Skip to main content
SpringerLink
Log in

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

  • Published:
Mammalian Genome Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Allison DB, Kaprio J, Korkeila M, Koskenvuo M, Neale MC et al (1996) The heritability of body mass index among an international sample of monozygotic twins reared apart. Int J Obes Relat Metab Disord 20:501–506

    CAS  PubMed  Google Scholar 

  • Altshuler D, Daly MJ, Lander ES (2008) Genetic mapping in human disease. Science 322:881–888

    Article  CAS  PubMed  Google Scholar 

  • Ankra-Badu GA, Pomp D, Shriner D, Allison DB, Yi N (2009) Genetic influences on growth and body composition in mice: multilocus interactions. Int J Obes 33:89–95

    Article  CAS  Google Scholar 

  • Belknap JK (2003) Chromosome substitution strains: some quantitative considerations for genome scans and fine mapping. Mamm Genome 14:723–732

    Article  PubMed  Google Scholar 

  • Black BL, Croom J, Eisen EJ, Petro AE, Edwards CL et al (1998) Differential effects of fat and sucrose on body composition in A/J and C57BL/6 mice. Metabolism 47:1354–1359

    Article  CAS  PubMed  Google Scholar 

  • Brockmann GA, Bevova MR (2002) Using mouse models to dissect the genetics of obesity. Trends Genet 18:367–376

    Article  CAS  PubMed  Google Scholar 

  • Broman KW, Wu H, Sen S, Churchill GA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19:889–890

    Article  CAS  PubMed  Google Scholar 

  • Buchner DA, Burrage LC, Hill AE, Yazbek SN, O’Brien WE et al (2008) Resistance to diet-induced obesity in mice with a single substituted chromosome. Physiol Genomics 35:116–122

    Article  CAS  PubMed  Google Scholar 

  • Calzolari E, Patracchini P, Palazzi P, Aiello V, Ferlini A et al (1993) Characterization of a deleted Y chromosome in a male with Turner stigmata. Clin Genet 43:16–22

    CAS  PubMed  Google Scholar 

  • Castro A, Zambrano N, Kaune H, Madariaga M, Lopez P et al (2004) YqTER deletion causes arrest of spermatogenesis in early puberty. J Pediatr Endocrinol Metab 17:1675–1678

    CAS  PubMed  Google Scholar 

  • Cheverud JM, Routman EJ, Duarte FA, van Swinderen B, Cothran K et al (1996) Quantitative trait loci for murine growth. Genetics 142:1305–1319

    CAS  PubMed  Google Scholar 

  • Collins S, Martin TL, Surwit RS, Robidoux J (2004) Genetic vulnerability to diet-induced obesity in the C57BL/6J mouse: physiological and molecular characteristics. Physiol Behav 81:243–248

    Article  CAS  PubMed  Google Scholar 

  • De Rosa M, De Brasi D, Zarrilli S, Paesano L, Pivonello R et al (1997) Short stature and azoospermia in a patient with Y chromosome long arm deletion. J Endocrinol Invest 20:623–628

    PubMed  Google Scholar 

  • Farber CR, Aten JE, Farber EA, de Vera V, Gularte R et al (2009) Genetic dissection of a major mouse obesity QTL (Carfhg2): integration of gene expression and causality modeling. Physiol Genomics 37:294–302

    Article  PubMed  Google Scholar 

  • Gordon RR, Hunter KW, Sorensen P, Pomp D (2008) Genotype × diet interactions in mice predisposed to mammary cancer. I. Body weight and fat. Mamm Genome 19:163–178

    Article  CAS  PubMed  Google Scholar 

  • Hinney A, Nguyen TT, Scherag A, Friedel S, Brönner G et al (2007) Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One 2:e1361

    Article  PubMed  Google Scholar 

  • Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q et al (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141

    Article  CAS  PubMed  Google Scholar 

  • Ihaka R, Gentleman R (1996) A language for data analysis and graphics. J Comput Graph Stat 5:299–314

    Article  Google Scholar 

  • Kelly T, Yang W, Chen CS, Reynolds K, He J (2008) Global burden of obesity in 2005 and projections to 2030. Int J Obes 32:1431–1437

    Article  CAS  Google Scholar 

  • Koza RA, Nikonova L, Hogan J, Rim JS, Mendoza T et al (2006) Changes in gene expression foreshadow diet-induced obesity in genetically identical mice. PLoS Genet 2:e81

    Article  PubMed  Google Scholar 

  • Krude H, Biebermann H, Luck W, Horn R, Brabant G et al (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:155–157

