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Influence of Genetic Background on Genetically Engineered Mouse Phenotypes

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Gene Knockout Protocols

Part of the book series: Methods in Molecular Biology ((MIMB,volume 530))

Abstract

The history of mouse genetics, which involves the study of strain-dependent phenotype variability, makes it clear that the genetic background onto which a gene-targeted allele is placed can cause considerable variation in genetically engineered mouse (GEM) phenotype. This variation can present itself as completely different phenotypes, as variations in penetrance of phenotype, or as variable expressivity of phenotype. In this chapter we provide examples from gene-targeting literature showing each of these types of phenotype variation. We discuss ways in which modifier genes can affect the phenotype of a mouse with a mutant gene, and we give examples of modifier locus identification. We also review approaches to minimize gene polymorphism and flanking gene differences between experimental animals, and between them and their controls. In addition, we discuss the advantages and disadvantages of performing the first analysis of a knockout mouse on a mixed genetic background. We conclude that a mixed background provides the quickest preview of possible strain-dependent phenotypes (1, 2). Finally, we review recent approaches to improving genetic diversity by generating new inbred strains that encompass a broader range of alleles within the mouse species.

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References

  1. Doetschman T. Interpretation of phenotype in genetically engineered mice. Lab Anim Sci 1999; 49(2):137–143.

    PubMed  CAS  Google Scholar 

  2. Sanford LP, Kallapur S, Ormsby I, Doetschman T. Influence of genetic background on knockout mouse phenotypes. Methods Mol Biol 2001; 158:217–225.

    PubMed  CAS  Google Scholar 

  3. Little CC. A possible Mendelian explanation for a type of inheritance apparently non-Mendelian in nature. Science 1914; 40(1042):904–906.

    Article  PubMed  CAS  Google Scholar 

  4. Little CC, Tyzzer EE. Further experimental studies on the inheritance of susceptibility to a transplantable carcinoma (JA) of the Japanese Waltzing Mouse. J Med Res 1916; 33:393–427.

    PubMed  CAS  Google Scholar 

  5. Schlager G. Selection for blood pressure levels in mice. Genetics 1974; 76(3):537–549.

    PubMed  CAS  Google Scholar 

  6. Glant TT, Bardos T, Vermes C, Chandrasekaran R, Valdez JC, Otto JM et al. Variations in susceptibility to proteoglycan-induced arthritis and spondylitis among C3H substrains of mice: evidence of genetically acquired resistance to autoimmune disease. Arthritis Rheum 2001; 44(3):682–692.

    Article  PubMed  CAS  Google Scholar 

  7. Baribault H, Penner J, Iozzo RV, Wilson-Heiner M. Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice. Genes Dev 1994; 8(24):2964–2973.

    Article  PubMed  CAS  Google Scholar 

  8. Baribault H, Price J, Miyai K, Oshima RG. Mid-gestational lethality in mice lacking keratin 8. Genes Dev 1993; 7(7A):1191–1202.

    Article  PubMed  CAS  Google Scholar 

  9. Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 1995; 269(5221):230–234.

    Article  PubMed  CAS  Google Scholar 

  10. Kallapur S, Ormsby I, Doetschman T. Strain dependency of TGFbeta1 function during embryogenesis. Mol Reprod Dev 1999; 52(4):341–349.

    Article  PubMed  CAS  Google Scholar 

  11. Kent G, Iles R, Bear CE, Huan LJ, Griesenbach U, McKerlie C et al. Lung disease in mice with cystic fibrosis. J Clin Invest 1997; 100(12):3060–3069.

    Article  PubMed  CAS  Google Scholar 

  12. Clarke LL, Grubb BR, Gabriel SE, Smithies O, Koller BH, Boucher RC. Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis. Science 1992; 257(5073):1125–1128.

    Article  PubMed  CAS  Google Scholar 

  13. Rozmahel R, Wilschanski M, Matin A, Plyte S, Oliver M, Auerbach W et al. Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet 1996; 12(3):280–287.

    Article  PubMed  CAS  Google Scholar 

  14. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992; 359(6397):693–699.

    Article  PubMed  CAS  Google Scholar 

  15. Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 1995; 121(6):1845–1854.

