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
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
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
Carlborg Ö, Brockmann GA, Haley C (2005) Simultaneous mapping of epistatic QTL in DU6i x DBA/2. Mamm Genome 16:481–494
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
Reifsnyder PC, Churchill G, Leiter EH (2000) Maternal environment and genotype interact to establish diabesity in mice. Genome Res 10:1568–1578
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
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
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
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
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
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
Schmidt C, Gonzaludo NP, Strunk S et al (2008) A metaanalysis of QTL for diabetes related traits in rodents. Physiol Genomics 34:42–53
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
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
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
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
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
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
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
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
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
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
Cox A, Dumont BL, Ding Y et al (2009) A new standard genetic map for the laboratory mouse. Genetics 182:1335–1344
Broman KW, Wu H, Sen S et al (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19:889–890
Seaton G, Haley CS, Knott SA et al (2002) QTL express: mapping quantitative trait loci in simple and complex pedigrees. Bioinformatics 18:339–340
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
Darvasi A, Soller M (1995) Advanced intercross lines, an experimental population for fine genetic mapping. Genetics 141:1199–1207
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
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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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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