Abstract
In this chapter, we will use the example of the identification of Tnni3k as a modulator of cardiac conduction to introduce you to the use of a murine F2-generation intercross as a powerful method for the identification of novel genes relevant for cardiovascular traits. Murine F2-progeny is a genetically diverse panel of mice with differences in phenotype manifestations, e.g. cardiovascular traits such as cardiomyopathy and ECG parameters. This chapter discusses the best strategies for using F2-mice for genetic mapping. Moreover, we provide an example of the feasibility of identification of new genes modulating cardiac function utilizing the technique of mapping quantitative trait loci (QTLs) and a systems genetics integration of available genetic, gene expression, and phenotypic data.
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References
Fuster V (2014) Global burden of cardiovascular disease: time to implement feasible strategies and to monitor results. J Am Coll Cardiol 64:520–522
Jouven X, Desnos M, Guerot C, Ducimetiere P (1999) Predicting sudden death in the population: the Paris Prospective Study I. Circulation 99:1978–1983
Zipes DP, Wellens HJ (1998) Sudden cardiac death. Circulation 98:2334–2351
Heeringa J, Van Der Kuip DAM, Hofman A et al. (2006) Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 27:949–953
Marsman RF, Tan HL, Bezzina CR (2014) Genetics of sudden cardiac death caused by ventricular arrhythmias. Nat Rev Cardiol 11:96–111
George AL Jr. (2013) Molecular and genetic basis of sudden cardiac death. J Clin Invest 123:75–83
Maron BJ, Maron MS, Semsarian C (2012) Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol 60:705–715
Schunkert H, König IR, Kathiresan S et al. (2011) Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 43:333–338
Beck JA, Lloyd S, Hafezparast M et al. (2000) Genealogies of mouse inbred strains. Nat Genet 24:23–25
Suzuki M, Carlson KM, Marchuk DA, Rockman HA (2002) Genetic modifier loci affecting survival and cardiac function in murine dilated cardiomyopathy. Circulation 105:1824–1829
Wheeler FC, Fernandez L, Carlson KM, Wolf MJ, Rockman HA, Marchuk DA (2005) QTL mapping in a mouse model of cardiomyopathy reveals an ancestral modifier allele affecting heart function and survival. Mamm Genome 16:414–423
Le Corvoisier P, Park HY, Carlson KM, Marchuk DA, Rockman HA (2003) Multiple quantitative trait loci modify the heart failure phenotype in murine cardiomyopathy. Hum Mol Genet 12:3097–3107
Maddatu TP, Garvey SM, Schroeder DG et al. (2005) Dilated cardiomyopathy in the nmd mouse: transgenic rescue and QTLs that improve cardiac function and survival. Hum Mol Genet 14:3179–3189
Wheeler FC, Tang H, Marks OA et al. (2009) Tnni3k modifies disease progression in murine models of cardiomyopathy. PLoS Genet 5, e1000647
Derry JM, Zhong H, Molony C et al. (2010) Identification of genes and networks driving cardiovascular and metabolic phenotypes in a mouse F2 intercross. PLoS One 5, e14319
Rocha JL, Eisen EJ, Van Vleck LD, Pomp D (2004) A large-sample QTL study in mice: I. Growth. Mamm Genome 15:83–99
Rocha JL, Eisen EJ, Dale Van Vleck L, Pomp D (2004) A large-sample QTL study in mice: II. Body composition. Mamm Genome 15:100–113
Sugiyama F, Churchill G, Li R et al. (2002) QTL associated with blood pressure, heart rate, and heart weight in CBA/CaJ and BALB/cJ mice. Physiol Genomics 10(1):5–12
Hersch M, Peter B, Kang HM et al (2012) Mapping genetic variants associated with beta-adrenergic responses in inbred mice. PLoS One 7, e41032
Lodder EM, Scicluna BP, Beekman L et al. (2014) An integrative genomic approach identifies multiple genes involved in cardiac collagen deposition. Circ Cardiovasc Genet 7:790–798
