Skip to main content
SpringerLink
Log in

Intersubspecific subcongenic mouse strain analysis reveals closely linked QTLs with opposite effects on body weight

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

A previous genome-wide QTL study revealed many QTLs affecting postnatal body weight and growth in an intersubspecific backcross mouse population between the C57BL/6J (B6) strain and wild Mus musculus castaneus mice captured in the Philippines. Subsequently, several closely linked QTLs for body composition traits were revealed in an F2 intercross population between B6 and B6.Cg-Pbwg1, a congenic strain on the B6 genetic background carrying the growth QTL Pbwg1 on proximal chromosome 2. However, no QTL affecting body weight has been duplicated in the F2 population, except for mapping an overdominant QTL that causes heterosis of body weight. In this study, we developed 17 intersubspecific subcongenic strains with overlapping and nonoverlapping castaneus regions from the B6.Cg-Pbwg1 congenic strain in order to search for and genetically dissect QTLs affecting body weight into distinct closely linked loci. Phenotypic comparisons of several developed subcongenic strains with the B6 strain revealed that two closely linked but distinct QTLs that regulate body weight, named Pbwg1.11 and Pbwg1.12, are located on an 8.9-Mb region between D2Mit270 and D2Mit472 and on the next 3.6-Mb region between D2Mit205 and D2Mit182, respectively. Further analyses using F2 segregating populations obtained from intercrosses between B6 and each of the two selected subcongenic strains confirmed the presence of these two body weight QTLs. Pbwg1.11 had an additive effect on body weight at 6, 10, and 13 weeks of age, and its castaneus allele decreased it. In contrast, the castaneus allele at Pbwg1.12 acted in a dominant fashion and surprisingly increased body weight at 6, 10, and 13 weeks of age despite the body weight of wild castaneus mice being 60% of that of B6 mice. These findings illustrate the complex genetic nature of body weight regulation and support the importance of subcongenic mouse analysis to dissect closely linked loci.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abiola O, Angel JM, Avner P, Bachmanov AA, Belknap JK et al (2003) The nature and identification of quantitative trait loci: a community’s view. Nat Rev Genet 4:911–916

    PubMed  Google Scholar 

  • Barton NH, Keightley PD (2002) Understanding quantitative trait variation. Nat Rev Genet 3:11–21

    Article  PubMed  CAS  Google Scholar 

  • Brockmann GA, Karatayli E, Haley CS, Renne U, Rottmann OJ et al (2004) QTLs for pre- and postweaning body weight and body composition in selected mice. Mamm Genome 15:593–609

    Article  PubMed  Google Scholar 

  • Bult CJ, Eppig JT, Kadin JA, Richardson JE, Blake JA et al (2008) The Mouse Genome Database (MGD): mouse biology and model systems. Nucleic Acids Res 36:D724–D728

    Article  PubMed  CAS  Google Scholar 

  • Christians JK, Senger LM (2007) Fine mapping dissects pleiotropic growth quantitative trait locus into linked loci. Mamm Genome 18:240–245

    Article  PubMed  CAS  Google Scholar 

  • Christians JK, Hoeflich A, Keightley PD (2006) PAPPA2, an enzyme that cleaves an insulin-like growth-factor-binding protein, is a candidate gene for a quantitative trait locus affecting body size in mice. Genetics 173:1547–1553

    Article  PubMed  CAS  Google Scholar 

  • Corva PM, Horvat S, Medrano JF (2001) Quantitative trait loci affecting growth in high growth (hg) mice. Mamm Genome 12:284–290

    Article  PubMed  CAS  Google Scholar 

  • Darvasi A (1997) Interval-specific congenic strains (ISCS): an experimental design for mapping a QTL into a 1-centimorgan interval. Mamm Genome 8:163–167

    Article  PubMed  CAS  Google Scholar 

  • Darvasi A, Soller M (1997) A simple method to calculate resolving power and confidence interval of QTL map location. Behav Genet 27:125–132

    Article  PubMed  CAS  Google Scholar 

  • Darvasi A, Weinreb A, Minke V, Wellert JI, Soller M (1993) Detecting marker-QTL linkage and estimating QTL gene effect and map location using a saturated genetic map. Genetics 134:943–951

    PubMed  CAS  Google Scholar 

  • de Vicente MC, Tanksley SD (1993) QTL analysis of transgressive segregation in an interspecific tomato cross. Genetics 134:585–596

    Google Scholar 

  • Dekkers JCM, Dentine MR (1991) Quantitative genetic variance associated with chromosomal markers in segregating populations. Theor Appl Genet 81:212–220

    Article  Google Scholar 

  • Estrada-Smith D, Castellani LW, Wong H, Wen PZ, Chui A et al (2004) Dissection of multigenic obesity traits in congenic mouse strains. Mamm Genome 15:14–22

    Article  PubMed  CAS  Google Scholar 

  • Falconer DS, Mackay TFC (1996) Introduction to quantitative genetics, 4th edn. Longmans Green, Harlow