    Article  CAS  PubMed  Google Scholar 

  • Lander ES, Botstein D (1989) Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121:185–199

    CAS  PubMed  Google Scholar 

  • Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247

    Article  CAS  PubMed  Google Scholar 

  • Lindgren CM, Heid IM, Randall JC, Lamina G, Steinthorsdottir V et al (2009) Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet 5:e10000508

    Article  Google Scholar 

  • Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH et al (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40:768–775

    Article  CAS  PubMed  Google Scholar 

  • Maes HH, Neale MC, Eaves LJ (1997) Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 27:325–351

    Article  CAS  PubMed  Google Scholar 

  • Malek RL, Wang HY, Kwitek AE, Greene AS, Bhagabati N (2006) Physiogenomic resources for rat models of heart, lung and blood disorders. Nat Genet 38:234–239

    Article  CAS  PubMed  Google Scholar 

  • Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA et al (2009) Finding the missing heritability of complex diseases. Nature 461:747–753

    Article  CAS  PubMed  Google Scholar 

  • Matin A, Collin GB, Asada Y, Varnum D, Nadeau JH (1999) Susceptibility to testicular germ-cell tumours in a 129.MOLF-Chr 19 chromosome substitution strain. Nat Genet 23(2):237–240

    Article  CAS  PubMed  Google Scholar 

  • Mills E, Kuhn CM, Feinglos MN, Surwit R (1993) Hypertension in C57BL/6J mouse model of non-insulin-dependent diabetes mellitus. Am J Physiol 264(1 Pt 2):R73–R78

    CAS  PubMed  Google Scholar 

  • Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H et al (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903–908

    Article  CAS  PubMed  Google Scholar 

  • Morgan TM, Krumholz HM, Lifton RP, Spertus JA (2007) Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study. JAMA 297:1551–1561

    Article  CAS  PubMed  Google Scholar 

  • Morris KH, Ishikawa A, Keightley PD (1999) Quantitative trait loci for growth traits in C57BL/6J × DBA/2J mice. Mamm Genome 10:225–228

    Article  CAS  PubMed  Google Scholar 

  • Mutch DM, Clement K (2006) Unraveling the genetics of human obesity. PLoS Genet 2:e188

    Article  PubMed  Google Scholar 

  • Nadeau JH, Singer JB, Matin A, Lander ES (2000) Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24:221–225

    Article  CAS  PubMed  Google Scholar 

  • National Institutes of Health (1998) Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. National Institutes of Health. Obesity Res 6(2):51S-209S

  • Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ et al (2006) Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 295:1549–1555

    Article  CAS  PubMed  Google Scholar 

  • Rebuffe-Scrive M, Surwit R, Feinglos M, Kuhn C, Rodin J (1993) Regional fat distribution and metabolism in a new mouse model (C57BL/6J) of non-insulin-dependent diabetes mellitus. Metabolism 42:1405–1409

    Article  CAS  PubMed  Google Scholar 

  • Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M (2008) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371:569–578

    Article  PubMed  Google Scholar 

  • Rocha JL, Eisen EJ, Van Vleck LD, Pomp D (2004) A large-sample QTL study in mice: I. Growth. Mamm Genome 15:83–99

    Article  CAS  PubMed  Google Scholar 

  • Schelbert B (2009) Comorbidities of obesity. Prim Care 36:271–285

    PubMed  Google Scholar 

  • Shao H, Burrage LC, Sinasac DS, Hill AE, Ernest SR et al (2008) Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis. Proc Natl Acad Sci USA 105:19910–19914

    Article  CAS  PubMed  Google Scholar 

  • Singer JB, Hill AE, Burrage LC, Olszens KR, Song J et al (2004) Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304:445–448

    Article  CAS  PubMed  Google Scholar 

  • Stylianou IM, Tsaih SW, DiPetrillo K, Ishimori N, Li R et al (2006) Complex genetic architecture revealed by analysis of high-density lipoprotein cholesterol in chromosome substitution strains and F2 crosses. Genetics 174:999–1007

    Article  CAS  PubMed  Google Scholar 

  • Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN (1988) Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37:1163–1167

    Article  CAS  PubMed  Google Scholar 

  • Surwit RS, Feinglos MN, Rodin J, Sutherland A, Petro AE et al (1995) Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism 44:645–651

    Article  CAS  PubMed  Google Scholar 

  • Vaisse C, Clement K, Guy-Grand B, Froguel P (1998) A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20:113–114

