Genome-wide, large-scale production of mutant mice by ENU mutagenesis

Abstract

In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model organisms such as Drosophila melanogaster and Caenorhabditis elegans. Here we report on a systematic, genome-wide, mutagenesis screen in mice. As part of the German Human Genome Project, we have undertaken a large-scale ENU-mutagenesis screen for dominant mutations and a limited screen for recessive mutations1. In screening over 14,000 mice for a large number of clinically relevant parameters, we recovered 182 mouse mutants for a variety of phenotypes. In addition, 247 variant mouse mutants are currently in genetic confirmation testing and will result in additional new mutant lines. This mutagenesis screen, along with the screen described in the accompanying paper2, leads to a significant increase in the number of mouse models3 available to the scientific community. Our mutant lines are freely accessible to non-commercial users (for information, see http://www.gsf.de/ieg/groups/enu-mouse.html).

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Figure 1: Structure of the ENU–mouse-mutagenesis research centre.
Figure 2: Mutants identified in the clinical chemical screen.
Figure 3: Mutants identified in the immunology screen.
Figure 4: Forelimbs of mouse mutant ALI4 (for abnormal limb 4), showing abnormal growth and nail colour caused by disturbance in the matrix of the nail bed and hyper-parakeratosis.

References

  1. 1

    Hrabé de Angelis, M. & Balling, R. Large scale ENU screens in the mouse. Genetics meets genomics. Mutat. Res. 400, 25–32 (1998).

  2. 2

    Nolan, P.M. et al. A systematic, genome-wide, phenotype-driven mutagenesis program for gene function studies in the mouse. Nature Genet. 25, 440–443 (2000).

  3. 3

    Brown, S. & Peters, J. Combining mutagenesis and genomics in the mouse—closing the phenotype gap. Trends Genet. 12, 433–435 (1996).

  4. 4

    Graw, J. et al. Mutation in the bA3/A1-crystallin encoding gene Cryba1 causes a dominant cataract in the mouse. Genomics 62, 67–73 (1999)

  5. 5

    Marschall, S. & Hrabé de Angelis, M. Cryopreservation of mouse spermatozoa–double your mouse space. Trends Genet. 15, 128–131 (1999).

  6. 6

    Marschall, S., Huffstadt, U., Balling, R. & Hrabé de Angelis, M. Reliable recovery of inbred mouse lines using cryopreserved spermatozoa. Mamm. Genome 10, 773–776 (1999).

  7. 7

    Whyte, M.P., Teitelbaum, S.L., Murphy, W.A., Bergfeld, M.A. & Avioli, L.V. Adult hypophosphatasia. Clinical, laboratory, and genetic investigation of a large kindred with review of the literature. Medicine 58, 329–347 (1979).

  8. 8

    Spickett, G.P. et al. Common variable immunodeficiency: how many diseases? Immunol. Today 18, 325–328 (1997).

  9. 9

    Ahearn, J.M. et al. Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen. Immunity 4, 251–262 (1996).

  10. 10

    Molina, H. et al. Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. Proc. Natl Acad. Sci. USA 93, 3357–3361 (1996).

  11. 11

    Russell, W.L. et al. Specific-locus test shows ethylnitrosourea to be the most potent mutagen in the mouse. Proc. Natl Acad. Sci. USA 76, 5918–5922 (1979).

  12. 12

    Justice, M.J., Noveroske, J.K., Weber, J.S., Zheng, B. & Bradley, A. Mouse ENU mutagenesis. Hum. Mol. Genet. 8, 1955–1963 (1999).

  13. 13

    Nolan, P.M., Kampfhamer, D. & Bucan, M. Random mutagenesis screen for dominant behavioral mutations in mice. Methods 13, 379–395 (1997).

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Acknowledgements

We thank A. Servatius, S. Prettin, G. Bergter, N. Hirsch, A. Mayer, S. Manz, S. Hoffmann, F. Golla, B. Beneckenstein, K. Lobenwein, A. Wolf and D. Kreitz for technical assistance; C. Schindewolf for comments and revision of the manuscript; and H. Wagner for support. Part of this project was supported by grants from the German Human Genome Project to R.B., E.W. and M.H.d.A. (01KW9610/1), and to K.P., J.R. and H.B. (01KW9636).

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Correspondence to Martin Hrabé de Angelis.

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de Angelis, M., Flaswinkel, H., Fuchs, H. et al. Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nat Genet 25, 444–447 (2000). https://doi.org/10.1038/78146

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