Advertisement

Mammalian Genome

, Volume 15, Issue 6, pp 472–481 | Cite as

Genetic complexity of an obesity QTL (Fob3) revealedby detailed genetic mapping

  • Ioannis M. Stylianou
  • Julian K. Christians
  • Peter D. Keightley
  • Lutz Bünger
  • Michael Clinton
  • Grahame Bulfield
  • Simon Horvat
Article

Abstract

Obesity is proving to be a serious health concern in the developed world as well as an unwanted component of growth in livestock production. While recent advances in genetics have identified a number of monogenic causes of obesity, these are responsible for only a small proportion of human cases of obesity. By divergent selection for high and low fat content over 60 generations, we have created Fat (F) and Lean (L) lines of mice that represent a model of polygenic obesity similar to the situation in human populations. From previous crosses of these lines, four body fat quantitative trait loci (QTL) were identified. We have created congenic lines (Fchr15L), by recurrent marker-assisted backcrossing, to introgress the QTL region with the highest LOD score, Fob3 on Chr 15, from the L-Iine into the F-line background. We have further mapped this QTL by progeny testing of recombinants, produced from crosses between the F-line and congenic Fchrl5L mice, showing that the Fob3 QTL region is a composite of at least two smaller effect QTL—the proximal QTL Fob3a is a late-onset obesity QTL, whereas the distal Fob3b is an early-onset obesity QTL.

Keywords

Quantitative Trait Locus Quantitative Trait Locus Analysis Dominance Effect Quantitative Trait Locus Region Significant Quantitative Trait Locus 

Notes

Acknowledgments

We are grateful to Pamela Mackay for help with genotyping the congenic lines and to Adrian White for technical assistance in the mouse facility. This project was supported by a BBSRC grant number 15/G12499 and the BBSRC Roslin Institute core strategic grant.

