GENETICS OF ALCOHOL RELATED INGESTIVE BEHAVIORS IN MICE

描述（由申请人提供）：乙醇（酒精）的过度消费对人类健康造成严重问题，并产生重大的负面经济影响。过度饮酒的倾向有遗传因素，发现相关基因可能会更好地控制饮酒。动物模型可以为发现这些基因提供有效的工具。我们研究的长期目标是定位克隆影响小鼠自愿乙醇消耗的基因。我们的实验室最近表明，与甜味受体基因Tas 1 r3相关的数量性状位点（QTL）影响酒精消费，这表明酒精的味道可能是调节摄入量的重要因素。初步的基因组扫描显示了其他几个影响乙醇和甜味剂摄入的基因座。 目前项目的目标是对这些基因座进行高分辨率遗传作图。在具体目标1中，我们将使用源自具有高[C57 BL/6 ByJ（B6）]和低[129 P3/J（129）]乙醇消耗的两个小鼠品系的F2杂交和回交世代进行QTL作图。密集的基因分型和连锁分析将检测基因座之间的差异负责B6和129小鼠的乙醇偏好。 在特定目标2中，将使用源自B6和129菌株的同源菌株的基于基因型的选择分离这些基因座。在这些同源株系中，将确定供体染色体片段的大小和位置，将以高分辨率确定QTL位置，并将评估QTL之间可能的上位相互作用。对乙醇的行为反应及其与甜味剂反应的关系的详细描述将有助于阐明QTL效应的可能机制。在具体目标3中，基于QTL位置和可能的作用机制，并使用小鼠和人类基因组的序列，将在包含QTL的基因组区域中分析候选基因。通过这三个目标，我们打算分离出参与乙醇偏好的基因座，确定小鼠中这些基因座的候选基因，并指定它们的人类直系同源物。

DESCRIPTION (provided by applicant): Excess consumption of ethanol (alcohol) imposes serious problems for human health and has major negative economic impact. A predisposition towards alcohol overconsumption has a genetic component, and the discovery of the genes involved may lead to better control of alcohol consumption. Animal models can provide an efficient tool for discovering such genes. The long-term goal of our studies is to positionally clone genes affecting voluntary ethanol consumption by mice. Our laboratory has recently shown that a quantitative trait locus (QTL) associated with the sweet taste receptor gene, Tas1r3, influences alcohol consumption, suggesting that the taste of alcohol may be an important factor in regulation of intake. A preliminary genome scan indicates several other loci that influence intake of both ethanol and sweeteners. The aim of the current project is high-resolution genetic mapping of these loci. In Specific Aim 1, we will conduct QTL mapping using F2 hybrid and backcross generations originating from two mouse strains with high [C57BL/6ByJ (B6)] and low [129P3/J (129)] ethanol consumption. Dense genotyping and linkage analyses will detect loci responsible for the difference between the B6 and 129 mice in ethanol preference. In Specific Aim 2, these loci will be isolated using genotype-based selection of congenic strains originating from the B6 and 129 strains. In these congenic strains, the size and location of the donor chromosomal fragments will be defined, QTL positions will be determined with high resolution, and possible epistatic interactions among QTLs will be assessed. Detailed characterization of the behavioral responses to ethanol and their relationships with responses to sweeteners will help to elucidate possible mechanisms underlying QTL effects. In Specific Aim 3, based on QTL positions and possible mechanisms of action, and using the sequences of mouse and human genomes, candidate genes will be analyzed in genomic regions encompassing the QTLs. Through these three aims, we intend to isolate loci involved in ethanol preference, identify candidate genes for these loci in mice, and specify their human orthologs.