Genetics of Alcohol Sensitivity in Drosophila

果蝇酒精敏感性的遗传学

• 批准号: 8016019
• 负责人: TRUDY F. MACKAY
• 金额: $ 31.26万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8016019
• 关键词: Address; Affect; Alcohol abuse; Alcohol dependence; Alcoholism; Alcohols; Alleles; Analysis of Variance; Animal Model; Architecture; Award; Behavior; Behavioral; Biological Models; Candidate Disease Gene; Cardiovascular Diseases; Cessation of life; Chronic; Complex; DNA; Data; Development; Drosophila genus; Drosophila melanogaster; Economics; Environmental Risk Factor; Exploratory/Developmental Grant; Future; Gastrointestinal Diseases; Genes; Genetic; Genetic Complementation Test; Genetic Models; Genetic Polymorphism; Genome; Genome Scan; Genotype; Goals; Human; Inbreeding; Individual; Induced Mutation; Injury; Maps; Medical; Modeling; Molecular; Mutation; Nature; Nucleotides; Parenting behavior; Pattern; Phenotype; Phosphorus; Population; Population Genetics; Population Heterogeneity; Predisposing Factor; Quantitative Trait Loci; Research; Resistance; Resolution; Staging; Stress; Systems Biology; Testing; Tissues; Traffic accidents; Transcript; Transcriptional Regulation; Transgenic Organisms; United States; Variant; alcohol behavior; alcohol effect; alcohol sensitivity; base; comparative genomics; design; fly; insight; molecular marker; nervous system disorder; novel; programs; response; social; socioeconomics; trait

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.

酗酒是全世界许多医疗、社会和经济问题的根源。而酒精是其中之一 在最广泛滥用的物质中，个体对酒精的敏感性和倾向差异很大 形成酒精依赖。然而，我们对遗传机制的理解和 造成这种与酒精相关的行为变化的环境因素还远未完全确定。这 之所以会出现困难，是因为与酒精相关的行为是复杂的特征，并且个体差异可归因于 多个相互作用的基因，其影响较小，其表达取决于环境因素。 该项目的长期目标是阐明酒精敏感性和耐受性的遗传结构 在强大的遗传模型系统（黑腹果蝇）中，并利用这些信息获得见解 研究了导致人们酒精依赖的遗传因素。具体 该提案的目的是：(1) 表征先前确定的影响 P 元件插入突变的特征 在更大的分子和表型细节上对乙醇中毒作用的敏感性和抵抗力，以及 确定这些基因相互作用的程度； (2) 采用系统生物学方法，其中 基因组转录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，以确定影响酒精敏感性的共同调控的遗传网络； (3) 对影响自然发生变异的数量性状位点进行高分辨率基因组扫描 选择用于增加和降低酒精敏感性的品系之间的酒精敏感性，并确定 导致选择系中酒精敏感性差异的位置候选基因； (4) 至 评估在候选基因中发现的影响酒精敏感性的多态性程度 先前的具体目标与酒精敏感性自然发生的变化有关。 美国大约有 1400 万人酗酒。长期酗酒是 造成大量交通事故并导致重伤或死亡的；神经病学, 胃肠道和心血管疾病；和社会经济问题，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。确定遗传因素的影响 与酒精相关的行为对人类来说是具有挑战性的，但在模型生物中可以更容易地解决。 全面描述果蝇酒精敏感性的遗传基础将有助于 未来的比较基因组方法，我们直接将这些信息纳入人类连锁和 关联研究以确定导致人类酒精依赖发展的基因 人口。