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Rapid accumulation of genome rearrangements in liver but not in brain of old mice

Nature Genetics volume 17, pages 431–434 (1997)Cite this article

Abstract

Somatic mutations have long been considered a possible cause of ageing1,2. To directly study mutational events in organs and tissues of ageing mammals, a transgenic mouse model has been generated that harbours lacZ reporter genes as part of chromosomally integrated plasmids3–5. Using this model, we determined spontaneous mutant frequencies and spectra in mouse liver and brain as a function of age. In the liver, mutant frequencies increased with age from birth to 34 months; in the brain, an increase was observed only between birth and 4–6 months. Molecular characterization of the mutations showed that a substantial portion involved genome rearrangement events, with one breakpoint in a reporter gene and the other in the mouse flanking sequence. In the liver, these genome rearrangements did not increase with age until after 27 months, when they increased rapidly. In brain, the frequency of genome rearrangements was lower than in liver and did not increase with age.

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References

  1. Failla, G. The aging process and carcinogenesis. Ann. NY Acad. Sci. 71, 1124–1135 (1958).

    Article  CAS  Google Scholar 

  2. Szilard, L On the nature of the aging process. Proc. Natl. Acad. Sci. USA 45, 35–45 (1959).

    Article  Google Scholar 

  3. Gossen, J.A., Martus, H-J., Wei, J.Y & Vijg, J. Spontaneous and X-ray-induced deletion mutations in a lacZ plasmid-based transgenic mouse model. Mutat. Res. 331, 89–97 (1995).

    Article  CAS  Google Scholar 

  4. Boerrigter, M.E.T.I., Dolle, M.E.T, Martus, H-J., Gossen, J.A & Vijg, J. Plasmid-based transgenic mouse model for studying in vivo mutations. Nature 377, 657–659 (1995).

    Article  CAS  Google Scholar 

  5. Dolle, M.E.T., Martus, H-J., Gossen, J.A., Boerrigter, M.E.T.I & Vijg, J. Evaluation of a plasmid-based transgenic mouse model for detecting in vivo mutations. Mutagenesis 11, 111–118 (1996).

    Article  CAS  Google Scholar 

  6. Rowe, L.B. et al. Maps from two interspecific backcross DNA panels available as a community genetic mapping resource. Mamm. Genome 5, 253–274 (1994).

    Article  CAS  Google Scholar 

  7. Harrison, D.E. & Archer, J.R. Physiological assays for biological age in mice: relationship of collagen, renal function, and longevity. Exp. Aging Res. 9, 245–251 (1983).

    Article  CAS  Google Scholar 

  8. Gossen, J.A., Molijn, A.C., Douglas, G.R. & Vijg, J. Application of galactose-sensitive E. coli strains as selective hosts for LacZ-plasmids. Nucleic Adds Res. 20, 3254 (1992).

    Article  CAS  Google Scholar 

  9. Gossen, J.A., de Leeuw, W. J.F., Bakker, A.Q. & Vijg, J. DNA sequence analysis of spontaneous mutations at a lacZ transgene integrated on the mouse X-chromosome. Mutagenesis 8, 243–247 (1993).

    Article  CAS  Google Scholar 

  10. Bronson, R.T. & Lipman, R.D. Reduction in rate of occurrence of age-related lesions in dietary restricted laboratory mice. Growth, Dev. Aging 55, 169–184 (1991).

    CAS  Google Scholar 

  11. Bronson, R.T. in Genetics of Aging II (ed. Harrison, D.E.) 280–358 (Telford, CaldwelI, New Jersey, 1990).

    Google Scholar 

  12. Ames, B.N., Shigenaga, M.K. & Hagen, T.M., Oxidants, antioxidants, and the degenerative diseases of aging. Proc. Natl. Acad. Sci. USA 90, 7915–7922 (1993).

    Article  CAS  Google Scholar 

  13. Martin, G.M., Austad, S.N. & Johnson, T.E. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nature Genet. 13, 25–34 (1996).

    Article  CAS  Google Scholar 

  14. Hsie, A.W. et al. Evidence for reactive oxygen species inducing mutations in mammalian cells. Proc. Natl. Acad. Sci. USA 83, 9616–9620 (1986).

    Article  CAS  Google Scholar 

  15. Gille, J.J.P., van Berkel, C.G.M. & Joenje, H. Mutagenicity of metabolic oxygen radicals in mammalian cell cultures. Carcinogenesis 15, 2695–2699 (1994).

    Article  CAS  Google Scholar 

  16. Mullaart, E., Boerrigter, M.E.T.I., Brouwer, A. & Vijg, J. Age-dependent accumulation of alkali-labile sites in DNA of post-mitotic but not in that of mitotic rat liver cells. Mech. Ageing Dev. 45, 41–49 (1988).

    Article  CAS  Google Scholar 

  17. Fraga, C.G., Shigenaga, M.K., Park, J-W., Degan, P. & Ames, B. Oxidative damage to DNA during aging: 8-hydroxy-2′-deoxyguanosine in rat organ DNA and urine. Proc. Natl, acad. Sci. USA 87, 4533–4537 (1990).

    Article  CAS  Google Scholar 

  18. Kaneko, T., Tahara, S. & Matsuo, M. Non-linear accumulation of 8-hydroxy-2'-deoxyguanosine, a marker of oxidized DNA damage, during aging. Mutat Res. 316, 277–285 (1996).

    Article  CAS  Google Scholar 

  19. Mullaart, E., Boerrigter, M.E.T.I., Boer, G.J. & Vijg, J. Spontaneous DNA breaks in the rat brain during development and ageing. Mutat. Res. 237, 9–15 (1990).

    Article  CAS  Google Scholar 

  20. Fukuchi, K., Martin, G.M. & Monnat, R.J., Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc. Natl. Acad. Sci. USA 86, 5893–5897 (1989).

    Article  CAS  Google Scholar 

  21. Yu, C-E et al. Positional cloning of the Werner's syndrome gene. Science 272, 258–262 (1996).

    Article  CAS  Google Scholar 

  22. Martin, G.M. & Turker, M.S. in Principles of Geriatric Medicine and Gerontology (eds Hazzard, W.R. et al.) 19–35 (McGraw-Hill, New-York, 1994).

    Google Scholar 

  23. van der Horst, G.T.J et al. Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition. Cell 89, 425–435 (1997).

    Article  CAS  Google Scholar 

  24. Vijg, J. & Douglas, G.R. in Technologies for Detection of DNA Damage and Mutations, part II(ed. Pfeifer, G.P.) 391–410(Plenum, New-York, 1996).

    Book  Google Scholar 

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Authors and Affiliations

  1. Beth Israel Deaconess Medical Center and Harvard Medical School, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts, 02115, USA

    Martijn E.T. Dollé, Heidi Giese, Craig L. Hopkins, Hans-Jörg Martus, Jeffrey M. Hausdorff & Jan Vijg

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  1. Martijn E.T. Dollé
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  2. Heidi Giese
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  3. Craig L. Hopkins
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  4. Hans-Jörg Martus
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  5. Jeffrey M. Hausdorff
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  6. Jan Vijg
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Dollé, M., Giese, H., Hopkins, C. et al. Rapid accumulation of genome rearrangements in liver but not in brain of old mice. Nat Genet 17, 431–434 (1997). https://doi.org/10.1038/ng1297-431

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