    PubMed  CAS  Google Scholar 

  16. Bonyadi M, Rusholme SA, Cousins FM, Su HC, Biron CA, Farrall M et al. Mapping of a major genetic modifier of embryonic lethality in TGF beta 1 knockout mice. Nat Genet 1997; 15(2):207–211.

    Article  PubMed  CAS  Google Scholar 

  17. Engle SJ, Hoying JB, Boivin GP, Ormsby I, Gartside PS, Doetschman T. Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res 1999; 59(14):3379–3386.

    PubMed  CAS  Google Scholar 

  18. Engle SJ, Ormsby I, Pawlowski S, Boivin GP, Croft J, Balish E et al. Elimination of colon cancer in germ-free Transforming Growth Factor beta1-deficient mice. Cancer Res 2002; 62(22):6362–6366.

    PubMed  CAS  Google Scholar 

  19. Sanford LP, Ormsby I, Gittenberger-de GA, Sariola H, Friedman R, Boivin GP et al. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 1997; 124(13):2659–2670.

    PubMed  CAS  Google Scholar 

  20. Bartram U, Molin DG, Wisse LJ, Mohamad A, Sanford LP, Doetschman T et al. Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in Tgfb2knockout mice. Circulation 2001; 103(22):2745–2752.

    PubMed  CAS  Google Scholar 

  21. Poelmann RE, Jongbloed MR, Molin DG, Fekkes ML, Wang Z, Fishman GI et al. The neural crest is contiguous with the cardiac conduction system in the mouse embryo: a role in induction? Anat Embryol (Berl) 2004; 208(5):389–393.

    Article  CAS  Google Scholar 

  22. Molin DG, Poelmann RE, DeRuiter MC, Azhar M, Doetschman T, Gittenberger-de Groot AC. Transforming growth factor beta-SMAD2 signaling regulates aortic arch innervation and development. Circ Res 2004; 95(11):1109–1117.

    Article  PubMed  CAS  Google Scholar 

  23. Proetzel G, Pawlowski SA, Wiles MV, Yin M, Boivin GP, Howles PN et al. Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet 1995; 11(4):409–414.

    Article  PubMed  CAS  Google Scholar 

  24. Maggio-Price L, Treuting P, Zeng W, Tsang M, Bielefeldt-Ohmann H, Iritani BM. Helicobacter infection is required for inflammation and colon cancer in SMAD3-deficient mice. Cancer Res 2006; 66:828–838.

    Article  PubMed  CAS  Google Scholar 

  25. Guilbault C, Saeed Z, Downey GP, Radzioch D. Cystic fibrosis mouse models. Am J Respir Cell Mol Biol 2007; 36(1):1–7.

    Article  PubMed  CAS  Google Scholar 

  26. Tang Y, McKinnon ML, Leong LM, Rusholme SA, Wang S, Akhurst RJ. Genetic modifiers interact with maternal determinants in vascular development of Tgfb1(–/–) mice. Hum Mol Genet 2003; 12(13):1579–1589.

    Article  PubMed  CAS  Google Scholar 

  27. Tang Y, Lee KS, Yang H, Logan DW, Wang S, McKinnon ML et al. Epistatic interactions between modifier genes confer strain-specific redundancy for Tgfb1 in developmental angiogenesis. Genomics 2005; 85(1):60–70.

    Article  PubMed  CAS  Google Scholar 

  28. Smithies O, Maeda N. Gene targeting approaches to complex genetic diseases: atherosclerosis and essential hypertension. Proc Natl Acad Sci USA 1995; 92(12):5266–5272.

    Article  PubMed  CAS  Google Scholar 

  29. Wolfer DP, Crusio WE, Lipp HP. Knockout mice: simple solutions to the problems of genetic background and flanking genes. Trends Neurosci 2002; 25(7):336–340.

    Article  PubMed  CAS  Google Scholar 

  30. Banbury Conference. Mutant mice and neuroscience: recommendations concerning genetic background. Banbury Conference on genetic background in mice [see comments]. Neuron 1997; 19(4):755–759.

    Google Scholar 

  31. Markel P, Shu P, Ebeling C, Carlson GA, Nagle DL, Smutko JS et al. Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains. Nat Genet 1997; 17(3):280–284.

