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Mammalian Genome

, Volume 15, Issue 2, pp 100–113 | Cite as

A large-sample QTL study in mice: II. Body composition

  • Joao L. Rocha
  • Eugene J. Eisen
  • L. Dale Van Vleck
  • Daniel Pomp
Article

Abstract

Using lines of mice having undergone long-term selection for high and low growth, a large-sample (n = ~1,000 F2) experiment was conducted to gain further understanding of the genetic architecture of complex polygenic traits. Composite interval mapping on data from male F2 mice (n = 552) detected 50 QTL on 15 chromosomes impacting weights of various organ and adipose subcomponents of growth, including heart, liver, kidney, spleen, testis, and subcutaneous and epididymal fat depots. Nearly all aggregate growth QTL could be interpreted in terms of the organ and fat subcomponents measured. More than 25% of QTL detected map to MMU2, accentuating the relevance of this chromosome to growth and fatness in the context of this cross. Regions of MMU7, 15, and 17 also emerged as important obesity “hot-spots.” Average degrees of directional dominance are close to additivity, matching expectations for body composition traits. A strong QTL congruency is evident among heart, liver, kidney, and spleen weights. Liver and testis are organs whose genetic architectures are, respectively, most and least aligned with that for aggregate body weight. In this study, growth and body weight are interpreted in terms of organ subcomponents underlying the macro aggregate traits, and anchored on the corresponding genomic locations.

Keywords

Genetic Architecture Composite Interval Mapping Testis Weight Spleen Weight Additive Gene Action 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We gratefully acknowledge Mary Ann Cushman, Stephenie Foster, and Grady Beck for collection of genotypic data. J.L. Rocha acknowledges the support of the Portuguese Foundation for Science and Technology. This research is a contribution of the University of Nebraska Agricultural Research Division (Lincoln, neb.; Journal Series No. 14110) and the North Carolina Agricultural Research Service, and was supported in part by funds provided through the Hatch Act. This research was also partially based upon work supported by the National Science Foundation under Grant No. 0091900 (Nebraska EPSCOR infrastructure improvement grant).

