Fine mapping of mouse chr 2 for body composition genes

描述（由申请人提供）：尽管我们的人群中普遍认识到过量体脂对健康的影响，但肥胖个体差异的决定因素尚未得到很好的理解。对小鼠的研究在理解人类遗传学方面取得了许多突破，包括瘦素及其受体，甜味受体和生长激素途径的成员。我们最近发现的体型变异的一个来源是小鼠2号染色体上靠近160 Mb的一个基因座或一组基因座。我们已经在几个杂交中证实，该区域的遗传变异与小鼠脂肪量的巨大差异有关，这些结果（1）在等位基因效应的方向和幅度上一致，（2）对环境变化有弹性。为了准备识别这些位点，我们使用标记辅助选择来培育两个相互的2号染色体置换菌株，其可以用作回交研究的亲本以精细地绘制相关位点（目的1）。这些菌株也是一个现成的起点，以构建同源基因，将该区域分离成连续较小的间隔（目标2）。一旦间隔非常小，将测量敲除小鼠的脂肪重量，以确定哪个基因负责这些性状（目的3）。目标3的策略利用了作为敲除小鼠项目（KOMP）一部分的敲除小鼠数量的增加。该项目的回报将是确定调节动物脂肪重量的自然变异来源。由于许多医学问题直接或间接地归因于身体成分的变化，因此了解它们的分子途径可能会为改善人类健康指明新的途径。

DESCRIPTION (provided by applicant): Despite the widely recognized health impacts of excess body fat in our population, the determinants of individual differences in obesity are not well understood. Studies in mice have led to many breakthroughs in understanding human genetics, including leptin and its receptor, sweet taste receptors, and members of the growth hormone pathway. One source of body size variation we have recently identified is a locus or cluster of loci on mouse chromosome 2 near 160 Mb. We have verified in several crosses that genetic variants in this region relate to large differences in fat mass in mice, and these results are (1) consistent in their direction and magnitude of allelic effect and (2) resilient to changes n environment. To prepare to identify these loci, we used marker-assisted selection to breed two reciprocal chromosome 2 substitution strains that can be used as parents for backcross studies to fine-map the relevant loci (Aim 1). These strains are also a ready-made start point to construct congenics to isolate this region into successively smaller intervals (Aim 2). Once the interval is very small, knockout mice will be measured for fat weight to determine which gene(s) is responsible for these traits (Aim 3). The strategy of Aim 3 makes use of the increased number of knockout mice available as a part of the Knockout Mouse Project (KOMP). The payoff of this project will be to identify a source of natural variation that regulates fat weight in animals. Because many medical problems are due directly or indirectly to changes in body composition, understanding their molecular pathways may point to new avenues to improve human health.