Genetic Architecture of Voluntary Exercise in Mice

小鼠自愿运动的遗传结构

基本信息

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
项目类别：
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

项目摘要

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）：运动会引起代谢变化，包括体重减轻、甘油三酯和低密度脂蛋白水平降低、高密度脂蛋白增加以及胰岛素敏感性增强。适度的体力活动已被证明对预防心脏病、心脏病发作和中风具有有益作用，并且被认为可以作为某些癌症的预防措施。复杂性状的遗传易感性，例如自愿锻炼的倾向，是由许多多基因（称为数量性状基因座（QTL））内的遗传变异组合的影响造成的。值得注意的是，目前还没有关于任何物种自愿行使 QTL 的报道。在三个具体目标中，我们的目标是通过使用独特的多基因小鼠模型识别控制自愿运动的 QTL 及其潜在的转录景观来解决这一知识空白：目标 1：定位用于自愿运动的 QTL：我们将创建一个 F4 群体800 只小鼠源自 HR 系和 C57BI/6J (B6) 之间的杂交，经过选择性培育以增加自主运动。该人群将针对自愿运动、热量摄入、体重增加和身体成分进行表型分析。所有小鼠都将针对 768 个均匀分布且信息丰富的 SNP 标记进行基因分型。目标 2：定位自愿运动的表达 QTL (eQTL)：我们将使用全基因组微阵列评估 HR x B6 F4 小鼠海马和腓肠肌的整体基因表达。使用目标 1 中的基因型，我们将绘制调节 mRNA 丰度显着变化的 eQTL。目标 3：识别自愿运动 QTL 的候选基因：合并目标 1 和 2 的结果，我们将识别顺式作用 eQTL 的子集，这些子集映射在自愿运动 QTL 的峰值下，并且其潜在表达表型与自愿运动相关锻炼。这些将接受经典的顺式-反式测试，以直接验证自愿运动倾向候选基因中顺式作用调节变异的存在。这些协同和综合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育种以提高跑步能力，为评估自愿运动倾向的遗传结构提供了独特的机会。这项研究将发现自愿锻炼的 QTL，这是肥胖和整体健康的一个鲜为人知但重要的组成部分，并进一步确定其潜在基因。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Quantitative trait loci for energy balance traits in an advanced intercross line derived from mice divergently selected for heat loss.

来自不同选择热损失的小鼠的高级杂交品系中能量平衡性状的数量性状位点。

DOI：
10.7717/peerj.392
发表时间：
2014
期刊：
PeerJ
影响因子：
2.7
作者：
Leamy LJ;Elo K;Nielsen MK;Thorn SR;Valdar W;Pomp D
通讯作者：
Pomp D

Exercise and diet affect quantitative trait loci for body weight and composition traits in an advanced intercross population of mice.

DOI：
10.1152/physiolgenomics.00115.2012
发表时间：
2012-12
期刊：
Physiological genomics
影响因子：
4.6
作者：
L. Leamy;S. A. Kelly;K. Hua;D. Pomp
通讯作者：
L. Leamy;S. A. Kelly;K. Hua;D. Pomp

Quantitative genomics of voluntary exercise in mice: transcriptional analysis and mapping of expression QTL in muscle.

小鼠自愿运动的定量基因组学：转录分析和肌肉中表达 QTL 的定位。

DOI：
10.1152/physiolgenomics.00023.2014
发表时间：
2014
期刊：
Physiological genomics
影响因子：
4.6
作者：
Kelly,ScottA;Nehrenberg,DerrickL;Hua,Kunjie;GarlandJr,Theodore;Pomp,Daniel
通讯作者：
Pomp,Daniel

Functional genomic architecture of predisposition to voluntary exercise in mice: expression QTL in the brain.

小鼠自愿运动倾向的功能基因组结构：大脑中的表达 QTL。

DOI：
10.1534/genetics.112.140509
发表时间：
2012
期刊：
Genetics
影响因子：
3.3
作者：
Kelly,ScottA;Nehrenberg,DerrickL;Hua,Kunjie;GarlandJr,Theodore;Pomp,Daniel
通讯作者：
Pomp,Daniel

Parent-of-origin effects on voluntary exercise levels and body composition in mice.

父母来源对小鼠自愿运动水平和身体成分的影响。

DOI：
10.1152/physiolgenomics.00139.2009
发表时间：
2010
期刊：
Physiological genomics
影响因子：
4.6
作者：
Kelly,ScottA;Nehrenberg,DerrickL;Hua,Kunjie;Gordon,RyanR;GarlandJr,Theodore;Pomp,Daniel
通讯作者：
Pomp,Daniel