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

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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.

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References

  • GA Brockmann MR Bevova (2002) ArticleTitleUsing mouse models to dissect the genetics of obesity Trends Genet 18 367–376 Occurrence Handle10.1016/S0168-9525(02)02703-8 Occurrence Handle1:CAS:528:DC%2BD38XlsVOlsrY%3D Occurrence Handle12127777

    Article  CAS  PubMed  Google Scholar 

  • L Bünger WG Hill (1999) ArticleTitleInbred lines of mice derived from long-term divergent selection on fat content and body weight Mamm Genome 10 645–648 Occurrence Handle10.1007/s003359901063 Occurrence Handle10341104

    Article  PubMed  Google Scholar 

  • L Bünger J Forsting KL McDonald S Horvat J Duncan et al. (2003) ArticleTitleLong-term divergent selection on fatness in mice indicates a regulation system independent of leptin production and reception FASEB J 17 85–87 Occurrence Handle10.1096/fj.02-0111fje Occurrence Handle1:CAS:528:DC%2BD3sXlvFOgtA%3D%3D Occurrence Handle12424222

    Article  CAS  PubMed  Google Scholar 

  • S Cases SJ Smith YW Zheng HM Myers SR Lear et al. (1998) ArticleTitleIdentification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis Proc Natl Acad Sci USA 95 13018–13023 Occurrence Handle10.1073/pnas.95.22.13018 Occurrence Handle1:CAS:528:DyaK1cXntFWktbg%3D Occurrence Handle9789033 Occurrence Handle23692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • YC Chagnon T Rankinen EE Snyder SJ Weisnagel L Perusse et al. (2003) ArticleTitleThe human obesity gene map: the 2002 update Obes Res 11 313–367 Occurrence Handle10.1038/oby.2003.47 Occurrence Handle1:CAS:528:DC%2BD3sXisVKgtLY%3D Occurrence Handle12634430

    Article  CAS  PubMed  Google Scholar 

  • JM Cheverud EJ Routman FA Duarte K Swinderen B Cothran Particlevan et al. (1996) ArticleTitleQuantative trait loci for murine growth Genetics 142 1305–1319 Occurrence Handle8846907 Occurrence Handle1207127 Occurrence Handle1:CAS:528:DyaK28XivVGjur8%3D

    PubMed  PubMed Central  CAS  Google Scholar 

  • JM Cheverud TT Vaughn LS Pletscher AC Peripato ES Adams et al. (2001) ArticleTitleGenetic architecture of adiposity in the cross of LG/J and SM/J inbred mice Mamm Genome 12 3–12 Occurrence Handle10.1007/s003350010218 Occurrence Handle1:CAS:528:DC%2BD3MXptlGqsw%3D%3D Occurrence Handle11178736

    Article  CAS  PubMed  Google Scholar 

  • JK Christians VK Bingham FK Oliver TT Heath PD Keightley (2003) ArticleTitleCharacterization of a QTL affecting skeletal size in mice Mamm Genome 14 175–183 Occurrence Handle10.1007/s00335-002-3041-2 Occurrence Handle1:CAS:528:DC%2BD3sXitFCgt7o%3D Occurrence Handle12647240

    Article  CAS  PubMed  Google Scholar 

  • GA Churchill RW Doerge (1994) ArticleTitleEmpirical threshold values for quantitative trait mapping Genetics 138 963–971 Occurrence Handle7851788 Occurrence Handle1206241 Occurrence Handle1:STN:280:DyaK2M7lsVOiug%3D%3D

    PubMed  PubMed Central  CAS  Google Scholar 

  • A Darvasi (1997) ArticleTitleInterval-specific congenic strains (ISCS): an experimental design for mapping a QTL into a 1-centimorgan interval Mamm Genome 8 163–167 Occurrence Handle10.1007/s003359900382 Occurrence Handle1:CAS:528:DyaK2sXit1aqurg%3D Occurrence Handle9069114

    Article  CAS  PubMed  Google Scholar 

  • DW Drolet KM Scully DM Simmons M Wegner KT Chu et al. (1991) ArticleTitleTEF, a transcription factor expressed specifically in the anterior pituitary during embryogenesis, defines a new class of leucine zipper proteins Genes Dev 5 1739–1753 Occurrence Handle10.1101/gad.5.10.1739 Occurrence Handle1:CAS:528:DyaK38XmtlSktb8%3D Occurrence Handle1916262

