MAPPING GENES FOR ADIPOSITY IN MICE

描述（申请人提供）：小鼠肥胖基因的直系同源物可能参与人类肥胖，并对人类健康产生重大影响。本申请的重点是鉴定小鼠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。该基因组扫描的一个主要发现是体重（LOD评分= 3.8）和9号染色体上的肥胖（LOD评分=3.2）相关的证据。9号染色体上的基因座占总性状方差的10 - 20%，具有加性遗传模式。除了这种基因组扫描之外，还有几项研究已经确定小鼠9号染色体是肥胖症的重要连锁区域，但尚未对该区域进行精细定位。这一目标将通过完成四个特定目标来实现：特定目标1：使用来自B6和129品系之间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来细化链接峰值。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同类系和亚同类系。重叠供体片段的比较将进一步细化性状基因座的位置，并限制候选基因的数量。具体目标3是评价候选基因：首先，通过比较其序列（小鼠基因组测序项目和Celera），鉴定B6和129菌株之间的多态性基因。然后将进行其他近交系小鼠之间的表型-基因型相关性，然后进行基因表达组织分布的实验室和计算机模拟试验，以及B6和129品系之间选定组织的基因表达差异。具体目标4的目标是使用转基因小鼠构建和随后的表型分析来确定高优先级候选物的基因功能。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.