QTL mapping age-related changes in lipid storage

描述(由申请人提供)： 肥胖定义为身体脂肪或脂肪组织过多，是一种对人类健康造成不利影响的疾病。脂肪组织过多的临床问题与一些慢性疾病密切相关，如II型糖尿病、代谢紊乱和冠心病。肥胖的病因是复杂的，既有基因网络的综合作用，也有饮食、年龄、性别和锻炼的影响。老龄化也是一个主要因素。脂肪质量的普遍增加通常发生在生命的第三十到七十年之间。有趣的是，肥胖和相关的代谢性疾病已被证明与慢性炎症状态有关，其特征是细胞因子产生异常和其他应激诱导的分子。衰老还伴随着免疫功能的普遍下降和伴随而来的与年龄相关的炎症反应的上调。该项目的假设是，进化保守的遗传途径通过利用共同的调节分子来调节年龄相关的甘油三酯储存和天然免疫功能的变化，这些途径可以通过对果蝇甘油三酯水平和免疫反应的QTL分析来识别。甘油三酯的储存和免疫反应都是复杂的多基因性状，依赖于大量基因的相互作用。因此，数量遗传学方法为识别导致这些性状与年龄相关的变化的多效性基因座提供了最大的希望。该项目的具体目标是：1)定位自然遗传变异影响甘油三酯储存和免疫反应的年龄相关变化的染色体区域(数量性状基因座或QTL)。2)确定影响年龄相关的甘油三酯储存和天然免疫反应变化的候选基因。候选基因将通过利用缺失的定量互补和与高级杂交品系的精细定位来精炼QTL的位置来识别。3)检验候选基因的自然序列变异与年龄相关的甘油三酯储存和天然免疫反应的表型变异之间的因果关系。为此，我们将使用来自随机交配群体的等位基因样本的连锁不平衡作图。这项研究将确定影响年龄相关的甘油三酯储存和免疫反应变化的基因和遗传网络，并阐明这些特征受多基因座调控的程度。这些基因的识别可能会为人类肥胖提供新的模型，并可能作为特定年龄风险评估的遗传标记。此外，已确定的基因可能成为治疗和预防与年龄相关的代谢和免疫功能障碍的潜在靶点。此外，对致病遗传多态的性质和频率的了解将有助于更好地理解在自然种群中维持这些性状遗传变异的机制。

DESCRIPTION (provided by applicant): Obesity, defined as an excess of body fat or adipose tissue, is a condition that adversely affects human health. The clinical problem of excessive adipose tissue resides in its strong association with a number of chronic diseases such as type II diabetes, metabolic disorders and coronary heart disease. The etiology of obesity is complex, resulting from the combined effect of a network of genes, and the influences of diet, age, gender and exercise. Aging is also a major contributor. A general increase in fat mass typically occurs between the third and seventh decades of life. Interestingly, obesity and related metabolic diseases have been shown to be associated with a state of chronic inflammation characterized by abnormal cytokine production and other stress-induced molecules. Aging is also accompanied by a general decline in immune function and a concomitant age-dependent up-regulation of the inflammatory response. The hypothesis of this project is that evolutionary conserved .qenetic pathways regulate age related changes in triglyceride storage and innate immune function through the utilization of common regulatory molecules, and that these pathways can be identified by QTL analyses of triglyceride levels and immune responses in Drosophila melano,qaster. Both triglyceride storage and immune response are complex polygenic traits, relying on the interaction of a large number of genes. Therefore, a quantitative genetic approach offers the most promise for identifying pleiotropic loci that contribute to the age-related changes in these traits. The specific aims of this project are to: 1) Map chromosomal regions (quantitative trait loci or QTL) at which natural genetic variation affects agerelated changes in triglyceride storage and immune response of D.melanogaster. 2) Identify candidate genes affecting age-related changes in both triglyceride storage and innate immune response. Candidate genes will be identified by refining the position of QTL using quantitative complementation to deficiencies and fine-scaled mapping with advanced intercross lines. 3) Test the causal relationship between natural sequence variation in candidate genes and phenotypic variation in age-related changes in triglyceride storage and innate immune response. To do this, we will use linkage disequilibrium mapping of a sample of alleles from a randomly mating population. This study will identify genes and genetic networks affecting age related changes in triglyceride storage and immune response and elucidate the extent to which these traits are regulated by pleiotropic loci. Identification of these genes will likely provide new models for human obesity and could serve as genetic markers for age-specific risk assessment. In addition, the genes identified could be potential targets for the treatment and prevention of age-related metabolic and immune dysfunction. Moreover, knowledge of the nature and frequency of causative genetic polymorphisms will lead to a better understanding of the mechanisms that maintain genetic variation in these traits in natural populations.