    Article  CAS  PubMed  Google Scholar 

  • SM Duthie PL Taylor L Anderson J Cook KA Eidne (1993) ArticleTitleCloning and functional characterisation of the human TRH receptor Mol Cell Endocrinol 95 R11–R15 Occurrence Handle10.1016/0303-7207(93)90043-J Occurrence Handle1:CAS:528:DyaK2cXht1Ggsb8%3D Occurrence Handle8243797

    Article  CAS  PubMed  Google Scholar 

  • SO Freytag TJ Geddes (1992) ArticleTitleReciprocal regulation of adipogenesis by Myc and C/EBP alpha Science 256 379–382 Occurrence Handle10.1126/science.256.5055.379 Occurrence Handle1:CAS:528:DyaK38XisV2rsrs%3D Occurrence Handle1566086

    Article  CAS  PubMed  Google Scholar 

  • JZ Gu X Lin DE Wells (1996) ArticleTitleThe human B22 subunit of the NADH-ubiquinone oxidoreductase maps to the region of chromosome 8 involved in branchio-oto-renal syndrome Genomics 35 6–10 Occurrence Handle10.1006/geno.1996.0316 Occurrence Handle1:CAS:528:DyaK28Xkt12qsrs%3D Occurrence Handle8661098

    Article  CAS  PubMed  Google Scholar 

  • CS Haley SA Knott (1992) ArticleTitleA simple regression method for mapping quantitative trait loci in line crosses using flanking markers Heredity 69 315–324 Occurrence Handle10.1038/hdy.1992.131 Occurrence Handle1:STN:280:DC%2BD283ovFaltQ%3D%3D Occurrence Handle16718932

    Article  CAS  PubMed  Google Scholar 

  • J Hasegawa K Osatomi RF Wu K Uyeda (1999) ArticleTitleA novel factor binding to the glucose response elements of liver pyruvate kinase and fatty acid synthase genes J Biol Chem 274 1100–1107 Occurrence Handle10.1074/jbc.274.2.1100 Occurrence Handle1:CAS:528:DyaK1MXmtFGksw%3D%3D Occurrence Handle9873057

    Article  CAS  PubMed  Google Scholar 

  • IM Hastings WG Hill (1989) ArticleTitleA note on the effect of different selection criteria on carcass composition in mice Anim Prod 48 229–233 Occurrence Handle10.1017/S0003356100003949

    Article  Google Scholar 

  • S Hofmann P Lichtner S Schuffenhauer KD Gerbitz T Meitinger (1998) ArticleTitleAssignment 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 141 Cytogenet Cell Genet 83 226–227 Occurrence Handle10.1159/000015185 Occurrence Handle1:CAS:528:DyaK1MXitFCjtbw%3D Occurrence Handle10072584

    Article  CAS  PubMed  Google Scholar 

  • S Horvat L Bünger VM Falconer P Mackay A Law et al. (2000) ArticleTitleMapping of obesity QTLs in a cross between mouse lines divergently selected on fat content Mamm Genome 11 2–7 Occurrence Handle10.1007/s003350010002 Occurrence Handle1:CAS:528:DC%2BD3cXos12iug%3D%3D Occurrence Handle10602985

    Article  CAS  PubMed  Google Scholar 

  • CO Ikeobi JA Woolliams DR Morrice A Law D Windsor et al. (2002) ArticleTitleQuantitative trait loci affecting fatness in the chicken Anim Genet 33 428–435 Occurrence Handle10.1046/j.1365-2052.2002.00911.x Occurrence Handle1:CAS:528:DC%2BD3sXjslyhu7g%3D Occurrence Handle12464017

    Article  CAS  PubMed  Google Scholar 

  • PD Keightley KH Morris A Ishikawa VM Falconer F Oliver (1998) ArticleTitleTest of candidate gene—quantitative trait locus association applied to fatness in mice Heredity 81 630–637 Occurrence Handle10.1046/j.1365-2540.1998.00450.x Occurrence Handle9885188

    Article  PubMed  Google Scholar 

  • K Kosuga S Hata T Osumi J Sakakibara T Ono (1995) ArticleTitleNucleotide sequence of a cDNA for mouse squalene epoxidase Biochim Biophys Acta 1260 345–348 Occurrence Handle10.1016/0167-4781(94)00245-X Occurrence Handle7873613

