Genetics of Alcohol Sensitivity in Rats

描述（由申请人提供）：发生酒精中毒的一个重要遗传风险因素是对急性剂量酒精的不同敏感性。利用来自选择性繁殖大鼠系的分离群体，我们绘制了大鼠1号和2号染色体上的数量性状位点（qtl），这些位点与酒精的急性反应、翻正反射（LORR）丧失的持续时间有关。我们随后产生了同源和重组同源系，这些同源系确认了qtl，同时减小了它们的基因组大小。我们假设在QTL区间中有一个或多个基因通过多态性对基因表达和/或基因产物结构的影响而导致LORR的遗传变异。第二个重要的假设是，这些相同的基因会影响酒精奖励相关行为的遗传变异。为了解决这些假设，该项目将开展四个具体目标：1)使用重组同源策略对1号染色体和2号染色体的qtl进行精细定位；2)在1号染色体和2号染色体qtl的精细定位区域鉴定候选基因；3)识别受qtl影响的功能通路和基因网络；4)确定1号染色体和2号染色体的qtl是否多效性与酒精奖励相关的行为。当代遗传和基因组学方法和分析方法，包括高通量DNA和RNA测序，将用于实现Aims的目标。我们建议，这些实验的结果将提供深入了解急性酒精敏感性的遗传变异的本质。这反过来将有助于更深入地了解人类酗酒的遗传风险。

DESCRIPTION (provided by applicant): An important genetic risk factor for the development of alcoholism is differential sensitivity to an acute dose of alcohol. Using segregating populations derived from selectively bred rat lines, we have mapped quantitative trait loci (QTLs) on rat chromosomes 1 and 2 for an acute response to alcohol, the duration of the loss of righting reflex (LORR). We have subsequently generated congenic and recombinant congenic lines that have confirmed the QTLs while simultaneously reducing their genomic size. We hypothesize that there are one or more genes within the QTL intervals that contribute to genetic variance for LORR through polymorphism- related effects on gene expression and/or on the structure of the genes' products. A second important hypothesis is that these same genes will influence genetic variance in alcohol reward-related behaviors. To address these hypotheses, the project will carry out four Specific Aims: 1) Fine-map the chromosome 1 and 2 QTLs using the recombinant congenic strategy; 2) Identify candidate genes in the fine-mapped areas of the chromosome 1 and 2 QTLs; 3) Identify enriched functional pathways and gene networks that are affected by the QTLs; and 4) Determine if the chromosome 1 and 2 QTLs are pleiotropic with alcohol reward-related behaviors. Contemporary genetic and genomic methods and analytical approaches, including high-throughput DNA and RNA sequencing, will be used to accomplish the goals of the Aims. We propose that the results of these experiments will offer insight into the nature of genetic variance for acute alcohol sensitivity. This in turn will contribute to a deeper understanding of genetic risk for human alcoholism.