References

  1. Brockmann, GA, Bevova, MR 2002Using mouse models to dissect the genetics of obesityTrends Genet18367376CrossRefGoogle Scholar
  2. Bünger, L, Hill, WG 1999Inbred lines of mice derived from long-term divergent selection on fat content and body weightMamm Genome10645648CrossRefGoogle Scholar
  3. Bünger, L, Forsting, J, McDonald, KL, Horvat, S, Duncan, J,  et al. 2003Long-term divergent selection on fatness in mice indicates a regulation system independent of leptin production and receptionFASEB J178587CrossRefGoogle Scholar
  4. Cases, S, Smith, SJ, Zheng, YW, Myers, HM, Lear, SR,  et al. 1998Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesisProc Natl Acad Sci USA951301813023CrossRefGoogle Scholar
  5. Chagnon, YC, Rankinen, T, Snyder, EE, Weisnagel, SJ, Perusse, L,  et al. 2003The human obesity gene map: the 2002 updateObes Res11313367CrossRefGoogle Scholar
  6. Cheverud, JM, Routman, EJ, Duarte, FA, Swinderen B Cothran, K,  et al. 1996Quantative trait loci for murine growthGenetics14213051319PubMedPubMedCentralGoogle Scholar
  7. Cheverud, JM, Vaughn, TT, Pletscher, LS, Peripato, AC, Adams, ES,  et al. 2001Genetic architecture of adiposity in the cross of LG/J and SM/J inbred miceMamm Genome12312CrossRefGoogle Scholar
  8. Christians, JK, Bingham, VK, Oliver, FK, Heath, TT, Keightley, PD 2003Characterization of a QTL affecting skeletal size in miceMamm Genome14175183CrossRefGoogle Scholar
  9. Churchill, GA, Doerge, RW 1994Empirical threshold values for quantitative trait mappingGenetics138963971PubMedPubMedCentralGoogle Scholar
  10. Darvasi, A 1997Interval-specific congenic strains (ISCS): an experimental design for mapping a QTL into a 1-centimorgan intervalMamm Genome8163167CrossRefGoogle Scholar
  11. Drolet, DW, Scully, KM, Simmons, DM, Wegner, M, Chu, KT,  et al. 1991TEF, a transcription factor expressed specifically in the anterior pituitary during embryogenesis, defines a new class of leucine zipper proteinsGenes Dev517391753CrossRefGoogle Scholar
  12. Duthie, SM, Taylor, PL, Anderson, L, Cook, J, Eidne, KA 1993Cloning and functional characterisation of the human TRH receptorMol Cell Endocrinol95R11R15CrossRefGoogle Scholar
  13. Freytag, SO, Geddes, TJ 1992Reciprocal regulation of adipogenesis by Myc and C/EBP alphaScience256379382CrossRefGoogle Scholar
  14. Gu, JZ, Lin, X, Wells, DE 1996The human B22 subunit of the NADH-ubiquinone oxidoreductase maps to the region of chromosome 8 involved in branchio-oto-renal syndromeGenomics35610CrossRefGoogle Scholar
  15. Haley, CS, Knott, SA 1992A simple regression method for mapping quantitative trait loci in line crosses using flanking markersHeredity69315324CrossRefGoogle Scholar
  16. Hasegawa, J, Osatomi, K, Wu, RF, Uyeda, K 1999A novel factor binding to the glucose response elements of liver pyruvate kinase and fatty acid synthase genesJ Biol Chem27411001107CrossRefGoogle Scholar
  17. Hastings, IM, Hill, WG 1989A note on the effect of different selection criteria on carcass composition in miceAnim Prod48229233CrossRefGoogle Scholar
  18. Hofmann, S, Lichtner, P, Schuffenhauer, S, Gerbitz, KD, Meitinger, T 1998Assignment of the human genes coding for cytochrome c oxidase subunits Va (COX5A), VIc (COX6C) and VIIc (COX7C) to chromosome bands 15q25, 8q22→;q23 and 5ql4 and of three pseudogenes (COX5AP1, COX6CP1, COX7CP1) to 14q22, 16pl2 and 13q14→;q21 by FISH and radiation hybrid mapping 141Cytogenet Cell Genet83226227CrossRefGoogle Scholar
  19. Horvat, S, Bünger, L, Falconer, VM, Mackay, P, Law, A,  et al. 2000Mapping of obesity QTLs in a cross between mouse lines divergently selected on fat contentMamm Genome1127CrossRefGoogle Scholar
  20. Ikeobi, CO, Woolliams, JA, Morrice, DR, Law, A, Windsor, D,  et al. 2002Quantitative trait loci affecting fatness in the chickenAnim Genet33428435CrossRefGoogle Scholar
  21. Keightley, PD, Morris, KH, Ishikawa, A, Falconer, VM, Oliver, F 1998Test of candidate gene—quantitative trait locus association applied to fatness in miceHeredity81630637CrossRefGoogle Scholar