    Article  PubMed  Google Scholar 

  • PW Laird A Zijderveld K Linders MA Rudnicki R Jaenisch et al. (1991) ArticleTitleSimplified mammalian DNA isolation procedure Nucleic Acids Res 19 4293 Occurrence Handle10.1093/nar/19.15.4293 Occurrence Handle1:CAS:528:DyaK3MXlslKltb0%3D Occurrence Handle1870982 Occurrence Handle328579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • ES Lander P Green (1987) ArticleTitleConstruction of multilocus genetic linkage maps in humans Proc Natl Acad Sci USA 84 2363–2367 Occurrence Handle10.1073/pnas.84.8.2363 Occurrence Handle1:STN:280:DyaL2s7nsFKksQ%3D%3D Occurrence Handle3470801 Occurrence Handle304651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • AS Law AL Archibald (2000) ArticleTitleFarm animal genome databases Brief Bioinform 1 151–160 Occurrence Handle10.1093/bib/1.2.151 Occurrence Handle1:CAS:528:DC%2BD3cXlsV2ktb4%3D Occurrence Handle11465026

    Article  CAS  PubMed  Google Scholar 

  • ME Legare FS Bartlett WN Frankel (2000) ArticleTitleA major effect QTL determined by multiple genes in epileptic EL mice Genome Res 10 42–48 Occurrence Handle10645948 Occurrence Handle310503 Occurrence Handle1:CAS:528:DC%2BD3cXpslyquw%3D%3D

    PubMed  PubMed Central  CAS  Google Scholar 

  • M Mehrabian PZ Wen J Fisler RC Davis AJ Lusis (1998) ArticleTitleGenetic loci controlling body fat, lipoprotein metabolism, and insulin levels in a multifactorial mouse model J Clin Investig 101 2485–2496 Occurrence Handle10.1172/JCI1748 Occurrence Handle1:CAS:528:DyaK1cXjvVajsbs%3D Occurrence Handle9616220 Occurrence Handle508838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • KH Morris A Ishikawa PD Keightley (1999) ArticleTitleQuantitative trait loci for growth traits in C57BL/6J × DBA/2] mice Mamm Genome 10 225–228 Occurrence Handle10.1007/s003359900977 Occurrence Handle1:CAS:528:DyaK1MXhs1OlsLw%3D Occurrence Handle10051315

    Article  CAS  PubMed  Google Scholar 

  • D Pomp (1997) ArticleTitleGenetic dissection of obesity in polygenic animal models Behav Genet 27 285–306 Occurrence Handle10.1023/A:1025631813018 Occurrence Handle1:STN:280:DyaK1c7otVSrtQ%3D%3D Occurrence Handle9519558

    Article  CAS  PubMed  Google Scholar 

  • T Rankinen L Perusse SJ Weisnagel EE Snyder YC Chagnon (2002) ArticleTitleThe human obesity gene map: the 2001 update Obes Res 10 196–243 Occurrence Handle10.1038/oby.2002.30 Occurrence Handle1:CAS:528:DC%2BD38XisFGlu78%3D Occurrence Handle11886943

    Article  CAS  PubMed  Google Scholar 

  • InstitutionalAuthorNameSAS Institute (1989) SAS/STAT User’s Guide, Version 6, 4th, ed, Volume 2 SAS Institute Inc. Cary, NC

    Google Scholar 

  • A Sewalem DM Morrice A Law D Windsor CS Haley et al. (2002) ArticleTitleMapping of quantitative trait loci for body weight at three, six, and nine weeks of age in a broiler layer cross Poult Sci 81 1775–1781 Occurrence Handle10.1093/ps/81.12.1775 Occurrence Handle1:STN:280:DC%2BD3s%2Fgs1Gmug%3D%3D Occurrence Handle12512565

    Article  CAS  PubMed  Google Scholar 

  • GL Sharp WG Hill A Robertson (1984) ArticleTitleEffects of selection on growth, body composition and food intake in mice. I. Responses in selected traits Genet Res 43 75–92 Occurrence Handle10.1017/S0016672300025738 Occurrence Handle1:STN:280:DyaL2c3gvFynsw%3D%3D Occurrence Handle6724302

