Fine mapping of mouse chr 2 for body composition genes

小鼠 chr 2 身体成分基因的精细定位

• 批准号: 8529519
• 负责人: DANIELLE Renee REED
• 金额: $ 29万
• 依托单位: MONELL CHEMICAL SENSES CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529519
• 关键词: Accounting; Adipose tissue; Adult; Affect; Alleles; Animals; Architecture; Backcrossings; Biology; Body Composition; Body Size; Body Weight; Body fat; Breeding; Candidate Disease Gene; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 2; Computer software; Confidence Intervals; Congenic Strain; Consomic Strain; DNA; DNA Sequence; DNA Sequence Rearrangement; Disease; Dropout; Environment; Event; Exons; Fatty acid glycerol esters; Genes; Genetic; Genetic Recombination; Genetic Variation; Genome; Genome Scan; Genomics; Genotype; Goals; Health; Human; Human Genetics; Human body; Inbred Mouse; Individual Differences; Influentials; Intervention; Knock-out; Knockout Mice; Lead; Length; Leptin; Location; Maps; Measures; Medical; Methods; Molecular; Morphologic artifacts; Mus; Nature; Obesity; Organ Weight; Outcome; Parents; Pathway interactions; Phenotype; Population; Probability; RNA Splicing; Residual state; Resolution; Somatotropin; Source; Stream; Surveys; Testing; Thinness; Tissues; Transcript; Triage; Variant; Walking; Weight; bone; congenic; endophenotype; falls; fusion gene; gene function; genetic variant; improved; male; member; new technology; novel; offspring; receptor; screening; sweet taste perception; trait

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.

描述（由申请人提供）：尽管多余的体内脂肪对我们的人群产生了广泛认可的健康影响，但对肥胖性个体差异的决定因素尚未得到充分了解。在小鼠中的研究导致了许多突破性的理解人类遗传学的突破，包括瘦素及其受体，甜味受体以及生长激素途径的成员。我们最近确定的体型变化的一种来源是小鼠2附近160 MB的小鼠染色体上的基因座或基因群。我们已经在几个十字架上验证了该区域的遗传变异与小鼠脂肪质量的较大差异有关，这些结果是（1）在等位基因效应的方向和幅度一致，以及（2）弹性易于变化n环境。为了准备确定这些基因座，我们使用了标记辅助选择来繁殖两种相互的染色体2替代菌株，这些替代品菌株可用作后交叉研究的父母，以对相关的基因座进行绘制（AIM 1）。这些菌株也是一个现成的起点，可以构建友善，将该区域延伸成较小的间隔（AIM 2）。一旦间隔很小，将测量敲除小鼠的脂肪重量，以确定哪些基因负责这些特征（AIM 3）。 AIM 3的策略可以利用增加的敲除小鼠数量作为敲除鼠标项目（KOMP）的一部分。该项目的回报将是确定自然变异来源，以调节动物的脂肪重量。由于许多医疗问题是由于身体成分的变化而直接或间接引起的，因此了解它们的分子途径可能会指出改善人类健康的新途径。