Advertisement

Somatic Cell and Molecular Genetics

, Volume 16, Issue 3, pp 267–282 | Cite as

Sex difference in methylation of single-copy genes in human meiotic germ cells: Implications for X chromosome inactivation, parental imprinting, and origin of CpG mutations

  • Daniel J. Driscoll
  • Barbara R. Migeon
Article

Abstract

To determine the methylation status of female germ cells in reference to the programmed reversal of X chromosome inactivation in these cells, we examined human fetal ovaries at developmental stages from the time germ cells initiate meiosis to when they cease to synthesize DNA (8–21 weeks gestation). Using methylation-sensitive restriction enzymes, we analyzed 57 MspI sites (32 sites in the CpG islands, and 25 nonclustered sites) from five X-linked housekeeping genes (HPRT, G6PD, P3, PGK, and GLA) and two tissue specific genes (X-linked F9 and autosomal EPO). Methylation patterns were compared to those of male germ cells, sperm, and somatic tissues of both sexes. All 32 MspI sites in CpG islands were unmethylated in germ-cell fractions of fetal ovary and adult testes, which could explain the reversibility of X inactivation in these tissues. However, whereas male meiotic germ cells were extensively methylated outside the islands (in the body of genes) and the methylation patterns resembled those of most somatic tissues, none of the 25 nonclustered CpGs was methylated in DNA contributed by the germ-cell component of fetal ovaries. The presence of faint MspI-like fragments in HpaII digests of fetal testes as well as fetal ovary prior to the onset of meiosis suggests that DNA of primordial germ cells is unmethylated in both sexes. Our observations of meiotic germ cells suggest that the female germ cells remain unmethylated, but that methylation in male germ cells occurs postnatally, prior to or during the early stages of spermatogenesis. In any event, the striking sex difference in methylation status of endogenous single-copy genes in meiotic germ cells could provide a molecular basis for parental imprinting of the mammalian genome.

Keywords

Germ Cell Somatic Tissue Primordial Germ Cell Male Germ Cell Chromosome Inactivation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literature cited

