Genotype-Phenotype relationships underlying aerobic capacity and metabolic health

有氧能力和代谢健康的基因型-表型关系

基本信息

批准号：
8714658
负责人：
STEVEN Loyal BRITTON
金额：
$ 58.94万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714658
关键词：
Accounting Aerobic Alleles Animals Archives Base Sequence Biochemical Bioinformatics Biologic Characteristic Biological Biological Models Biology Blood Blood Glucose Blood Pressure Body Composition Body Weight Body fat Body mass index Breeding Candidate Disease Gene Cardiac Cardiovascular Diseases Chronic Clinical Computer Simulation DNA Data Diabetes Mellitus Disease Event Exercise Fatty Acids Frequencies Gene Expression Gene Frequency Generations Genes Genetic Genetic Drift Genetic Models Genetic Predisposition to Disease Genetic Recombination Genetic Variation Genomics Genotype Glucose Goals Haplotypes Health Heart Heritability Human Hypertension Hypotension Inflammation Insulin Insulin Resistance Knowledge Life Expectancy Link Liver Longevity Lung Capacity Maps Measures Messenger RNA Metabolic Metabolic syndrome Modality Molecular Myocardium Myosin ATPase Nature Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Oxidative Phosphorylation Oxidative Stress Paper Pathway Analysis Pathway interactions Patients Phenotype Physiological Physiology Population Publishing Quantitative Trait Loci Rattus Recording of previous events Resolution Resources Rest Running Signal Transduction Skeletal Muscle Source Structure System Testing Tissue Sample Tissues Translating Treadmill Tests Triglycerides Variant Weight Gain Work base design disorder risk functional genomics gene discovery genetic pedigree genetic variant genome sequencing glucose metabolism improved inflammatory marker insight lipid metabolism mRNA Expression positional cloning progenitor public health relevance trait

项目摘要

DESCRIPTION (provided by applicant): A decrease in aerobic capacity in humans is associated with increased risk of disease, including obesity, insulin resistance, hypertension, and type 2 diabetes. Further, oxidative capacity is strongly correlated with life expectancy. To understand the biological mechanisms linking aerobic capacity and metabolic health we will employ a model system consisting of two lines of rat established through divergent selection for high and low inborn (i.e., untrained) running capacity, with controlled breeding to maximize their outbred nature. The high capacity runners (HCRs) and low capacity runners (LCRs) are genetically heterogeneous and highly differentiated in aerobic capacity after >32 generations. They display large differences in weight gain, blood pressure, body mass index, lung capacity, lipid and glucose metabolism, measures of inflammation and oxidative stress and lifespan. Despite extensive studies, the underlying molecular basis for the enhanced health of the HCRs and increased disease risk of LCRs is not known. Our preliminary data have revealed strong heritability of running capacity within each line, and increasing genetic differentiation as well a robust HCR-LCR differences in mRNA and metabolite levels under a variety of condition. In this proposal, we test the hypothesis that functional DNA variants in a limited number of genes were contributed by the eight founder strains, and their frequencies were driven increasingly apart in the two lines through selection, accounting for the molecular and physiological variation of the two lines. We propose to identify these causal genes with the following specific aims (SAs): SA1. Identify quantitative trait loci (QTL) for running distance, related metabolic traits, and gen expression variation in an HCR-LCR intercross population (n~650). SA2. Discover causal genes/variants using a combination of genetic and functional genomic approaches, including eQTLs (SA1), ancestral haplotype from the funder lines, signatures of positive selection after 32 generations, sequencing-based discovery of functional variants altered by selection, gene expression network analysis, and in silico fine mapping using known variants from founder strains. Functional relevance of candidate genes will be interpreted in the context of rich prior knowledge HCR-LCR gained over the years. This proposed three-year study will leverage several unique advantages of the HCR/LCR system: the two lines have been kept largely outbred to maintain genetic diversity; the pedigree is completely known, with tissue samples archived for analysis, and past recombination events have led to recognizable haplotype structure at 2-3 cM resolution, ideal for fine mapping. We expect to find functional alleles at multiple loci that have evolved hand-in-hand and are relevant for the health differences between lines. Many of these genes may be directly relevant for the corresponding human phenotypes or, at a minimum, provide clues to important pathways that could be targeted for improving human metabolic health. Our ultimate goal is to gain a deeper mechanistic understanding of metabolic health, and translate this understanding to improved therapies for patients.

描述（由申请人提供）：人类有氧能力的降低与疾病风险增加相关，包括肥胖、胰岛素抵抗、高血压和 2 型糖尿病。此外，氧化能力与预期寿命密切相关。为了了解有氧能力和代谢健康之间的生物学机制，我们将采用一个模型系统，该系统由两个大鼠系组成，通过对先天（即未经训练的）跑步能力的不同选择而建立，并通过控制繁殖来最大化其远交性质。高容量跑步者 (HCR) 和低容量跑步者 (LCR) 具有遗传异质性，并且在超过 32 代后有氧能力存在高度差异。他们在体重增加、血压、体重指数、肺活量、脂质和葡萄糖代谢、炎症和氧化应激指标以及寿命方面表现出巨大差异。尽管进行了广泛的研究，但 HCR 健康增强和 LCR 疾病风险增加的潜在分子基础尚不清楚。我们的初步数据显示，每个品系内的运行能力具有很强的遗传性，并且遗传分化不断增加，并且在各种条件下，mRNA和代谢物水平存在显着的HCR-LCR差异。在本提案中，我们测试了这样的假设：有限数量的基因中的功能性 DNA 变异是由八个创始菌株贡献的，并且通过选择，它们的频率在两个品系中逐渐分开，从而解释了两个品系的分子和生理变异线。我们建议通过以下特定目标（SA）来识别这些因果基因：SA1。识别 HCR-LCR 杂交群体 (n~650) 中跑步距离、相关代谢性状和基因表达变异的数量性状位点 (QTL)。 SA2。结合遗传和功能基因组方法发现因果基因/变异，包括 eQTL (SA1)、资助者系的祖先单倍型、32 代后正选择的特征、基于测序的发现因选择而改变的功能变异、基因表达网络分析，并使用创始菌株的已知变体进行计算机精细绘图。候选基因的功能相关性将在多年来获得的丰富的 HCR-LCR 先验知识的背景下进行解释。这项为期三年的研究将利用 HCR/LCR 系统的几个独特优势：这两个品系在很大程度上是近亲繁殖以保持遗传多样性；谱系是完全已知的，组织样本存档用于分析，过去的重组事件导致了分辨率为 2-3 厘米的可识别单倍型结构，非常适合精细绘图。我们期望在多个基因座上找到功能性等位基因，这些基因座是携手进化的，并且与品系之间的健康差异相关。其中许多基因可能与相应的人类表型直接相关，或者至少为改善人类代谢健康的重要途径提供线索。我们的最终目标是获得对代谢健康更深入的机制理解，并将这种理解转化为改进患者的治疗方法。