    Article  CAS  PubMed  Google Scholar 

  • BA Taylor L Rowe (1987) ArticleTitleThe congenital goiter mutation is linked to the thyroglobulin gene in the mouse Proc Natl Acad Sci USA 84 1986–1990 Occurrence Handle10.1073/pnas.84.7.1986 Occurrence Handle1:STN:280:DyaL2s7nsFGqug%3D%3D Occurrence Handle2882514 Occurrence Handle304567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • JB Kaam ParticleVan MA Groenen H Bovenhuis A Veenendaal AL Vereijken et al. (1999) ArticleTitleWhole genome scan in chickens for quantitative trait loci affecting growth and feed efficiency Poult Sci 78 15–23 Occurrence Handle10.1093/ps/78.1.15 Occurrence Handle10023741

    Article  PubMed  Google Scholar 

  • PM Visscher CS Haley (1996) ArticleTitleDetection of putative quantitative trait loci in line crosses under infinitesimal genetic models Theor App Gene 93 691–702 Occurrence Handle10.1007/BF00224064 Occurrence Handle1:STN:280:DC%2BC2c7gt1Wkuw%3D%3D

    Article  CAS  Google Scholar 

  • PM Visscher R Thompson CS. Haley (1996) ArticleTitleConfidence intervals in QTL mapping by bootstrapping Genetics 143 1013–1020 Occurrence Handle8725246 Occurrence Handle1207319 Occurrence Handle1:CAS:528:DyaK28XjvV2htb4%3D

    PubMed  PubMed Central  CAS  Google Scholar 

  • Y Wang PE Kowalski I Thalmann DM Ornitz DL Mager (1998) ArticleTitleOtoconin-90, the mammalian otoconial matrix protein, contains two domains of homology to secretory phospholipase A2 Proc Natl Acad Sci USA 95 15345–15350 Occurrence Handle10.1073/pnas.95.26.15345 Occurrence Handle1:CAS:528:DyaK1MXhvFalsw%3D%3D Occurrence Handle9860971 Occurrence Handle28045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • CH Warden JS Fisler SM Shoemaker PZ Wen KL Svenson et al. (1995) ArticleTitleIdentification of four chromosomal loci determining obesity in a multifactorial mouse model J Clin Investig 95 1545–1552 Occurrence Handle10.1172/JCI117827 Occurrence Handle1:CAS:528:DyaK2MXkslyktrw%3D Occurrence Handle7706460 Occurrence Handle295638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DB West J Goudey-Lefevre B York GE Truett (1994) ArticleTitleDietary obesity linked to genetic loci on chromosomes 9 and 15 in a polygenic mouse model J Clin Investig 94 1410–1416 Occurrence Handle10.1172/JCI117477 Occurrence Handle1:CAS:528:DyaK2cXmvFCiu70%3D Occurrence Handle7929816 Occurrence Handle295268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • WHO-World Health Organisation. Anonymous. Controlling the global obesity epidemic. (2003 Jun). WHO/NHD/00.6

  • B York K Lei DB West (1996) ArticleTitleSensitivity to dietary obesity linked to a locus on chromosome 15 in a CAST/Ei × C57BL/6J F2 intercross Mamm Genome 7 677–681 Occurrence Handle10.1007/s003359900204 Occurrence Handle1:CAS:528:DyaK28XmvFOjurc%3D Occurrence Handle8703121

    Article  CAS  PubMed  Google Scholar 

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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.

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Authors and Affiliations

  1. Roslin Institute (Edinburgh), Roslin, EH25 9PS, Scotland, UK

    Ioannis M. Stylianou, Michael Clinton, Grahame Bulfield & Simon Horvat

  2. Institute of Cell, Animal and Population Biology, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JT, Scotland, UK

    Ioannis M. Stylianou, Julian K. Christians, Peter D. Keightley & Grahame Bulfield

  3. Animal Breeding & Development, Sustainable Livestock Systems, SAC, Bush Estate, Penicuik Midlothian, EH26 0PH, UK

    Lutz Bünger

  4. Biotechnical Faculty, Zootechnical Department, University of Ljubljana, Domzale, 1230, Slovenia

    Simon Horvat

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  1. Ioannis M. Stylianou
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  2. Julian K. Christians
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  3. Peter D. Keightley
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  4. Lutz Bünger
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  6. Grahame Bulfield
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Correspondence to Simon Horvat.

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Stylianou, I.M., Christians, J.K., Keightley, P.D. et al. Genetic complexity of an obesity QTL (Fob3) revealedby detailed genetic mapping. Mamm Genome 15, 472–481 (2004). https://doi.org/10.1007/s00335-004-3039-z

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