References

  1. 1.
    Airey, DC, Lu, L, Williams, RW 2001Genetic control of the mouse cerebellum: identification of quantitative trait loci modulating size and architecture.J Neurosc2150995109Google Scholar
  2. 2.
    Barsh, GS, Schwartz, MW 2002Genetic approaches to studying energy balance: perception and integration.Nat Rev Genet3589600PubMedGoogle Scholar
  3. 3.
    Basten, CJ, Weir, BS, Zeng, Z-B 2001QTL Cartograher, version 1.15North Carolina State UniversityRaleigh, NCGoogle Scholar
  4. 4.
    Beavis, WD 1998Power, precision, and accuracy.Paterson, AH eds. Molecular Dissection of Complex Traits.CRC PressBoca Raton, Fla145162Google Scholar
  5. 5.
    Belknap, JK, Phillips, TJ, O’Toole, LA 1992Quantitative trait loci associated with brain weight in the BXD/Ty recombinant inbred mouse strains.Brain Res Bull29337344CrossRefPubMedGoogle Scholar
  6. 6.
    Bray, GA, Tartaglia, LA 2000Medicinal strategies in the treatment of obesity.Nature404672677PubMedGoogle Scholar
  7. 7.
    Brem, RB, Yvert, G, Clinton, R, Kruglyak, L 2002Genetic dissection of transcriptional regulation in budding yeast.Science296752755CrossRefPubMedGoogle Scholar
  8. 8.
    Brockmann, GA, Bevova, MR 2002Using mouse models to dissect the genetics of obesity.Trends Genet18367376CrossRefPubMedGoogle Scholar
  9. 9.
    Brockmann, GA, Renne, U, Kopplow, K, Das, P 1998aGenetic markers for the detection of quantitative trait loci with special consideration of body weight and fat.Acta Theriol435362Google Scholar
  10. 10.
    Brockmann, GA, Haley, CS, Renne, U, Knott, SA, Schwerin, M 1998bQuantitative trait loci affecting body weight and fatness from a mouse line selected for extreme high growth.Genetics150369381Google Scholar
  11. 11.
    Brockmann, GA, Kratzsch, J, Haley, CS, Renne, U, Schwerin, M,  et al. 2000Single QTL effects, epistasis, and pleiotropy account for two-thirds of the phenotypic F2 variance of growth and obesity in DU6i × DBA/2 mice.Genome Res1019411957PubMedGoogle Scholar
  12. 12.
    Chagnon, YC, Rankinen, T, Snyder, EE, Weisnagel, SJ, Perusse, L,  et al. 2003The human obesity gene map: the 2002 update.Obes Res11313367PubMedGoogle Scholar
  13. 13.
    Churchill, GA, Doerge, RW 1994Empirical threshold values for quantitative trait mapping.Genetics138963971PubMedGoogle Scholar
  14. 14.
    Consoli, L, Lefevre, A, Zivy, M, de Vienne, D, Damerval, C 2002QTL analysis of proteome and transcriptome variations for dissecting the genetic architecture of complex traits in maize.Plant Mol Biol48575581CrossRefPubMedGoogle Scholar
  15. 15.
    de Vienne, D, Maurice, A, Josse, JM, Leonardi, A, Damerval, C 1994Mapping factors controlling genetic expression.Cell Mol Biol (Noisy-le-Grand)402939Google Scholar
  16. 16.
    Doerge, RW 2002Mapping and analysis of quantitative trait loci in experimental populations.Nat Rev Genet34352PubMedGoogle Scholar
  17. 17.
    Dumas, P, Sun, Y, Corbell, G, Trenblay, S, Pausova, Z,  et al. 2000Mapping of quantitative trait loci (QTL) of differential stress gene expression in rat recombinant inbred strains.Hypertens18545551CrossRefPubMedGoogle Scholar
  18. 18.
    Eisen, EJ 1989Selection experiments for body composition in mice and rats: a review.Livest Prod Sci231732CrossRefGoogle Scholar
  19. 19.
    Falconer, DS, Mackay, TF 1996Introduction to Quantitative Genetics.Longman Group Ltd.Harlow, UKGoogle Scholar
  20. 20.
    Fisler, JS, Warden, CH 1997Mapping of mouse obesity genes: a generic approach to a complex trait.J Nutr1271909S1916SPubMedGoogle Scholar
  21. 21.
    Flegal, KM, Carroll, MD, Ogden, CL, Johnson, CL 2002Prevalence and trends in obesity among US adults, 1999–2000.JAMA (J am Med Assoc)28817231727CrossRefGoogle Scholar
  22. 22.
    Flint, J, Mott, R 2001Finding the molecular basis of quantitative traits: successes and pitfalls.Nat Rev Genet2437445CrossRefPubMedGoogle Scholar
  23. 23.
    Gu, L, Johnson, MW, Lusis, AJ 1999Quantitative trait locus analysis of plasma lipoprotein levels in an autoimmune mouse model.Arterioscler Thromb Vase Biol19442453Google Scholar
  24. 24.
    Horvat, S, Bunger, L, Falconer, VM, Mackay, P, Law, A,  et al. 2000Mapping of obesity QTLs in a cross between mouse lines divergently selected on fat content.Mamm Genome1127PubMedGoogle Scholar
  25. 25.
    Lakoubova, OA, Dushkin, H, Beier, DR 1995Localization of a murine recessive polycystic kidney disease mutation and modifying loci that affect disease severity.Genomics26107114CrossRefPubMedGoogle Scholar
  26. 26.