  22. Kosuga, K, Hata, S, Osumi, T, Sakakibara, J, Ono, T 1995Nucleotide sequence of a cDNA for mouse squalene epoxidaseBiochim Biophys Acta1260345348CrossRefGoogle Scholar
  23. Laird, PW, Zijderveld, A, Linders, K, Rudnicki, MA, Jaenisch, R,  et al. 1991Simplified mammalian DNA isolation procedureNucleic Acids Res194293CrossRefGoogle Scholar
  24. Lander, ES, Green, P 1987Construction of multilocus genetic linkage maps in humansProc Natl Acad Sci USA8423632367CrossRefGoogle Scholar
  25. Law, AS, Archibald, AL 2000Farm animal genome databasesBrief Bioinform1151160CrossRefGoogle Scholar
  26. Legare, ME, Bartlett, FS, Frankel, WN 2000A major effect QTL determined by multiple genes in epileptic EL miceGenome Res104248PubMedPubMedCentralGoogle Scholar
  27. Mehrabian, M, Wen, PZ, Fisler, J, Davis, RC, Lusis, AJ 1998Genetic loci controlling body fat, lipoprotein metabolism, and insulin levels in a multifactorial mouse modelJ Clin Investig10124852496CrossRefGoogle Scholar
  28. Morris, KH, Ishikawa, A, Keightley, PD 1999Quantitative trait loci for growth traits in C57BL/6J × DBA/2] miceMamm Genome10225228CrossRefGoogle Scholar
  29. Pomp, D 1997Genetic dissection of obesity in polygenic animal modelsBehav Genet27285306CrossRefGoogle Scholar
  30. Rankinen, T, Perusse, L, Weisnagel, SJ, Snyder, EE, Chagnon, YC 2002The human obesity gene map: the 2001 updateObes Res10196243CrossRefGoogle Scholar
  31. SAS Institute 1989SAS/STAT User’s Guide, Version 6, 4th, ed, Volume 2SAS Institute Inc.Cary, NCGoogle Scholar
  32. Sewalem, A, Morrice, DM, Law, A, Windsor, D, Haley, CS,  et al. 2002Mapping of quantitative trait loci for body weight at three, six, and nine weeks of age in a broiler layer crossPoult Sci8117751781CrossRefGoogle Scholar
  33. Sharp, GL, Hill, WG, Robertson, A 1984Effects of selection on growth, body composition and food intake in mice. I. Responses in selected traitsGenet Res437592CrossRefGoogle Scholar
  34. Taylor, BA, Rowe, L 1987The congenital goiter mutation is linked to the thyroglobulin gene in the mouseProc Natl Acad Sci USA8419861990CrossRefGoogle Scholar
  35. Kaam, JB, Groenen, MA, Bovenhuis, H, Veenendaal, A, Vereijken, AL,  et al. 1999Whole genome scan in chickens for quantitative trait loci affecting growth and feed efficiencyPoult Sci781523CrossRefGoogle Scholar
  36. Visscher, PM, Haley, CS 1996Detection of putative quantitative trait loci in line crosses under infinitesimal genetic modelsTheor App Gene93691702CrossRefGoogle Scholar
  37. Visscher, PM, Thompson, R, Haley, CS. 1996Confidence intervals in QTL mapping by bootstrappingGenetics14310131020PubMedPubMedCentralGoogle Scholar
  38. Wang, Y, Kowalski, PE, Thalmann, I, Ornitz, DM, Mager, DL 1998Otoconin-90, the mammalian otoconial matrix protein, contains two domains of homology to secretory phospholipase A2Proc Natl Acad Sci USA951534515350CrossRefGoogle Scholar
  39. Warden, CH, Fisler, JS, Shoemaker, SM, Wen, PZ, Svenson, KL,  et al. 1995Identification of four chromosomal loci determining obesity in a multifactorial mouse modelJ Clin Investig9515451552CrossRefGoogle Scholar
  40. West, DB, Goudey-Lefevre, J, York, B, Truett, GE 1994Dietary obesity linked to genetic loci on chromosomes 9 and 15 in a polygenic mouse modelJ Clin Investig9414101416CrossRefGoogle Scholar
  41. WHO-World Health Organisation. Anonymous. Controlling the global obesity epidemic. (2003 Jun). WHO/NHD/00.6Google Scholar
  42. York, B, Lei, K, West, DB 1996Sensitivity to dietary obesity linked to a locus on chromosome 15 in a CAST/Ei × C57BL/6J F2 intercrossMamm Genome7677681CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Ioannis M. Stylianou
    • 1
    • 2
  • Julian K. Christians
    • 2
  • Peter D. Keightley
    • 2
  • Lutz Bünger
    • 3
  • Michael Clinton
    • 1
  • Grahame Bulfield
    • 1
    • 2
  • Simon Horvat
    • 1
    • 4
  1. 1.Roslin Institute (Edinburgh)ScotlandUK
  2. 2.Institute of Cell, Animal and Population BiologyUniversity of EdinburghScotlandUK
  3. 3.Animal Breeding & Development, Sustainable Livestock SystemsSACUK
  4. 4.Biotechnical Faculty, Zootechnical DepartmentUniversity of LjubljanaDomzaleSlovenia

Personalised recommendations