Article

Mammalian Genome

, Volume 21, Issue 3, pp 115-129

First online:

Genetic resistance to diet-induced obesity in chromosome substitution strains of mice

  • Lindsay C. BurrageAffiliated withDepartment of Genetics, Case Western Reserve University School of MedicineDepartment of Pediatrics, University Hospitals Case Medical Center
  • , Annie E. Baskin-HillAffiliated withDepartment of Genetics, Case Western Reserve University School of Medicine
  • , David S. SinasacAffiliated withDepartment of Genetics, Case Western Reserve University School of MedicineBiochemical Genetics Laboratory, Alberta Children’s Hospital
  • , Jonathan B. SingerAffiliated withBroad Institute of MIT and Harvard UniversityClinical Pharmacogenetics, Novartis Institutes for Biomedical Research
  • , Colleen M. CronigerAffiliated withDepartment of Nutrition, Case Western Reserve University School of Medicine
  • , Andrew KirbyAffiliated withCenter for Human Genetics Research, MGH Simches Research Center
  • , E. J. KulbokasAffiliated withCenter for Human Genetics Research, MGH Simches Research Center
  • , Mark J. DalyAffiliated withCenter for Human Genetics Research, MGH Simches Research Center
  • , Eric S. LanderAffiliated withDepartment of Systems Biology, Harvard Medical School
    • , Karl W. BromanAffiliated withDepartment of Biostatistics and Medical Informatics, University of Wisconsin
    • , Joseph H. NadeauAffiliated withDepartment of Genetics, Case Western Reserve University School of Medicine Email author 

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Abstract

Discovery of genes that confer resistance to diseases such as diet-induced obesity could have tremendous therapeutic impact. We previously demonstrated that the C57BL/6J-ChrA/J/NaJ panel of chromosome substitution strains (CSSs) is a unique model for studying resistance to diet-induced obesity. In the present study, three replicate CSS surveys showed remarkable consistency, with 13 A/J-derived chromosomes reproducibly conferring resistance to high-fat-diet-induced obesity. Twenty CSS intercrosses, one derived from each of the 19 autosomes and chromosome X, were used to determine the number and location of quantitative trait loci (QTLs) on individual chromosomes and localized six QTLs. However, analyses of mean body weight in intercross progeny versus C57BL/6J provided strong evidence that many QTLs discovered in the CSS surveys eluded detection in these CSS intercrosses. Studies of the temporal effects of these QTLs suggest that obesity resistance was dynamic, with QTLs acting at different ages or after different durations of diet exposure. Thus, these studies provide insight into the genetic architecture of complex traits such as resistance to diet-induced obesity in the C57BL/6J-ChrA/J/NaJ CSSs. Because some of the QTLs detected in the CSS intercrosses were not detected using a traditional C57BL/6J × A/J intercross, our results demonstrate that surveys of CSSs and congenic strains derived from them are useful complementary tools for analyzing complex traits.