FINE MAPPING OF GENES REGULATING HEAT LOSS

调控热量损失的基因的精细定位

基本信息

批准号：
6526108
负责人：
DANIEL POMP
金额：
$ 28.15万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-01 至 2004-08-31
项目状态：
已结题

项目摘要

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.

近三分之一的美国人口超重，导致动脉粥样硬化、高血压和糖尿病，造成西方人口死亡的大部分，估计占美国医疗保健总费用的 5%。肥胖是一种复杂的特征，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基础或倾向。由于人类数量性状位点（QTL）识别研究固有的复杂性和低功效，最近人们在各种动物模型中从基因角度剖析肥胖及其相关影响。尽管具有潜在的重要性，但通过代谢率（MR）控制能量需求和消耗的基因尚未得到足够的重视。内布拉斯加大学已经建立了高度独特的小鼠群体，这些小鼠群体经历了长期的 MR 发散选择，以热量损失衡量（随后进行全同胞交配以创建近交系），作为研究小鼠多基因控制的模型能量平衡和身体成分。这些品系（MH=高MR；ML=低MR）在这些目标性状方面表现出极端的表型差异，并且在遗传上倾向于高和低能量消耗。品系之间的遗传差异不受性别、年龄和饮食等因素的影响。 MH 和 ML 之间的杂交将产生大量 F2 群体。 F2 群体将对 MR（通过直接量热法）、采食量和身体成分进行表型分析，并对整个基因组中约 160 个微卫星标记进行基因分型。将确定控制 MR、维持能量需求和脂肪百分比的 QTL 位置。通过将 MH 和 ML 与 F10 相结合而创建的高级杂交系中，将使用有针对性的密集基因分型对具有最大影响的 QTL 进行精细定位。这项研究的长期目标是通过分析导致小鼠高或低代谢率和维持需求的基因座，了解人类肥胖的多基因控制的复杂性质。在小鼠中发现的 QTL 可能与人类具有同源性，对能量平衡和脂肪沉积具有重要影响。这项研究可能会通过候选位置克隆最终鉴定这些基因座。这些努力将通过改进诊断、治疗和预防方法，为对抗人类肥胖的长期斗争做出贡献。