  1. 1.
    Wolf, S.F., Jolly, D.J., Lunnen, K.D., Friedmann, T., and Migeon, B.R. (1984).Proc. Natl. Acad. Sci. U.S.A. 812806–2810.PubMedGoogle Scholar
  2. 2.
    Wolf, S.F., Dintzis, S., Toniolo, D., Persico, G., Lunnen, K.D., Axelman, J., and Migeon, B.R. (1984).Nucleic Acids Res. 129333–9348.PubMedGoogle Scholar
  3. 3.
    Keith, D.H., Singer-Sam, J., and Riggs, A.D. (1986).Mol. Cell. Biol. 64122–4125.PubMedGoogle Scholar
  4. 4.
    Toniolo, D., Martini, G., Migeon, B.R., and R. Dono. (1988).EMBO J. 7401–406.PubMedGoogle Scholar
  5. 5.
    Kaslow, D.C., and Migeon, B.R. (1987).Proc. Natl. Acad. Sci. U.S.A. 846210–6214.PubMedGoogle Scholar
  6. 6.
    Lock, L.F., Takagi, N., and Martin, G.R. (1987).Cell 4839–46.PubMedGoogle Scholar
  7. 7.
    Migeon, B.R., Wolf, S.F., Axelman, J., Kaslow, D.C. and Schmidt, M. (1985).Proc. Natl. Acad. Sci. U.S.A. 823390–3394.PubMedGoogle Scholar
  8. 8.
    Yen, P.H., Patel, P., Chinault, A.C., Mohandas, T., and Shapiro, L.J. (1984).Proc. Natl. Acad. Sci. U.S.A. 811759–1763.PubMedGoogle Scholar
  9. 9.
    Migeon, B.R., Schmidt, M., Axelman, J., and Ruta Cullen, C. (1986).Proc. Natl. Acad. Sci. U.S.A. 832182–2186.PubMedGoogle Scholar
  10. 10.
    Gartler, S.M., Liskay, R.M., Campbell, B.K., Sparks, R., and Grant, N. (1972).Cell Differen. 1215–218.Google Scholar
  11. 11.
    Migeon, B.R., and Jelalian, K. (1977).Nature 269242–243.PubMedGoogle Scholar
  12. 12.
    Kratzer, P.G., and Chapman, V.M. (1981).Proc. Natl. Acad. Sci. U.S.A. 783093–3097.PubMedGoogle Scholar
  13. 13.
    Gill, P., Jeffreys, A.J., and Werrett, D.J. (1985).Nature 318577–579.PubMedGoogle Scholar
  14. 14.
    Blandau, R.J., White, B.J., and Rumery, R.E. (1963).Fertil. Steril. 14482–489.PubMedGoogle Scholar
  15. 15.
    Migeon, B.R., Jan de Beur, S., and Axelman, J. (1989).Exp. Cell Res. 182597–609.PubMedGoogle Scholar
  16. 16.
    Alcalay, M., and Toniolo, D. (1988).Nucleic Acids Res. 169527–9543.PubMedGoogle Scholar
  17. 17.
    Tsuji, S., Martin, B.M., Kaslow, D.C., Migeon, B.R., Choudary, P.V., Stubblefield, B.K., Mayor, J.A., Murrary, G.J., Barranger, J.A., and Ginns, E.I. (1987).Eur. J. Biochem. 165275–280.PubMedGoogle Scholar
  18. 18.
    Bishop, D.F., Kornreich, R., and Desnick, R.J. (1988).Proc. Natl. Acad. Sci. U.S.A. 853903–3907.PubMedGoogle Scholar
  19. 19.
    Anson, D.S., Choo, K.H., Rees, D.J.G., Gianelli, F., Gould, K., Huddleston, J.A., and Brownlee, G.G. (1984).EMBO. J. 31053–1060.PubMedGoogle Scholar
  20. 20.
    Ruta Cullen, C., Hubberman, P., Kaslow, D.C., and Migeon, B.R. (1986).EMBO J. 92223–2229.Google Scholar
  21. 21.
    Semenza, G.L., Ladias, J.A.A., and Antonarakis, S.E. (1987).Nucleic Acids Res. 156768.PubMedGoogle Scholar
  22. 22.
    Jacobs, K., Shoemaker, C., Rudersdorf, R., Neill, S.D., Kaufman, R.J., Mufson, A., Seehra, J., Jones, S.J., Hewick, R., Fritsch, E.F., Kawakita, M., Shimizu, T., and Miyake, T. (1985).Nature 313806–810.PubMedGoogle Scholar
  23. 23.
    Baker, T.G. (1963).Proc. R. Soc. London B 158417–433.Google Scholar
  24. 24.
    Monk, M., and Harper, M.I. (1979).Nature 281311–313.PubMedGoogle Scholar
  25. 25.
    Andina, R.J. (1978).Exp. Cell Res. 111211–218.PubMedGoogle Scholar
  26. 26.
    Sanford, J.P., Clark, H.J., Chapman, V.M. and Rossant, J. (1987).Genes Dev. 11039–1046.PubMedGoogle Scholar
  27. 27.
    Monk, M., Boubelik, M., and Lehnert, S. (1987).Development 99371–382.PubMedGoogle Scholar
  28. 28.
    Singh, R.P., and Carr, D.H. (1966).Anat. Rec. 155369–384.PubMedGoogle Scholar
  29. 29.
    Clement, P.B. (1987).Am. J. Surg. Pathol. 11277.PubMedGoogle Scholar
  30. 30.
    Valdes-Dapena, M.A. (1967).Ann. N.Y. Acad. Sci. 142597–613.PubMedGoogle Scholar
  31. 31.
    Skakkebaek, N.E., and Heller, C.G. (1973).J. Reprod. Fertil. 32379–386.PubMedGoogle Scholar
  32. 32.
    Sanford, J.P., Forrester, L., Chapman, V., Chandley, A., and Hastie, N. (1984).Nucleic Acids Res. 122823–2836.PubMedGoogle Scholar
  33. 33.
    McCarrey, J., and Thomas, K. (1987).Nature 326501–505.PubMedGoogle Scholar
  34. 34.
    Groudine, M., and Conkin, K.F. (1985).Science 2281061–1068.PubMedGoogle Scholar
  35. 35.
    Swain, J.L., Stewart, T.A., and Leder, P. (1987).Cell 50719–727.PubMedGoogle Scholar
  36. 36.
    Sapienza, C., Paquette, J., Ivan, T.H., and Peterson, A. (1989).Development 107165–168.PubMedGoogle Scholar
  37. 37.
    McLaren, A. (1988).Phil. Trans. R. Soc London B 3223–9.Google Scholar
  38. 38.
    McGrath, J., and Solter, D. (1984).Cell 37179–183.PubMedGoogle Scholar
  39. 39.
    Surani, M.A.H., Barton, S.C., and Norris, M.L. (1984).Nature 308548–550.PubMedGoogle Scholar
  40. 40.
    Cattanach, B.M., and Kirk, M. (1985).Nature 315496–498.PubMedGoogle Scholar
  41. 41.
    Nicholls, R.D., Knoll, J.H.M., Butler, M.G., Karam, S., and Lalande, M. (1989).Nature 342281–285.PubMedGoogle Scholar
  42. 42.
    Samollow, P.B., Ford, A.L., and VandeBerg, J.L. (1987).Genetics 115185–195.PubMedGoogle Scholar
  43. 43.
    Silva, A.J., and White, R. (1988).Cell 54145–152.PubMedGoogle Scholar
  44. 44.
    Cooper, D.N., and Youssoufian, H. (1988).Hum. Genet. 78151–155.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1990

Authors and Affiliations

  • Daniel J. Driscoll
    • 1
  • Barbara R. Migeon
    • 1
  1. 1.Department of PediatricsThe Johns Hopkins University School of MedicineBaltimore

Personalised recommendations