Kirk EP, Hyun C, Thomson PC et al. (2006) Quantitative trait loci modifying cardiac atrial septal morphology and risk of patent foramen ovale in the mouse. Circ Res 98:651–658
Blizard DA, Lionikas A, Vandenbergh DJ et al. (2009) Blood pressure and heart rate QTL in mice of the B6/D2 lineage: sex differences and environmental influences. Physiol Genomics 36:158–166
Andreux PA, Williams EG, Koutnikova H et al. (2012) Systems genetics of metabolism: the use of the BXD murine reference panel for multiscalar integration of traits. Cell 150:1287–1299
Smolock EM, Ilyushkina IA, Ghazalpour A et al. (2012) Genetic locus on mouse chromosome 7 controls elevated heart rate. Physiol Genomics 44:689–698
Howden R, Liu E, Miller-DeGraff L et al. (2008) The genetic contribution to heart rate and heart rate variability in quiescent mice. Am J Physiol Heart Circ Physiol 295:59–68
Berthonneche C, Peter B, Schupfer F et al. (2009) Cardiovascular response to beta-adrenergic blockade or activation in 23 inbred mouse strains. PLoS One 4, e6610
Scicluna BP, Tanck MWT, Remme CA et al. (2011) Quantitative trait loci for electrocardiographic parameters and arrhythmia in the mouse. J Mol Cell Cardiol 50:380–389
Lodder EM, Scicluna BP, Milano A et al. (2012) Dissection of a quantitative trait locus for pr interval duration identifies Tnni3k as a novel modulator of cardiac conduction. PLoS Genet 8, e1003113
Wiltshire SA, Leiva-Torres GA, Vidal SM (2011) Quantitative trait locus analysis, pathway analysis, and consomic mapping show genetic variants of Tnni3k, Fpgt, or H28 control susceptibility to viral myocarditis. J Immunol 186:6398–6405
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
Keane TM, Goodstadt L, Danecek P et al. (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477:289–294
Wong K, Bumpstead S, Van Der Weyden L et al. (2012) Sequencing and characterization of the FVB/NJ mouse genome. Genome Biol 13:R72
Lincoln SE, Lander ES (1992) Systematic detection of errors in genetic linkage data. Genomics 14:604–610
Broman KW, Wu H, Sen S, Churchill GA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19:889–890
Bogue MA, Grubb SC (2004) The Mouse Phenome Project. Genetica 122:71–74
Yalcin B, Adams DJ, Flint J, Keane TM (2012) Next-generation sequencing of experimental mouse strains. Mamm Genome 23:490–498
Wang JR, de Villena FP, McMillan L (2012) Comparative analysis and visualization of multiple collinear genomes. BMC Bioinformatics 13(Suppl 3):13
Sander JD, Joung JK (2014) CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol 32:347–355
Remme CA, Verkerk AO, Nuyens D et al. (2006) Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD. Circulation 114:2584–2594
Bezzina C, Veldkamp MW, van Den Berg MP et al. (1999) A single Na(+) channel mutation causing both long-QT and Brugada syndromes. Circ Res 85:1206–1213
Tang H, Xiao K, Mao L, Rockman HA, Marchuk DA (2013) Overexpression of TNNI3K, a cardiac-specific MAPKKK, promotes cardiac dysfunction. J Mol Cell Cardiol 54:101–111
Milano A, Lodder EM, Bezzina CR (2015) TNNI3K in cardiovascular disease and prospects for therapy. J Mol Cell Cardiol 82:167–173
Acknowledgements
We gratefully acknowledge the support from the Netherlands CardioVascular Research Initiative (CVON-PREDICT project) to E.M.L. and C.R.B. and of the AMC foundation (Ph.D. scholarship) to S.P.
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Podliesna, S., Bezzina, C.R., Lodder, E.M. (2017). Complex Genetics of Cardiovascular Traits in Mice: F2-Mapping of QTLs and Their Underlying Genes. In: Schughart, K., Williams, R. (eds) Systems Genetics. Methods in Molecular Biology, vol 1488. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6427-7_20
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DOI: https://doi.org/10.1007/978-1-4939-6427-7_20
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