    Article  PubMed  CAS  Google Scholar 

  32. Wakeland E, Morel L, Achey K, Yui M, Longmate J. Speed congenics: a classic technique in the fast lane (relatively speaking). Immunol Today 1997; 18(10):472–477.

    Article  PubMed  CAS  Google Scholar 

  33. Darvasi A, Soller M. Advanced intercross lines, an experimental population for fine genetic mapping. Genetics 1995; 141(3):1199–1207.

    PubMed  CAS  Google Scholar 

  34. Bommireddy R, Ormsby I, Yin M, Boivin GP, Babcock GF, Doetschman T. TGFbeta1 inhibits Ca2+-Calcineurin-mediated activation in thymocytes. J Immunol 2003; 170(7):3645–3652.

    PubMed  CAS  Google Scholar 

  35. Hoying JB, Yin M, Diebold R, Ormsby I, Becker A, Doetschman T. Transforming growth factor beta1 enhances platelet aggregation through a non-transcriptional effect on the fibrinogen receptor. J Biol Chem 1999; 274(43):31008–31013.

    Article  PubMed  CAS  Google Scholar 

  36. Schultz JJ, Witt SA, Glascock BJ, Nieman ML, Reiser PJ, Nix SL et al. TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest 2002; 109(6):787–796.

    CAS  Google Scholar 

  37. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007; 448(7151):313–317.

    Google Scholar 

  38. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 2007; 448(7151):318–324.

    Google Scholar 

  39. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126(4):663–676.

    Article  PubMed  CAS  Google Scholar 

  40. Matsushima Y, Sakurai T, Ohoka A, Ohnuki T, Tada N, Asoh Y et al. Four strains of spontaneously hyperlipidemic (SHL) mice: phenotypic distinctions determined by genetic backgrounds. J Atheroscler Thromb 2001; 8(3):71–79.

    PubMed  CAS  Google Scholar 

  41. Shi W, Wang NJ, Shih DM, Sun VZ, Wang X, Lusis AJ. Determinants of atherosclerosis susceptibility in the C3H and C57BL/6 mouse model: evidence for involvement of endothelial cells but not blood cells or cholesterol metabolism. Circ Res 2000; 86(10):1078–1084.

    PubMed  CAS  Google Scholar 

  42. Shi W, Pei H, Fischer JJ, James JC, Angle JF, Matsumoto AH et al. Neointimal formation in two apolipoprotein E-deficient mouse strains with different atherosclerosis susceptibility. J Lipid Res 2004; 45(11):2008–2014.

    Article  PubMed  CAS  Google Scholar 

  43. Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P et al. Initial sequencing and comparative analysis of the mouse genome. Nature 2002; 420(6915):520–562.

    Article  PubMed  CAS  Google Scholar 

  44. Wade CM, Kulbokas EJ, III, Kirby AW, Zody MC, Mullikin JC, Lander ES et al. The mosaic structure of variation in the laboratory mouse genome. Nature 2002; 420(6915):574–578.

    Article  PubMed  CAS  Google Scholar 

  45. Ideraabdullah FY, Casa-Esperon E, Bell TA, Detwiler DA, Magnuson T, Sapienza C et al. Genetic and haplotype diversity among wild-derived mouse inbred strains. Genome Res 2004; 14(10A):1880–1887.

    Article  PubMed  CAS  Google Scholar 

  46. Churchill GA, Airey DC, Allayee H, Angel JM, Attie AD, Beatty J et al. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet 2004; 36(11):1133–1137.

    Article  PubMed  CAS  Google Scholar 

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  1. BIO5 Institute, University of Arizona, Tucson, AZ, USA

    Thomas Doetschman

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    © 2009 Humana Press, a part of Springer Science+Business Media, LLC

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    Doetschman, T. (2009). Influence of Genetic Background on Genetically Engineered Mouse Phenotypes. In: Wurst, W., Kühn, R. (eds) Gene Knockout Protocols. Methods in Molecular Biology, vol 530. Humana Press. https://doi.org/10.1007/978-1-59745-471-1_23

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    • DOI: https://doi.org/10.1007/978-1-59745-471-1_23

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    • Publisher Name: Humana Press

    • Print ISBN: 978-1-934115-26-8

    • Online ISBN: 978-1-59745-471-1

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