    Jansen, RC 2003Studying complex biological systems using multifactorial perturbation.Nat Rev Genet4145151CrossRefPubMedGoogle Scholar
  27. 27.
    Jansen, RC, Nap, JP 2001Genetical genomics: the added value from segregation.Trends Genet17388391CrossRefPubMedGoogle Scholar
  28. 28.
    Jerez-Timaure, N, Pomp, D, Eisen, EJ 2002Confirmation of quantitative trait loci (QTL) affecting body weight and fatness in a congenic line of mice.J Anim Sci8045abstPubMedGoogle Scholar
  29. 29.
    Keightley, PD, Morris, KH, Ishikawa, A, Falconer, VM, Oliver, F 1998Test of candidate gene-quantitative trait locus association applied to fatness in mice.Heredity81630637CrossRefPubMedGoogle Scholar
  30. 30.
    Kramer, MG, Vaughn, TT, Pletscher, LS, Ellison, KK, Adams, E,  et al. 1998Genetic variation in body weight gain and composition in the intercross of Large (LG/J) and Small (SM/J) inbred strains of mice.Genet Mol Biol21211218Google Scholar
  31. 31.
    Lasater, L, Kingsbery, B 1987The New Cattle Industry, 1st ed.Kingsbery CommunicationsWoodinville, WashingtonGoogle Scholar
  32. 32.
    Leamy, LJ, Pomp, D, Eisen, EJ, Cheverud, JM 2002Pleiotropy of quantitative trait loci for organ weights and limb bone lengths in mice.Physiol Genomics102129PubMedGoogle Scholar
  33. 33.
    Lembertas, AV, Perusse, L, Chagnon, YC, Fisler, JS, Warden, CH,  et al. 1997Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q.J Clin Invest10012401247PubMedGoogle Scholar
  34. 34.
    Le Roy, I, Tordjman, S, Samour, DM, Degrelle, H, Roubertoux, PL 2001Genetic architecture of testis and seminal vesicle weights in mice.Genetics158333340PubMedGoogle Scholar
  35. 35.
    Machleder, D, Ivandic, B, Welch, C, Castellani, L, Reue, K,  et al. 1997Complex genetic control of HDL levels in mice in response to an atherogenic diet.J Clin Invest9914061419PubMedGoogle Scholar
  36. 36.
    Mehrabian, M, Wen, P-Z, Fisler, J, Davis, RC, Lusis, AJ 1998Genetic loci controlling body fat, lipoprotein metabolism, and insulin levels in a multifactorial mouse model.J Clin Invest10124852496PubMedGoogle Scholar
  37. 37.
    Mehrabian, M, Castellani, LW, Wen, P-Z, Wong, J, Rithaporn, T,  et al. 2000Genetic control of HDL levels and composition in an interspecific mouse cross (CAST/Ei × C57BL/6J).J Lipid Res4119361946PubMedGoogle Scholar
  38. 38.
    Melchinger, AE, Utz, HF, Schon, CC 1998Quantitative trait locus (QTL) mapping using different testers and independent population samples in maize reveals low power of QTL detection and large bias in estimates of QTL effects.Genetics149383403PubMedGoogle Scholar
  39. 39.
    Moody, DE, Pomp, D, Nielsen, MK, Van Vleck, LD 1999Identification of quantitative trait loci influencing traits related to energy balance in selection and inbred lines of mice.Genetics152699711Google Scholar
  40. 40.
    NHLBI (1998) Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. NIH Publication No. 98-4083Google Scholar
  41. 41.
    Pomp, D 1997Genetic dissection of obesity in polygenic animal models.Behav Genet27285306CrossRefPubMedGoogle Scholar
  42. 42.
    Pomp, D, Jerez-Timaure, N, Allan, MF, Eisen, EJ 2002Integrated genomic, proteomic and metabolomic dissection of polygenic selection response for murine growth and fatness.Proc 7th World Congr Genet Appl Livest Prod32447450Google Scholar
  43. 43.
    Purcell-Huynh, DA, Weinreb, A, Castellani, LW, Mehrabian, M, Doolittle, MH,  et al. 1995Analysis of a genetic cross between inbred mouse strains NZB/BINJ and SM/J using a complete linkage map approach.J Clin Invest9618451858PubMedGoogle Scholar
  44. 44.
    Roberts, AW, Hasegawa, M, Metcalf, D, Foote, SJ 2000Identification of a genetic locus modulating splenomegaly induced by granulocyte colony-stimulating factor in mice.Leukemia14657661CrossRefPubMedGoogle Scholar
  45. 45.
    Rocha, JL, Eisen, EJ, Van Vleck, LD, Pomp, D 2004aA large-sample QTL study in mice: I. Growth.Mamm Genome158399Google Scholar
  46. 46.
    Rocha, JL, Siewerdt, F, Eisen, EJ, Van Vleck, LD, Pomp, D 2004cA large-sample QTL study in mice: III. Reproduction.Mamm Genome..in pressGoogle Scholar
  47. 47.
    SAS Institute Inc.1985SAS User’s Guide: Basics.SASCary, N.C.Google Scholar
  48. 48.
    SAS Institute Inc.1996SAS System for Mixed ModelsSASCary, N.C.Google Scholar
  49. 49.
    Schadt, EE, Monks, SA, Drake, TA, Lusis, AJ, Che, N,  et al. 2003aGenetics of gene expression surveyed in maize, mouse and man.Nature422297302Google Scholar
  50. 50.
    Schadt, EE, Monks, SA, Friend, SH 2003bA new paradigm for drug discovery: integrating clinical, genetic, genomic and molecular phenotype data to identify drug targets.Biochem Soc Trans31437443Google Scholar
