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Positional Cloning of Diabetes Genes

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Animal Models in Diabetes Research

Part of the book series: Methods in Molecular Biology ((MIMB,volume 933))

Abstract

Several mouse strains are diabetic already at the juvenile age or develop diabetes mellitus during their life. Before these strains become diabetic, they often show several or all features of the metabolic syndrome, which is very similar to the etiology of diabetes in humans. Under the assumption that natural mutations are responsible for the development of diabetes in those mouse strains, they are valuable resources for the identification of diabetes genes and modifiers. Usually, several steps are necessary to detect the causative genes in the genome. These include the initial identification of the genomic regions contributing to the disease which is typically done by linkage mapping in an F2 intercross or backcross population, fine mapping of the identified chromosomal interval to narrow down the target region carrying the causative genetic variation and subsequent functional and genetic characterization of the target gene or a small subset of genes. Here, we give a general overview on genetic models and the strategy for identifying diabetes genes and provide a specific protocol for the mapping and fine mapping of chromosomal regions carrying diabetes genes.

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References

  1. Brockmann GA, Kratzsch J, Haley CS et al (2000) Single QTL effects, epistasis, and pleiotropy account for two thirds of the phenotypic F2 variance of growth and obesity in DU6i x DBA/2 mice. Genome Res 10:1941–1957

    Article  PubMed  CAS  Google Scholar 

  2. Brockmann GA, Tsaih S, Neuschl C et al (2009) Genetic factors contributing to obesity and body weight can act through mechanisms affecting muscle weight, fat weight or both. Physiol Genomics 36:114–126

    PubMed  CAS  Google Scholar 

  3. Carlborg Ö, Brockmann GA, Haley C (2005) Simultaneous mapping of epistatic QTL in DU6i x DBA/2. Mamm Genome 16:481–494

    Article  PubMed  CAS  Google Scholar 

  4. Stylianou IM, Korstanje R, Li R et al (2006) Quantitative trait locus analysis for obesity reveals multiple networks of interacting loci. Mamm Genome 17:22–36

    Article  PubMed  Google Scholar 

  5. Reifsnyder PC, Churchill G, Leiter EH (2000) Maternal environment and genotype interact to establish diabesity in mice. Genome Res 10:1568–1578

    Article  PubMed  CAS  Google Scholar 

  6. Jarvis JP, Kenney-Hunt J, Ehrich TH et al (2005) Maternal genotype affects adult offspring lipid, obesity, and diabetes phenotypes in LGXSM recombinant inbred strains. J Lipid Res 46:1692–1702

    Article  PubMed  CAS  Google Scholar 

  7. Abbasi A, Corpeleijn E, van der Schouw YT et al (2011) Maternal and paternal transmission of type 2 diabetes: influence of diet, lifestyle and adiposity. J Intern Med 270:388–396

    Article  PubMed  CAS  Google Scholar 

  8. Penesova A, Bunt JC, Bogardus C et al (2010) Effect of paternal diabetes on pre-diabetic phenotypes in adult offspring. Diabetes Care 33:1823–1828

    Article  PubMed  CAS  Google Scholar 

  9. Zeggini E, Scott LJ, Saxena R et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638–645

    Article  PubMed  CAS  Google Scholar 

  10. Chadt A, Leicht K, Deshmukh A et al (2008) Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity. Nat Genet 40:1354–1359

    Article  PubMed  CAS  Google Scholar 

  11. Scherneck S, Nestler M, Vogel H et al (2009) Positional cloning of zinc finger doma in transcription factor Zfp69, a candidate gene for obesity-associated diabetes contributed by mouse locus Nidd/SJL. PLoS Genet 5:e1000541

    Article  PubMed  Google Scholar 

  12. Schmidt C, Gonzaludo NP, Strunk S et al (2008) A metaanalysis of QTL for diabetes related traits in rodents. Physiol Genomics 34:42–53

    Article  PubMed  CAS  Google Scholar 

  13. Svenson KL, von Smith R, Magnani PA et al (2007) Multiple trait measurements in 43 inbred mouse strains capture the phenotypic diversity characteristic of human populations. J Appl Physiol 102:2369–2378