    Google Scholar 

  • Farber CR, Medrano JF (2007) Fine mapping reveals sex bias in quantitative trait loci affecting growth, skeletal size and obesity-related traits on mouse chromosomes 2 and 11. Genetics 75:349–360

    Google Scholar 

  • Farber CR, Corva PM, Medrano JF (2006) Genome-wide isolation of growth and obesity QTL using mouse speed congenic strains. BMC Genomics 7:102

    Article  PubMed  Google Scholar 

  • Fawcett G, Jarvis J, Roseman C, Wang B, Wolf J et al (2010) Fine-mapping of obesity-related quantitative trait loci in an F9/10 advanced intercross line. Obesity 18:1383–1392

    Article  PubMed  CAS  Google Scholar 

  • Flint J, Valdar W, Shifman S, Mott R (2005) Strategies for mapping and cloning quantitative trait genes in rodents. Nat Rev Genet 6:271–286

    Article  PubMed  CAS  Google Scholar 

  • Fox JG, Barthold SW, Davisson MT, Newcomer CE, Quimby FW, Smith AL (2007) The Mouse in biomedical research, 2nd edn. Academic Press, San Diego

    Google Scholar 

  • Furuse T, Takano-Shimizu T, Moriwaki K, Shiroishi T, Koide T (2002) QTL analyses of spontaneous activity by using mouse strains from Mishima battery. Mamm Genome 13:411–415

    Article  PubMed  CAS  Google Scholar 

  • Glazier AM, Nadeau JH, Aitman TJ (2002) Finding genes that underlie complex traits. Science 298:2345–2349

    Article  PubMed  CAS  Google Scholar 

  • Horvat S, Bunger L, Falconer VM, Mackay P, Law A et al (2000) Mapping of obesity QTLs in a cross between mouse lines divergently selected on fat content. Mamm Genome 11:2–7

    Article  PubMed  CAS  Google Scholar 

  • Hyne V, Kearsey MJ (1995) QTL analysis: further uses of ‘marker regression’. Theor Appl Genet 91:471–476

    Article  Google Scholar 

  • Ishikawa A (2009) Mapping an overdominant quantitative trait locus for heterosis of body weight in mice. J Hered 100:5001–5004

    Article  Google Scholar 

  • Ishikawa A, Namikawa T (2004) Mapping major quantitative trait loci for postnatal growth in an intersubspecific backcross between C57BL/6J and Philippine wild mice by using principal component analysis. Genes Genet Syst 79:27–39

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa A, Matsuda Y, Namikawa T (2000) Detection of quantitative trait loci for body weight at 10 weeks from Philippine wild mice. Mamm Genome 11:824–830

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa A, Hatada S, Nagamine Y, Namikawa T (2005) Further mapping of quantitative trait loci for postnatal growth in an intersubspecific backcross of wild Mus musculus castaneus and C57BL/6J mice. Genet Res 85:127–137

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa A, Kim EH, Bolor H, Mollah MBR, Namikawa T (2007) A growth QTL (Pbwg1) region of mouse chromosome 2 contains closely linked loci affecting growth and body composition. Mamm Genome 18:229–239

    Article  PubMed  CAS  Google Scholar 

  • Kenney-Hunt JP, Vaughn TT, Pletscher LS, Peripato A, Routman E et al (2006) Quantitative trait loci for body size components in mice. Mamm Genome 17:526–537

    Article  PubMed  Google Scholar 

  • Kobayashi N, Toyoda T (2008) Statistical search on the Semantic Web. Bioinformatics 24:1002–1010

    Article  PubMed  CAS  Google Scholar 

  • Leamy LJ, Pomp D, Eisen EJ, Cheverud JM (2002) Pleotrophy of quantitative trait loci for organ weights and limb bone lengths in mice. Physiol Genomics 10:21–29

    PubMed  CAS  Google Scholar 

  • Leibel RL (2008) Molecular physiology of weight regulation in mice and humans. Int J Obes 32:S98–S108

    Article  CAS  Google Scholar 

  • Lionikas A, Blizard DA, Gerhard GS, Vandenbergh DJ, Stout JT et al (2005) Genetic determinants of weight of fast- and slow-twitch skeletal muscle in 500-day-old mice of the C57BL/6J and DBA/2J lineage. Physiol Genomics 21:184–192

    Article  PubMed  CAS  Google Scholar 

  • Mackay TFC, Stone EA, Ayroles JF (2009) The genetics of quantitative traits: challenges and prospects. Nat Rev Genet 10:565–577

    Article  PubMed  CAS  Google Scholar 

  • Masinde GL, Li X, Gu W, Davidson H, Hamilton-Ulland M et al (2002) Quantitative trait loci (QTL) for lean body mass and body length in MRL/MPJ and SJL/J F2 mice. Funct Integr Genomics 2:98–104

    Article  PubMed  CAS  Google Scholar 

  • Mehrabian M, Wen PZ, Fisler J, Davis RC, Lusis AJ (1998) Genetic loci controlling body fat, lipoprotein metabolism, and insulin levels in a multifactorial mouse model. J Clin Invest 101:2485–2496

