FINE MAPPING OF GENES REGULATING HEAT LOSS

调控热量损失的基因的精细定位

• 批准号: 2903557
• 负责人: DANIEL POMP
• 金额: $ 26.79万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2903557
• 关键词: Mus musculus; age difference; bioenergetics; body composition; calorimetry; chromosomes; genetic mapping; genetic markers; genetic recombination; genotype; human genetic material tag; laboratory mouse; nutrient intake activity; nutrition related tag; obesity; phenotype; pleiotropism; quantitative trait loci; sex differentiation

Nearly one-third of the U.S. population is overweight, contributing to atherosclerosis, hypertension and diabetes, and accounting for a majority of deaths in Western populations and an estimated 5 percent of total U.S. health care costs. Obesity is a complex trait that is influenced by environmental and genetic factors and their interactions. Obesity clearly has a polygenic basis or predisposition. Due to the complexities and low power inherent in quantitative trait loci (QTL) identification studies in humans, there have recently been major efforts to genetically dissect obesity and its correlated effects in a variety of animal models. Despite their potential significance, genes controlling energy requirements and expenditure through metabolic rate (MR) have not received sufficient emphasis. Highly unique populations of mice have been established at the University of Nebraska that have undergone long-term divergent selection for MR measured as heat loss (followed by full-sib mating to create inbred lines), as a model for study of the polygenic control of energy balance and body composition. These lines (MH=high MR; ML=low MR) exhibit extreme phenotypic divergence for these target traits and are genetically predisposed to high and low energy expenditure. The genetic differences between the lines are recalcitrant to factors such as gender, age and diet. A large F2 population will be made from crosses between MH and ML. The F2 population will be phenotyped for MR (by direct calorimetry), feed intake and body composition, and genotyped at approximately 160 microsatellite markers throughout the genome. Locations of QTL controlling MR, maintenance energy requirements and fat percentage will be identified. QTL with largest effects will be fine-mapped using targeted dense genotyping in an advanced intercross line created by intermating MH and ML to F10. The long-term goal of this research is to understand the complex nature of the polygenic control of obesity in humans through analysis of loci predisposing mice to high or low metabolic rate and maintenance requirements. QTL identified in mice likely have homologs in humans with important effects on energy balance and fat deposition. This research may lead to eventual identification of these loci through candidate positional cloning. These efforts will contribute to the long-term battle against human obesity by facilitating improved methods for diagnosis, treatment and prevention.

美国人口中将有近三分之一的人超重，导致了动脉粥样硬化，高血压和糖尿病，并且在西方人口中占多数死亡，估计占美国医疗保健总成本的5％。 肥胖是一个复杂的特征，受环境和遗传因素及其相互作用的影响。 肥胖显然具有多基因或倾向。 由于人类定量性状基因座（QTL）识别研究固有的复杂性和低功率，最近在各种动物模型中遗传剖析肥胖症及其相关作用，最近已经采取了重大努力。 尽管具有潜在的意义，但通过代谢率（MR）控制能量需求和支出的基因尚未得到足够的重点。内布拉斯加州大学已经建立了高度独特的小鼠种群，这些小鼠已对MR进行了长期分歧选择，以衡量的是热量损失（随后是全sib交配以形成近交系列），作为研究能量控制能量平衡和身体组成的多基因控制的模型。 这些线（MH =高MR; ML =低MR）对于这些目标性状表现出极端的表型差异，并且在遗传上易于高和低能量消耗。 这条线之间的遗传差异是对性别，年龄和饮食等因素的顽固差异。 MH和ML之间的十字架将构成大量的F2人群。 F2群体将进行MR（通过直接量热法），饲料摄入和身体组成，并在整个基因组中以大约160个微卫星标记为基因分型。 将确定控制MR，维护能量需求和脂肪百分比的QTL位置。 QTL具有最大效果的QTL将使用通过将MH和ML与F10相结合的高级间跨线中的靶向密度基因分型进行细化。这项研究的长期目标是通过分析基因座的小鼠倾向于高或低代谢率和维持要求，了解人类肥胖的多基因控制的复杂性。 在小鼠中鉴定出的QTL可能在人类中具有同源物，对能量平衡和脂肪沉积有重要影响。 这项研究可能会导致通过候选位置克隆对这些基因座的最终识别。 这些努力将通过促进改进的诊断，治疗和预防方法来促进与人类肥胖的长期战斗。