Genetic Architecture of Voluntary Exercise in Mice

小鼠自愿运动的遗传结构

• 批准号: 8004347
• 负责人: DANIEL POMP
• 金额: $ 10.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-11 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004347
• 关键词: Accounting; Address; Alleles; Animal Model; Architecture; Bayesian Method; Body Composition; Body Weight; Body Weight decreased; Body fat; Breeding; Candidate Disease Gene; Cis-Trans Tests; Complex; Data; Data Set; Economics; Energy Intake; Environment; Exercise; Expenditure; Gastrocnemius Muscle; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Recombination; Genetic Variation; Genome; Genotype; Goals; Health; Health Expenditures; Heart Diseases; High Density Lipoproteins; Hippocampus (Brain); Human; Individual; Investigation; Knowledge; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Measures; Messenger RNA; Metabolic; Methods; Modeling; Mus; Myocardial Infarction; Nature; Obesity; Obesity associated disease; Outcome; Pathway interactions; Phenotype; Physical activity; Physiological; Physiology; Play; Polygenic Traits; Population; Positioning Attribute; Predisposition; Preventive; Principal Investigator; Quantitative Trait Loci; Reporting; Research; Resources; Rodent; Role; Running; Stroke; Susceptibility Gene; Testing; Tissues; Variant; Weight; base; energy balance; genome-wide; human disease; innovation; insulin sensitivity; low density lipoprotein triglyceride; meetings; molecular phenotype; mouse genome; mouse model; novel strategies; prevent; social; tool; trait; Accounting; Address; Alleles; Animal Model; Architecture; Bayesian Method; Body Composition; Body Weight; Body Weight decreased; Body fat; Breeding; Candidate Disease Gene; Cis-Trans Tests; Complex; Data; Data Set; Economics; Energy Intake; Environment; Exercise; Expenditure; Gastrocnemius Muscle; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Recombination; Genetic Variation; Genome; Genotype; Goals; Health; Health Expenditures; Heart Diseases; High Density Lipoproteins; Hippocampus (Brain); Human; Individual; Investigation; Knowledge; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Measures; Messenger RNA; Metabolic; Methods; Modeling; Mus; Myocardial Infarction; Nature; Obesity; Obesity associated disease; Outcome; Pathway interactions; Phenotype; Physical activity; Physiological; Physiology; Play; Polygenic Traits; Population; Positioning Attribute; Predisposition; Preventive; Principal Investigator; Quantitative Trait Loci; Reporting; Research; Resources; Rodent; Role; Running; Stroke; Susceptibility Gene; Testing; Tissues; Variant; Weight; base; energy balance; genome-wide; human disease; innovation; insulin sensitivity; low density lipoprotein triglyceride; meetings; molecular phenotype; mouse genome; mouse model; novel strategies; prevent; social; tool; trait

DESCRIPTION (provided by applicant): Exercise induces metabolic changes including loss of weight, reduction in triglyceride and LDL levels, increased HDL, and enhanced insulin sensitivity. Moderate physical activity has been shown to have beneficial effect in preventing heart disease, heart attack and stroke, and has been implicated as a preventive measure for some cancers. Genetic predisposition to complex traits, such as propensity for voluntary exercise, results from effects of combinations of genetic variations within a number of polygenes, known as quantitative trait loci (QTL). Remarkably, no QTL have been reported for voluntary exercise in any species. In three specific aims, our goal is to address this gap in knowledge by identifying QTL controlling voluntary exercise, and its underlying transcriptional landscape, using a unique polygenic mouse model: Aim 1: Localize QTL for voluntary exercise: We will create an F4 population of 800 mice originating from a cross between the HR line, selectively bred for increased voluntary exercise, and C57BI/6J (B6). This population will be phenotyped for voluntary exercise, caloric intake, and weight gain and body composition. All mice will be genotyped for 768 evenly spaced and fully-informative SNP markers. Aim 2: Localize expression QTL (eQTL) for voluntary exercise: We will evaluate global gene expression in hippocampus and gastrocnemius muscle from HR x B6 F4 mice with whole-genome microarrays. Using genotypes from Aim 1, we will map eQTL that regulate significant variation in mRNA abundance. Aim 3: Identify candidate genes underlying QTL for voluntary exercise: Merging results from Aims 1 and 2, we will identify subsets of cis-acting eQTL that map under peaks of QTL for voluntary exercise, and for which the underlying expression phenotypes are correlated with voluntary exercise. These will be subjected to classical cis-trans tests to directly validate the presence of cis-acting regulatory variation within candidate genes for voluntary exercise predisposition. These synergistic and integrated methods, applied to a powerful polygenic mouse model that has undergone long-term selective breeding for increased running, offer a unique opportunity to evaluate the genetic architecture of predisposition to voluntary exercise. This research will discover QTL for voluntary exercise, a poorly understood yet important component of obesity and overall health, and advance to identify their underlying genes.

描述（由申请人提供）：运动引起代谢变化，包括体重减轻，甘油三酸酯和LDL水平的减少，HDL增加以及增强的胰岛素敏感性。中度的体育锻炼已被证明对预防心脏病，心脏病发作和中风具有有益作用，并被牵涉到某些癌症的预防措施。对复杂性状的遗传倾向，例如自愿运动的倾向，是由于多基因（称为定量性状基因座（QTL））内遗传变异的组合的影响。值得注意的是，在任何物种中尚无QTL自愿运动。在三个具体目标中，我们的目标是使用独特的多基因鼠标模型来识别QTL控制自愿锻炼及其基本的转录景观，以解决这一知识的差距：AIM 1：本地化QTL以进行自愿锻炼：我们将创建来自HR线的800只小鼠的F4人群，该小鼠源自HR线之间的杂交，源自HR，选择性地brepers for Voluntornary sorvelovers and c57bi/c57bi/c57bi/c57bi/c57bi/b6/b6。该人群将被表型用于自愿运动，热量摄入以及体重增加和身体成分。所有小鼠将针对768个均匀间隔且完全有信息的SNP标记进行基因分型。 AIM 2：自愿运动的本地化表达QTL（EQTL）：我们将评估来自HR X B6 F4小鼠的全基因组微阵列的海马和胃肌肌肉的全球基因表达。使用AIM 1的基因型，我们将绘制eqtl，以调节mRNA丰度的显着变化。 AIM 3：确定QTL的候选基因进行自愿运动：与目标1和2合并结果，我们将确定在QTL峰下映射的顺式作用EQTL子集以进行自愿运动，并且基础表达表型与自愿运动相关。这些将经过经典的顺式传播测试，以直接验证候选基因内的顺式作用调节变异是否具有自愿运动易感性。这些协同和集成的方法应用于强大的多基因小鼠模型，该模型经过长期选择性繁殖以增加运行，提供了一个独特的机会来评估自愿运动的易感性遗传结构。这项研究将发现自愿运动的QTL，这是肥胖和整体健康的知名度但重要的组成部分，并促进其识别其潜在基因。