    Article  PubMed  CAS  Google Scholar 

  • Mizutani S, Gomi H, Hirayama I, Tetsuro I (2006) Chromosome 2 locus Nidd5 has a potent effect on adiposity in the TSOD mouse. Mamm Genome 17:375–384

    Article  PubMed  CAS  Google Scholar 

  • Noor MAF, Cunningham AL, Larkin JC (2001) Consequences of recombination rate variation on QTL mapping studies: Simulations based on the Drosophila melanogaster genome. Genetics 159:581–588

    PubMed  CAS  Google Scholar 

  • Oliver F, Christians JK, Liu X, Rhind S, Verma V, Davison C et al (2005) Regulatory variation at glypican-3 underlines a major growth QTL in mice. PLoS Biol 3:e135

    Article  PubMed  Google Scholar 

  • Prevoršek Z, Gorjanc G, Paigen B, Horvat S (2010) Congenic and bioinformatics analyses resolved a major-effect Fob3b QTL on mouse Chr 15 into two closely linked loci. Mamm Genome 21:172–185

    Article  PubMed  Google Scholar 

  • Shao H, Sinasac DS, Burrage LC, Hodges CA, Supelak PJ et al (2010) Analyzing complex traits with congenic strains. Mamm Genome 21:276–286

    Article  PubMed  Google Scholar 

  • Shockley KR, Churchill GA (2006) Gene expression analysis of mouse chromosome substitution strains. Mamm Genome 17:598–614

    Article  PubMed  CAS  Google Scholar 

  • Stoehr JP, Byers JE, Clee SM, Lan H, Boronenkov IV et al (2004) Identification of major quantitative trait loci controlling body weight variation in ob/ob mice. Diabetes 53:245–249

    Article  PubMed  CAS  Google Scholar 

  • Terčič D, Holcman A, Dovč P, Morrice DR, Burt DW et al (2010) Identification of chromosomal regions associated with growth and carcass traits in an F3 full sib intercross line originating from a cross of chicken lines divergently selected on body weight. Anim Genet 40:743–748

    Google Scholar 

  • Toland E, Saad Y, Yerga-Woolwine S, Ummel S, Farms P, Ramdath R et al (2008) Closely linked non-additive blood pressure quantitative trait loci. Mamm Genome 19:209–218

    Article  PubMed  Google Scholar 

  • Visscher PM, Haley CS (1996) Detection of putative quantitative trait loci in line crosses under infinitesimal genetic models. Theor Appl Genet 93:691–702

    Article  Google Scholar 

  • Wade CM, Daly MJ (2005) Genetic variation in laboratory mice. Nat Genet 37:1175–1180

    Article  PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Yang H, Bell TA, Churchill GA, Villena FPM (2007) On the subspecific origin of the laboratory mouse. Nat Genet 39:1100–1107

    Article  PubMed  CAS  Google Scholar 

  • Yoshida Y, Makita Y, Heida N, Asano S, Matsushima A et al (2009) PosMed (Positional Medline): prioritizing genes with an artificial neural network comprising medical documents to accelerate positional cloning. Nucleic Acids Res 37:W147–W152

    Article  PubMed  CAS  Google Scholar 

  • Yuan R, Flurkey K, Aelst-Bouma RV, Zhang W, King B, Austad S et al (2006) Altered growth characteristics of skin fibroblasts from wild-derived mice, and genetic loci regulating fibroblast clone size. Aging Cell 5:203–212

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

M. B. R. Mollah was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) Scholarship of Japanese Government. This work was supported by Grants-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science to A. Ishikawa.

Author information

Authors and Affiliations

  1. Laboratory of Animal Genetics, Division of Applied Genetics and Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya, Aichi, 464-8601, Japan

    Md. Bazlur R. Mollah & Akira Ishikawa

Authors
  1. Md. Bazlur R. Mollah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akira Ishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akira Ishikawa.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 79 kb)

335_2011_9323_MOESM2_ESM.pdf

Supplementary Fig. 1. Construction of 17 subcongenic strains for the growth QTL Pbwg1 on mouse Chr 2. The black bar indicates the minimum genomic region derived from the M. m. castaneus mouse, and the gray bar indicates the region from the B6 mouse. The hatched bar indicates a gray zone where recombination occurred. Distal and proximal borders of each subcongenic strain are arbitrarily drawn by vertical lines. Physical map positions (Mb) of microsatellite markers are shown on the horizontal line (Supplementary Table 1). Size (Mb) indicates the minimum length of the castaneus donor region.(PDF 431 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mollah, M.B.R., Ishikawa, A. Intersubspecific subcongenic mouse strain analysis reveals closely linked QTLs with opposite effects on body weight. Mamm Genome 22, 282–289 (2011). https://doi.org/10.1007/s00335-011-9323-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-011-9323-9

Keywords

Search

Navigation