Abstract

The investigator proposes to fine-map and positionally clone quantitative trait loci (QTLs) responsible for variation in body size and obesity in the cross of LG/J by SM/J inbred mouse strains. The use of animal models for mapping obesity-related genes has several advantages relative to working in human populations. Principally, powerful, replicable experimental designs are available for gene mapping and validation. Under previous support, 11 QTLs for body size in a replicate F2 intercross population have been confirmed and it has been determined which of these QTLs affects adiposity levels. The investigator is narrowing QTL support intervals in the F10 generation of an Advanced Intercross (AI) line from 20 cM to less than 5 cM. Under the present proposal, the QTL support intervals will be further limited to approximately 1 cM by saturation mapping in the F7 and F10 AI line generations, by performing Recombinant Inbred Segregation Tests and forming congenic strains. In addition, previously cloned candidate genes will be sequenced to determine whether they show molecular polymorphism between the LG/J and SM/J strains. Once support intervals reach the 1 cM level, positional cloning will be performed using bacterial artificial chromosomes (BACs). When a compelling candidate gene is identified by database searches or positional cloning, it will be tested using the quantitative hybrid complementation test. In addition to positional cloning of the QTLs, congenic strains will be formed for each QTL and will be tested, along with the LGxSM recombinant inbred strains for a variety of obesity-related traits.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052514-06
Application #
6517414
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Yanovski, Susan Z
Project Start
1997-05-15
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2004-04-30
Support Year
6
Fiscal Year
2002
Total Cost
$263,529
Indirect Cost

  Institution

Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Tarakanova, Vera L; Leung-Pineda, Van; Hwang, Seungmin et al. (2007) Gamma-herpesvirus kinase actively initiates a DNA damage response by inducing phosphorylation of H2AX to foster viral replication. Cell Host Microbe 1:275-86
Kenney-Hunt, Jane P; Vaughn, Ty T; Pletscher, L Susan et al. (2006) Quantitative trait loci for body size components in mice. Mamm Genome 17:526-37
Kardia, Sharon L R; Bielak, Lawrence F; Lange, Leslie A et al. (2006) Epistatic effects between two genes in the renin-angiotensin system and systolic blood pressure and coronary artery calcification. Med Sci Monit 12:CR150-8
Ehrich, Thomas H; Kenney-Hunt, Jane P; Pletscher, L Susan et al. (2005) Genetic variation and correlation of dietary response in an advanced intercross mouse line produced from two divergent growth lines. Genet Res 85:211-22
Wolf, Jason B; Leamy, Larry J; Routman, Eric J et al. (2005) Epistatic pleiotropy and the genetic architecture of covariation within early and late-developing skull trait complexes in mice. Genetics 171:683-94
Ehrich, Thomas H; Hrbek, Tomas; Kenney-Hunt, Jane P et al. (2005) Fine-mapping gene-by-diet interactions on chromosome 13 in a LG/J x SM/J murine model of obesity. Diabetes 54:1863-72
Leamy, L J; Workman, M S; Routman, E J et al. (2005) An epistatic genetic basis for fluctuating asymmetry of tooth size and shape in mice. Heredity 94:316-25
Zhao, Wei; Chen, Ying Q; Casella, George et al. (2005) A non-stationary model for functional mapping of complex traits. Bioinformatics 21:2469-77
Wu, Rongling; Ma, Chang-Xing; Hou, Wei et al. (2005) Functional mapping of quantitative trait loci that interact with the hg mutation to regulate growth trajectories in mice. Genetics 171:239-49
Jarvis, Joseph P; Kenney-Hunt, Jane; Ehrich, Thomas H et al. (2005) Maternal genotype affects adult offspring lipid, obesity, and diabetes phenotypes in LGXSM recombinant inbred strains. J Lipid Res 46:1692-702

Showing the most recent 10 out of 26 publications