Genetics of Alcohol Sensitivity in Drosophila

果蝇酒精敏感性的遗传学

• 批准号: 6849534
• 负责人: TRUDY F. MACKAY
• 金额: $ 17.34万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6849534
• 关键词: Drosophilidae; arthropod genetics; behavioral /social science research tag; behavioral genetics; behavioral habituation /sensitization; drug tolerance; ethanol; genetic mapping; genetic screening; genetic strain; pharmacogenetics; quantitative trait loci; sensory depression

Alcoholism is the cause of widespread social and human health problems. Alcohol sensitivity, the development of tolerance to alcohol, and susceptibility to addiction varies among individuals. This variation is attributable to segregating alleles at multiple interacting genes with small effects, whose expression is sensitive to environmental factors. Determining what genetic factors affect variation in alcohol sensitivity, tolerance and addiction is challenging in humans, but can be addressed more readily in genetic model organisms. The long-term goal of this project is to understand the quantitative genetic architecture of sensitivity and tolerance to ethanol, using Drosophila melanogaster as a model system. The short-term goals for this two-year exploratory R21 proposal are (1) to identify new candidate genes and pathways regulating alcohol sensitivity and tolerance; and (2) to map quantitative trait loci (QTLs) affecting naturally occurring variation in these traits with high resolution. We will screen ca. 800 co-isogenic P-element insertion lines to identify genes affecting alcohol sensitivity and tolerance, and couple this screen with gene expression analysis to expand the known collection of genes that contribute to these traits. We will also perform high resolution QTL mapping studies on a series of isogenic recombinant introgression lines to identify chromosomal regions and genes that contribute to variation in ethanol sensitivity; and screen a collection of 300 inbred lines recently derived from nature for ethanol sensitivity and tolerance to identify extreme lines for subseqeunt QTL analyses. These studies will provide the preliminary data for a full R01 application in which we will propose to fully characterize the candidate genes implicated by these studies. Given the evolutionary conservation of important biological processes across taxa as diverse as yeast, nematodes, Drosophila, mice, and humans, genes and pathways discovered in model organisms can be incorporated as candidate genes in human linkage and association studies.

酗酒是广泛的社会和人类健康问题的原因。酒精敏感性、对酒精的耐受性以及成瘾的易感性因人而异。这种变异归因于多个相互作用基因上等位基因的分离，影响较小，其表达对环境因素敏感。确定哪些遗传因素影响酒精敏感性、耐受性和成瘾性的变化对人类来说具有挑战性，但在遗传模型生物中可以更容易地解决。该项目的长期目标是使用黑腹果蝇作为模型系统，了解对乙醇的敏感性和耐受性的定量遗传结构。这项为期两年的探索性 R21 提案的短期目标是（1）确定调节酒精敏感性和耐受性的新候选基因和途径； (2) 以高分辨率绘制影响这些性状自然发生变异的数量性状基因座 (QTL)。我们将筛选大约。 800 个同基因 P 元件插入系，用于识别影响酒精敏感性和耐受性的基因，并将此筛选与基因表达分析结合起来，以扩展有助于这些性状的已知基因集合。我们还将对一系列同基因重组渗入系进行高分辨率 QTL 作图研究，以确定导致乙醇敏感性变化的染色体区域和基因；并筛选最近从自然界衍生的 300 个自交系的乙醇敏感性和耐受性，以确定用于后续 QTL 分析的极端品系。这些研究将为完整的 R01 应用提供初步数据，我们将在其中建议全面表征这些研究所涉及的候选基因。鉴于酵母、线虫、果蝇、小鼠和人类等不同类群的重要生物过程的进化保守性，在模式生物中发现的基因和途径可以作为候选基因纳入人类连锁和关联研究中。