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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK076050-03
Application #
7643165
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Karp, Robert W
Project Start
2007-07-05
Project End
2012-06-30
Budget Start
2009-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$286,160
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Nutrition
Type
Schools of Public Health
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kelly, Scott A; Zhao, Liyang; Jung, Kuo-Chen et al. (2017) Prevention of tumorigenesis in mice by exercise is dependent on strain background and timing relative to carcinogen exposure. Sci Rep 7:43086
Didion, John P; Morgan, Andrew P; Yadgary, Liran et al. (2016) R2d2 Drives Selfish Sweeps in the House Mouse. Mol Biol Evol 33:1381-95
Kelly, Scott A; Hua, Kunjie; Wallace, Jennifer N et al. (2015) Maternal exercise before and during pregnancy does not impact offspring exercise or body composition in mice. J Negat Results Biomed 14:13
Kelly, Scott A; Villena, Fernando Pardo-Manuel de; Pomp, Daniel (2015) The 'Omics' of Voluntary Exercise: Systems Approaches to a Complex Phenotype. Trends Endocrinol Metab 26:673-675
Kelly, Scott A; Nehrenberg, Derrick L; Hua, Kunjie et al. (2014) Quantitative genomics of voluntary exercise in mice: transcriptional analysis and mapping of expression QTL in muscle. Physiol Genomics 46:593-601
Gatti, Daniel M; Svenson, Karen L; Shabalin, Andrey et al. (2014) Quantitative trait locus mapping methods for diversity outbred mice. G3 (Bethesda) 4:1623-33
Kelly, Scott A; Pomp, Daniel (2013) Genetic determinants of voluntary exercise. Trends Genet 29:348-57
Leamy, Larry J; Kelly, Scott A; Hua, Kunjie et al. (2013) Quantitative trait loci for bone mineral density and femoral morphology in an advanced intercross population of mice. Bone 55:222-9
Kelly, Scott A; Bell, Timothy A; Selitsky, Sara R et al. (2013) A novel intronic single nucleotide polymorphism in the myosin heavy polypeptide 4 gene is responsible for the mini-muscle phenotype characterized by major reduction in hind-limb muscle mass in mice. Genetics 195:1385-95
Kelly, Scott A; Nehrenberg, Derrick L; Hua, Kunjie et al. (2012) Functional genomic architecture of predisposition to voluntary exercise in mice: expression QTL in the brain. Genetics 191:643-54

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