  51. 51.
    Smith, GC 1991Responding to a changing consumer: repositioning beef in the diet—safety, nutrient content and palatability.The King Ranch and the Texas A&M University System: Partners in Progress since 1891Texas A&M UniversityCollege Station, TXM1M11Google Scholar
  52. 52.
    Spearow, JL, Nutson, PA, Mailliard, WS, Porter, M, Barkley, M 1999Mapping genes that control hormone-induced ovulation rate in mice.Biol Reprod61857872PubMedGoogle Scholar
  53. 53.
    Suto, J, Matsuura, S, Yamanaka, H, Sekikawa, K 1999Quantitative trait loci that regulate plasma lipid concentration in hereditary obese KK and KK-Ay mice.Biochim Biophys Acta1453385395CrossRefPubMedGoogle Scholar
  54. 54.
    Taylor, BA, Phillips, SJ 1996Detection of obesity QTLs on mouse chromosomes 1 and 7 by selective DNA pooling.Genomics34389398Google Scholar
  55. 55.
    Taylor, BA, Phillips, SJ 1997Obesity QTLs on mouse chromosomes 2 and 17.Genomics43249257Google Scholar
  56. 56.
    Taylor, BA, Tarantino, LM, Phillips, SJ 1999Gender-influenced obesity QTLs identified in a cross involving the KK type II diabetes-prone mouse strain.Mamm Genome10963968Google Scholar
  57. 57.
    Taylor, BA, Wnek, C, Schroeder, D, Phillips, SJ 2001Multiple obesity QTLs identified in an intercross between the NZO (New Zealand obese) and the SM (small) mouse strains.Mamm Genome1295103Google Scholar
  58. 58.
    Utz, HF, Melchinger, AE, Schon, CC 2000Bias and sampling error of the estimated proportion of genotypic variance explained by quantitative trait loci determined from experimental data in maize using cross validation and validation with independent samples.Genetics15418391849PubMedGoogle Scholar
  59. 59.
    Vaughn, TT, Pletscher, LS, Peripato, A, Ellison, KK, Adams, E,  et al. 1999Mapping quantitative trait loci for murine growth: a closer look at genetic architecture.Genet Res Camb74313322CrossRefGoogle Scholar
  60. 60.
    Warden, CH, Fisler, JS, Shoemaker, SM, Wen, P-Z, Svenson, KL,  et al. 1995Identification of four chromosomal loci determining obesity in a multifactorial mouse model.J Clin Invest9515451552PubMedGoogle Scholar
  61. 61.
    Wayne, ML, McIntyre, LM 2002Combining mapping and arraying: an approach to candidate gene identification.Proc Natl Acad Sci USA991490314906CrossRefPubMedGoogle Scholar
  62. 62.
    West, DB, Boozer, CN, Moody, DL, Atkinson, RL 1992Dietary obesity in nine inbred mouse strains.Am J Physiol262R1025R1032PubMedGoogle Scholar
  63. 63.
    West, DB, Lefevre, JG, York, B, Truett, GE 1994Dietary obesity linked to genetic loci on chromosomes 9 and 15 in a polygenic mouse model.J Clin Invest9414101416PubMedGoogle Scholar
  64. 64.
    West, DB, Truett, GE, Lefevre, JG, York, B 1995Loci on chromosomes 4, 7, 9,12, & 15 control a significant proportion of the dietary obesity phenotype in the mouse.FASEB J9A722Google Scholar
  65. 65.
    Williams, RW 2000Mapping genes that modulate mouse brain development: a quantitative genetic approach.Goffinet, AMRakic, P eds. Mouse Brain Development, Results and Problems in Cell Differentiation, vol 30Springer-VerlagBerlin, Germany2149Google Scholar
  66. 66.
    Williams, RW, Airey, DC, Kulkarni, A, Zhou, G, Lu, L 2001Genetic dissection of the olfactory bulbs of mice: QTLs on four chromosomes modulate bulb size.Behav Genet316177CrossRefPubMedGoogle Scholar
  67. 67.
    York, B, Lei, K, West, DB 1996Sensitivity to dietary obesity linked to a locus on chromosome 15 in a CAST/Ei × C57BL/6J F2 intercross.Mamm Genome7677681Google Scholar
  68. 68.
    Zeng, Z-B 1993Theoretical basis for separation of multiple linked gene effects in mapping quantitative trait loci.Proc Natl Acad Sci USA901097210976PubMedGoogle Scholar
  69. 69.
    Zeng, Z-B 1994Precision mapping of quantitative trait loci.Genetics13614571468PubMedGoogle Scholar
  70. 70.
    Zidek, V, Musilova, A, Pintir, J, Simakova, M, Pravenec, M 1998Genetic dissection of testicular weight in the mouse with the BXD recombinant inbred strains.Mamm Genome9503505CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 2004

Authors and Affiliations

  • Joao L. Rocha
    • 1
  • Eugene J. Eisen
    • 2
  • L. Dale Van Vleck
    • 3
  • Daniel Pomp
    • 1
  1. 1.Department of Animal ScienceUniversity of Nebraska, Lincoln, Nebraska 68583-0908USA
  2. 2.Department of Animal ScienceNorth Carolina State University, Raleigh, North Carolina 27695-7621USA
  3. 3.USDA, ARS, USMARC, Lincoln, Nebraska 68583-0908USA

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