以确定导致人类酒精依赖发展的基因 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.