RAPID ISOLATION OF DIET-RESPONSIVE OBESITY GENES

饮食诱导的肥胖症（DIO）与以下疾病的发生率增加有关： 动脉粥样硬化、糖尿病和高血压。 虽然基因鉴定 任何复杂疾病的基础都是困难的，这些问题将 增加DIO，在那里将很难区分基因，导致 导致DIO的自发性肥胖。 相反，工具 可用于分析小鼠的复杂疾病，结合 相对容易控制饮食，这表明，识别和 用小鼠模型分离引起DIO的基因是可能的。 这个项目的长期目标是分离和鉴定基因 导致DIO。 该提案的特点是使用现有的 能够快速检测和分离DIO的同类小鼠品系 基因. 同源小鼠品系是由近交系小鼠品系通过 它们与背景相同 除了一小部分 来源于供体菌株的染色体区域。 利用现有 同源菌株作为定位克隆的快速方法是通用的， 对寻找新基因的影响，有助于其他复杂的 疾病可能是伟大的。 第一个目的是研究DIO基因的分离， 同源株系和背景株系的F2杂交。 我们已经确定了五个 表现出显著不同的身体脂质的同类小鼠品系 百分比或肥胖指数（脂肪垫重量总和除以胴体 当两者都被放置在高脂肪上时， 高糖饮食 将对这些菌株中的每一种进行适用性检测， 通过检查100只F2小鼠的位置克隆资源， 同源株和背景株的杂交。 鉴定两 分离群体，对应于同源和背景菌株 基因型，将通过检查个体表型或 表型的组合。 第二个目标是启动基因的定位克隆， 饮食引起的肥胖 一个包含了一个新的肥胖基因的杂交， 显示出肥胖特征最明显的分离为两个 组将扩大到包括1000只F2小鼠。 这些老鼠将被分型 寻找基因座附近所有可用的PCR标记 当我们识别标记时 在DIO潜在基因的1 cM内，那么我们将分离出 基因组克隆（YAC、BAC、P1或PAC克隆）。 将构建重叠群 包括DIO基因

Diet-induced obesity (DIO) is associated with increased incidences of atherosclerosis, diabetes, and hypertension. While identification of genes underlying any complex disease is difficult in humans, these problems will be increased for DIO, where it will be hard to distinguish genes that cause spontaneous obesity from those that cause DIO. In contrast, the tools available for analysis of complex disease in mice, combined with the relative ease of controlling diets, suggest that identification and isolation of genes causing DIO will be possible with mouse models. The long range goal of this project is to isolate and identify genes causing DIO. This proposal is distinguished by its use of existing congenic mouse strains to enable rapid detection and isolation of DIO genes. Congenic mouse strains are derived from inbred mouse strains by a regimen of crossing and selection They are identical to a background strain except for a small chromosomal region derived from a donor strain. The use of existing congenic strains as a rapid approach to positional cloning is generic and the impact on the search for novel genes contributing to other complex diseases could be great. The first objective is to examine the segregation of genes underling DIO in F2 crosses of congenic and background strains. We have identified five strains of congenic mice that exhibit significantly different body lipid percent or adiposity index (sum of fat pad weights divided by carcass weight) than their background strains when both are placed on a high-fat, high-sucrose diet. Each of these strains will be tested for suitability as a resource for positional cloning by examining 100 F2 mice derived from crosses of the congenic and background strains. Identification of two segregating groups, corresponding to congenic and background strain genotypes, will be made by examination of individual phenotypes or combinations of phenotypes. The second objective is to initiate positional cloning of genes underlying diet-induced obesity. The one cross that includes a novel obesity gene and that exhibits the most distinct segregation of obesity traits into two groups will be expanded to include 1000 F2 mice. These mice will be typed for all available PCR markers near the locus. When we identify markers within 1 cM of the gene underlying DIO, then we will isolate linked genomic clones (YAC, BAC, P1 or PAC clones). A contig will be constructed that includes the DIO gene.