MAPPING GENES FOR ADIPOSITY IN MICE

描述（由申请人提供）：小鼠肥胖基因同源物可能与人类肥胖有关，对人类健康有重大影响。该应用程序的重点是识别小鼠9号染色体上影响肥胖的一个或多个基因。作为这项工作的前奏，我们使用来自B6和129菌株的F2群体进行了基因组扫描。这次基因组扫描的一个主要发现是体重（LOD评分为3.8）和9号染色体上的肥胖（LOD评分为3.2）之间存在联系的证据。9号染色体上的位点占总性状变异的10% ~ 20%，具有加性遗传模式。除了基因组扫描之外，还有几项研究已经确定了小鼠9号染色体是肥胖的一个重要联系区域，但还没有对这个区域进行精细的测绘。这一目标将通过完成四个特定目标来实现：特定目标1：利用B6和129株F2杂交的457只小鼠对9号染色体进行精细定位。将创建一个密集的地图，以细化联动峰。具体目标2将是创建具有正肥胖等位基因渗入供体遗传背景的小鼠的先天性和亚先天性系。重叠供体片段的比较将进一步细化性状位点的定位，并限制候选基因的数量。特异性目标3将是候选基因的评估：首先，B6和129菌株之间的多态性基因将通过比较它们的序列（小鼠基因组测序计划和Celera）进行鉴定。然后在其他小鼠近交系之间进行表型-基因型相关性分析，然后进行实验室和计算机分析基因表达的组织分布，以及B6与129菌株在选定组织中的基因表达差异。Specific Aim 4的目的是通过转基因小鼠构建和随后的表型分析来确定高优先级候选基因的功能。了解每个分子在肥胖中的重要作用将是开发安全有效的治疗方法的重要一步。

DESCRIPTION (provided by applicant): Orthologs of mouse obesity genes may be involved in human obesity, and have a significant impact on human health. The focus of this application is to identify a gene or genes on mouse chromosome 9 that influence adiposity. As a prelude to this work, we have conducted a genome scan using an F2 population derived from the B6 and 129 strains. A major finding from this genome scan was evidence for linkage of body weight (LOD score--3.8) and adiposity on chromosome 9 (LOD scores=3.2). The locus on chromosome 9 accounts for between 10 and 20% of the total trait variance, and has an additive mode of inheritance. There have been several studies, in addition to this genome scan, that have identified mouse chromosome 9 as an important area of linkage for obesity, yet no fine mapping of this region has been done. This goal will be met by the completion of four Specific Aims: Specific Aim 1: Fine mapping of chromosome 9 using 457 mice from the F2 intercross between B6 and 129 strains. A dense map will be created to refine the linkage peak. Specific Aim 2 will be the creation of congenic and subcongenic lines of mice with the plus adiposity allele introgressed into the donor genetic background. Comparison of overlapping donor fragments will further refine the location of the trait locus, and restrict the number of candidate genes. Specific Aim 3 will be an evaluation of candidate genes: first, genes that are polymorphic between the B6 and 129 strain will be identified by comparison of their sequences (Mouse Genome Sequencing Project and Celera). Then phenotype-genotype correlations among other inbred strains of mice will be conducted, followed by laboratory and in silico assays of the tissue distribution of gene expression, and gene expression differences between the B6 and 129 strains for selected tissues. The goal of Specific Aim 4 is to determine gene function of high-priority candidates using transgenic mouse construction, and subsequent phenotype analysis. Understanding the role of each molecule important in obesity will be a significant step towards the development of safe and effective therapeutics.