MAPPING GENES FOR ADIPOSITY IN MICE

小鼠肥胖基因的直系同源物可能与人类肥胖有关，并对人类肥胖的发生有重要影响。 人体健康本申请的重点是鉴定小鼠9号染色体上的一个或多个基因， 影响肥胖。作为这项工作的前奏，我们使用F2群体进行了基因组扫描， 来源于B6和129菌株。这次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）。9号染色体上的基因座 占总性状方差的10 - 20%，并具有加性遗传模式。那里 除了这个基因组扫描，已经有几项研究确定了小鼠9号染色体是一个 肥胖症的重要联系领域，但还没有精细的映射这一地区已经完成。这一目标将会实现 通过完成四个具体目标：具体目标1：使用457只小鼠对9号染色体进行精细定位， B6与129菌株间的F_2代杂交。将创建一个密集的地图来细化链接峰值。具体 目的二是建立正肥胖等位基因渐渗的同类系和亚同类系小鼠 捐赠者的基因背景重叠供体片段的比较将进一步精确定位 限制候选基因的数量。具体目标3将是对候选人的评估 基因：首先，通过比较B6和129菌株之间的多态性基因， 小鼠基因组测序计划（Mouse Genome Sequencing Project）和Celera。然后， 将对其他近交系小鼠进行组织的实验室和计算机分析， 基因表达分布以及B6和129菌株之间的基因表达差异 组织中具体目标4的目标是使用转基因技术确定高优先级候选者的基因功能。 小鼠构建和随后的表型分析。了解每个分子的作用， 肥胖症将是朝着开发安全和有效的治疗方法迈出的重要一步。 表演

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 f_om 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 fimgments 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 distr_ution 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. 'ERFORMANCE