    Article  CAS  PubMed  Google Scholar 

  • Velissariou V, Sismani C, Christopoulou S, Kaminopetros P, Hatzaki A et al (2007) Loss of the Y chromosome PAR2 region and additional rearrangements in two familial cases of satellited Y chromosomes: cytogenetic and molecular analysis. Eur J Med Genet 50:291–300

    Article  CAS  PubMed  Google Scholar 

  • Vogel H, Nestler M, Ruschendorf F, Block M-D, Tischer S et al (2009) Characterization of Nob3, a major quantitative locus for obesity and hyperglycemia on mouse chromosome 1. Physiol Genomics 38:226–232

    Article  PubMed  Google Scholar 

  • Walley AJ, Asher JE, Froguel P (2009) The genetic contribution to non-syndromic human obesity. Nat Rev Genet 10:431–441

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Beydoun MA, Liang L, Caballero B, Kumanyika SK (2008) Will all Americans become overweight or obese? Estimating the progression and cost of the US obesity epidemic. Obesity 16:2323–2330

    Article  PubMed  Google Scholar 

  • Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM et al (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41:25–34

    Article  CAS  PubMed  Google Scholar 

  • Wuschke S, Dahm S, Schmidt C, Joost H-G, Al-Hasani H (2007) A meta-analysis of quantitative trait loci associated with body weight and adiposity in mice. Int J Obesity 31:829–841

    CAS  Google Scholar 

  • Yan LL, Daviglus ML, Liu K, Stamler J, Wang R et al (2006) Midlife body mass index and hospitalization and mortality in older age. JAMA 295:190–198

    Article  CAS  PubMed  Google Scholar 

  • Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG et al (1998) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20:111–112

    Article  CAS  PubMed  Google Scholar 

  • Youngren KK, Nadeau JH, Matin A (2003) Testicular cancer susceptibility in the 129.MOLF-Chr19 mouse strain: additive effects, gene interactions and epigenetic modifications. Hum Mol Genet 12:389–398

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Gershenfeld HK (2003) Genetic contributions to body weight in mice: relationship of exploratory behavior to weight. Obes Res 11:828–838

    Article  PubMed  Google Scholar 

  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L et al (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Gary Churchill for thoughtful discussions about this work, and Drs. Mark Adams, Richard Hanson, Matthew Warman, and Arthur Zinn for their critical comments of this article. We thank Nicole Nadeau and Christine Jimenez for their assistance. This work was funded by National Institutes of Health (T32 GM07250-30) (LCB), National Center for Research Resources (RR12305), National Cancer Institute (U54CA116867), and the Charles B. Wang Foundation. DSS was supported by a Canadian Diabetes Association Fellowship.

Author information

Author notes

  1. Lindsay C. Burrage

    Present address: Department of Pediatrics, University Hospitals Case Medical Center, Cleveland, OH, 44106, USA

  2. David S. Sinasac

    Present address: Biochemical Genetics Laboratory, Alberta Children’s Hospital, Calgary, Alberta, T3B 6A8, Canada

  3. Jonathan B. Singer

    Present address: Clinical Pharmacogenetics, Novartis Institutes for Biomedical Research, Cambridge, MA, 02139, USA

Authors and Affiliations

  1. Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Lindsay C. Burrage, Annie E. Baskin-Hill, David S. Sinasac & Joseph H. Nadeau

  2. Broad Institute of MIT and Harvard University, Cambridge, MA, 02142, USA

    Jonathan B. Singer

  3. Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Colleen M. Croniger

  4. Center for Human Genetics Research, MGH Simches Research Center, Boston, MA, 02114, USA

    Andrew Kirby, E. J. Kulbokas & Mark J. Daly

  5. Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA

    Eric S. Lander

  6. Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, 53706, USA

    Karl W. Broman

Authors
  1. Lindsay C. Burrage
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annie E. Baskin-Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David S. Sinasac
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan B. Singer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Colleen M. Croniger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew Kirby
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. J. Kulbokas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mark J. Daly
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eric S. Lander
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Karl W. Broman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Joseph H. Nadeau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph H. Nadeau.

Additional information

L. C. Burrage and A. E. Baskin-Hill contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 456 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burrage, L.C., Baskin-Hill, A.E., Sinasac, D.S. et al. Genetic resistance to diet-induced obesity in chromosome substitution strains of mice. Mamm Genome 21, 115–129 (2010). https://doi.org/10.1007/s00335-010-9247-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-010-9247-9

Keywords

Search

Navigation