Abstract
In mammals, X-chromosome dosage compensation is achieved by inactivating one X chromosome in female cells1. To test the hypothesis2 that genes on the silent X chromosome reactivate as a consequence of ageing, we examined the X-linked hypoxanthine phosphoribosyltransferase (HPRT) locus in 41 women who are heterozygous for mutations at this locus, leading to severe deficiency of the enzyme (Lesch-Nyhan syndrome3). We find that heterozygotes who are more than 10 yr old have an excess of HPRT+ skin fibroblast clones (59% rather than the 50% expected as a consequence of random X inactivation) but this excess does not increase with age. Further studies of eight of these heterozygotes show that the silent locus does not detectably reactivate spontaneously in culture, but only in response to treatment with 5-aza-2-deoxycytidine, a potent inhibitor of methylation. There is no age difference in the frequency of this reactivation as assayed by HATr clones, and a more sensitive autoradiographic assay shows only a twofold difference between young and old heterozy-gotes. Thus, age-related reactivation is not a feature of all X-linked loci, and may have species, tissue and locus-specific determinants.
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References
Lyon, M. F. Biol. Rev. 47, 1–35 (1972).
Wareham, K. A., Lyon, M. F., Glenister, P. H. & Williams, E. D. Nature 327, 725–727 (1987).
Lesch, M. & Nyhan, W. L. Am. J. Med. 36, 561–570 (1964).
Cattanach, B. M. Genet. Res. 23, 291–306 (1974).
Holliday, R. & Tarrant, G. M. Nature 238, 26–30 (1972).
Holliday, R. Expl Cell Res. 166, 543–552 (1986).
Holliday, R. Nature 327, 661–662 (1987).
Harris, M. Cell 29, 483–492 (1982).
Migeon, B. R., Der Kaloustian, V. M., Nyhan, W. L., Young, W. J. & Childs, B. Science 160, 425–427 (1968).
Migeon, B. R. Biochem. Genet. 4, 377–384 (1970).
Migcon, B. R. Am. J. hum. Genet. 23, 199–210 (1971).
Trainor, K. J. et al. in Mechanisms of Ageing and Development 27, 83–86 (1984).
Nyhan, W. L., Bakay, B., Connor, J. D., Marks, J. F. & Keele, D. K. Proc. natn. Acad. Sci. U.S.A. 65, 214–218 (1970).
Dancis, J. et al. Life Sci. 7, 587–591 (1968).
Albertini, R. J. & DeMars, R. Biochem. Genet. 11, 397–411 (1974).
Mohandas, T., Sparkes, R. S. & Shapiro, L. J. Science 211, 393–396 (1981).
Beggs, A., Axelman, J. & Migeon, B. R. Somatic Cell Genet. 12, 585–594 (1986).
Kaslow, D. C. & Migeon, B. R. Proc. natn. Acad. Sci. U.S.A. 84, 6210–6214 (1987).
Wolf, S. F., Jolly, D. J., Lunnen, K. D., Friedmann, T. & Migeon, B. R. Proc. natn. Acad. Sci. U.S.A. 81, 2806–2810 (1984).
Yen, P. H., Patel, P., Chinault, A. C., Mohandas, T. & Shapiro, L. J. Proc. natn. Acad. Sci. U.S.A. 81, 1759–1763 (1984).
Migeon, B. R. Nature 239, 87–89 (1972).
Wolf, S. F. & Migeon, B. R. Nature 295, 667–671 (1982).
Wolf, S. F. et al. Nucleic Acids Res. 12, 9333–9348 (1984).
Riggs, A. D., Singer-Sam, J. & Keith, D. H. in Biology and Biochemistry of DNA Methylation (eds Cantoni, G. L. & Razin, A.) 211–222 (Liss, New York, 1985).
Bird, A. P. Nature 321, 209–213 (1986).
Ruta Cullen, C., Hubberman, P., Kaslow, D. C. & Migeon, B. R. EMBO J. 9, 2223–2229 (1986).
Hannibal, M. C., Cullen, C. R., Kaslow, D. C., Davies, K. E. & Migeon, B. R. Am. J. hum. Genet. 39, A201 (1986).
Mullins, L. J., Veres, G., Caskey, C. T. & Chapman, V. Molec. cell. Biol. 7, 3916–3922 (1987).
Wilson, V. L., Smith, R. A., Mas, S. & Cutler, R. G. J. biol. Chem. 262, 9948–9951 (1987).
Fairweather, D. S., Fox, M. & Margison, G. P. Expl Cell Res. 168, 153–159 (1987).
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Migeon, B., Axelman, J. & Beggs, A. Effect of ageing on reactivation of the human X-linked HPRT locus. Nature 335, 93–96 (1988). https://doi.org/10.1038/335093a0
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DOI: https://doi.org/10.1038/335093a0
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