    Article  PubMed  CAS  Google Scholar 

  14. Naggert J, Svenson KL, Smith RV et al (2011) Diet effects on bone mineral density and content, body composition, and plasma glucose, leptin, and insulin levels in 43 inbred strains of mice on a high-fat atherogenic diet. MPD:Naggert1. Mouse Phenome Database web site, The Jackson Laboratory, Bar Harbor. http://phenome.jax.org. Accessed June 2011

  15. Plum L, Kluge R, Giesen K et al (2000) Type 2 diabetes-like hyperglycemia in a backcross model of NZO and SJL mice: characterization of a susceptibility locus on chromosome 4 and its relation with obesity. Diabetes 49:1590–1596

    Article  PubMed  CAS  Google Scholar 

  16. Peirce JL, Lu L, Gu J et al (2004) A new set of BXD recombinant inbred lines from advanced intercross populations in mice. BMC Genet 5:7

    Article  PubMed  Google Scholar 

  17. Taylor BA (1989) Recombinant inbred strains. In: Lyon ML (ed) Genetic variation in the laboratory mouse, 2nd edn. Oxford University Press, Oxford, pp 773–796

    Google Scholar 

  18. Hrbek T, de Brito RA, Wang B et al (2006) Genetic characterization of a new set of recombinant inbred lines (LGXSM) formed from the intercross of SM/J and LG/J inbred mouse strains. Mamm Genome 17:417–429

    Article  PubMed  CAS  Google Scholar 

  19. Churchill GA; The Complex Trait Consortium (2004) The collaborative cross, a community resource for the genetic analysis of complex traits. Nat Genet 36:1133–1137

    Article  Google Scholar 

  20. Schmitt A, Bortfeldt R, Neuschl C et al (2009) RandoMate: a program for the generation of random mating schemes for small laboratory animals. Mamm Genome 20:321–325

    Article  PubMed  Google Scholar 

  21. Yang H, Ding Y, Hutchins LN et al (2009) A customized and versatile high-density genotyping array for the mouse. Nat Methods 6:663–666

    Article  PubMed  CAS  Google Scholar 

  22. Liu BH (1998) Multi-locus models, marker coverage and map density. In: Liu BH (ed) Statistical genomics—linkage, mapping, and QTL analysis. CRC Press, Boca Raton, pp 345–358

    Google Scholar 

  23. Cox A, Dumont BL, Ding Y et al (2009) A new standard genetic map for the laboratory mouse. Genetics 182:1335–1344

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  25. Seaton G, Haley CS, Knott SA et al (2002) QTL express: mapping quantitative trait loci in simple and complex pedigrees. Bioinformatics 18:339–340

    Article  PubMed  CAS  Google Scholar 

  26. Seaton G, Hernandez J, Grunchec JA et al (2006) GridQTL: a grid portal for QTL mapping of compute intensive datasets. In: Proceedings of the 8th world congress on genetics applied to livestock production, Belo Horizonte, 13–18 Aug 2006

    Google Scholar 

  27. Darvasi A, Soller M (1995) Advanced intercross lines, an experimental population for fine genetic mapping. Genetics 141:1199–1207

    PubMed  CAS  Google Scholar 

  28. Peirce JL, Broman KW, Lu L et al (2008) Genome Reshuffling for Advanced Intercross Permutation (GRAIP): simulation and permutation for advanced intercross population analysis. PLoS One 3:e1977

    Article  PubMed  Google Scholar 

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Acknowledgement

The project was supported by the National Genome Research Network (NGFNplus 01GS0829) and the German Research Foundation (DFG GRK 1208).

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Correspondence to Gudrun A. Brockmann .

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Brockmann, G.A., Neuschl, C. (2012). Positional Cloning of Diabetes Genes. In: Joost, HG., Al-Hasani, H., Schürmann, A. (eds) Animal Models in Diabetes Research. Methods in Molecular Biology, vol 933. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-068-7_18

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  • DOI: https://doi.org/10.1007/978-1-62703-068-7_18

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-067-0

  • Online ISBN: 978-1-62703-068-7

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