Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Sex–determining genes on mouse autosomes identified by linkage analysis of C57BL/6J–YPOS sex reversal

Nature Genetics volume 14, pages 206–209 (1996) Cite this article

Abstract

A powerful approach for identifying mammalian primary (gonadal) sex determination genes is the molecular genetic analyses of sex reversal conditions (that is, XX individuals with testicular tissue and XY individuals with ovarian tissue)1–4. Here we determined the number and chromosomal location of autosomal and X-linked genes that cause sex reversal in C57BL/6J (B6) mice carrying a Y chromosome of Mus domesticus poschiavinus origin (Ypos). B6 XYPOS mice develop either as females with exclusively ovarian tissue or as true hermaphrodites with ovarian and testicular tissue. In contrast, the YPOS chromosome is fully masculinizing on most other inbred strain backgrounds. B6-YPOS sex reversal appears to result from the incompatibility of the Sry (sex determining region, Y chromosome) allele carried on the YPOS chromosome5 with B6-derived autosomal or X-linked loci6–9. We found strong evidence for the location of one gene, designated tda1 (testis-determining, autosomal 1), at the distal end of Chromosome (Chr) 4 and a second gene, tda2, in the central region of Chr 2. A third gene, tda3, on Chr 5 is implicated, but the evidence here is not as strong. We suggest that B6 alleles at these loci predispose XYPOS fetuses to ovarian tissue development, but no single locus or combination of loci is necessary and sufficient to cause sex reversal. The IDA proteins may regulate Sry expression or form complexes with the SRY protein to regulate other genes, or the tda genes may be activated or repressed by the SRY protein.

This is a preview of subscription content, access via your institution

Access options

Similar content being viewed by others

References

  1. Goodfellow, P.M., Berkovitz, G., Hawkins, J.R., Harley, V.R. & Lovell-Badge, R. Sex determination, sex-reversal and SRY: a review in Gonadal Development and Function (ed. Hillier, S.G.) 5–15 (Raven Press, New York, 1992).

    Google Scholar 

  2. Goodfellow, P.N. & Lovell-Badge, R. SRY and sex determination in mammals. Ann. Rev. Genet. 27, 71–92 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Bogan, J.S. & Page, D.C., Ovary? Testis?—A mammalian dilemma. Cell 76, 603–607 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Pringle, M.J. & Page, D.C. Somatic and germ cell sex determination in the developing gonad in Infertility in the male (eds Howard, S. & Lipshultz, L) (Mosby Publishing, St. Louis, 1996).

    Google Scholar 

  5. Eicher, E.M., Shown, E.R. & Washburn, L.L. Sex reversal in C57BL/6J-YPOS mice corrected by a Sry transgene. Trans. B Roy. Soc. 350, 263–269 (1995).

    Article  CAS  Google Scholar 

  6. Eicher, E.M., Washburn, L.L., Whitney, J.B. III & Morrow, K.E. Mus poschiavinus Y chromosome in the C57BL/6J murine genome causes sex reversal. Science 217, 535–537 (1982).

    Article  CAS  PubMed  Google Scholar 

  7. Eicher, E.M. & Washburn, L.L. Genetic control of sex determination in mice. Ann. Rev. Genet. 20, 327–360 (1986).

    Article  CAS  PubMed  Google Scholar 

  8. Eicher, E.M. Autosomal genes involved in mammalian primary sex determination. Trans. B Roy. Soc. 322, 109–118 (1988).

    Article  CAS  Google Scholar 

  9. Eicher, E.M. Sex and trinucleotide repeats. Nature Genet. 6, 221–223 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Beamer, W.G., Whitten, W.K. & Eicher, E.M. Spontaneous sex mosaicism in BALB/cWt mice in Genetic Mosaics and Chimeras in Mammals (ed. Russell, L. B.) 195–208 (Plenum Press, New York, 1978).

    Chapter  Google Scholar 

  11. Eicher, E.M., Beamer, W.G., Washburn, L.L. & Whitten, W.K. A cytogenetic investigation of inherited true hermaphroditism in BALB/cWt mice. Cytogenet. Cell Genet. 28, 104–115 (1980).

    Article  CAS  PubMed  Google Scholar 

  12. Todd, J.A. et al. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature 351, 542–547 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Rise, M.L., Frankel, W.N., Coffin, J.M. & Seyfried, T.N. Genes for epilepsy mapped in the mouse. Science 253, 669–673 (1991).

    Article  CAS  PubMed  Google Scholar 

  14. Wright, E. et at. The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos. Nature Genet 9, 15–20 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Swain, A., Zanaria, E., Hacker, A., Lovell-Badge, R. & Camerino, G., Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nature Genet. 12, 404–409 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Nadeau, J. & Taylor, B.A. Length of chromosomal segments conserved since divergence of man and mouse. Proc. Natl. Acad. Sci. USA 81, 814–818 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nadeau, J.H. et al. Comparative map of mice and humans. Mamm. Genome 1, S461–S515 (1991).

    Article  PubMed  Google Scholar 

  18. Koopman, P., Gubbay, J., Vivian, N., Goodfellow, P. & Lovell-Badge, R. Male development of chromosomally female mice transgenic for Sry. Nature 352, 117–121 (1991).

    Article  Google Scholar 

  19. Sinclair, A.M. et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346, 240–244 (1990).

    Article  CAS  PubMed  Google Scholar 

  20. Berta, P. et al. Genetic evidence equating SRY and the testis-determining factor. Nature 348, 448–450 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. Hacker, A., Capel, B., Goodfellow, P. & Lovell-Badge, R. Expression of Sry, the mouse sex determining gene. Development 121, 1603–1614 (1995).

    CAS  PubMed  Google Scholar 

  22. Nasrin, N. et al. DNA-binding properties of the product of the testis-determining gene and a related protein. Nature 354, 317–320 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. Palmer, S.J. & Burgoyne, P.S. The Mus musculus domesticus Tdy allele acts later than the Mus musculus musculus Tdy allele: a basis for XY sex-reversal in C57BL/6-Ypos mice. Development 113, 709–714 (1991).

    CAS  PubMed  Google Scholar 

  24. Washburn, L.L. & Eicher, E.M. Sex reversal in XY mice caused by dominant mutation on chromosome 17. Nature 303, 338–340 (1983).

    Article  CAS  PubMed  Google Scholar 

  25. Washburn, L.L. & Eicher, E.M. Normal testis determination in the mouse depends on genetic interaction of a locus on chromosome 17 and the Y chromosome. Genetics 123, 173–179 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Burgoyne, P.S. & Palmer, S.J. Cellular basis of sex determination and sex reversal in mammals in Gonadal Development and Function (ed. Hillier, S.G.)17–29 (Raven Press, New York, 1993).

    Google Scholar 

  27. Dietrich, W. F. et al A comprehensive genetic map of the mouse genome. Nature 380, 149–152 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Sokal, R.R. & Rolfe, F.J. Biometry. Second edn (W.H. Freeman and Company, New York, 1981).

    Google Scholar 

  29. Lander, E.S. & Schork, N.J. The genetic dissection of complex traits. Science 256, 2037–2048 (1994).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609, USA

    Eva M. Eicher, Linda L. Washburn, Nicholas J. Schork, Barbara K. Lee & Elaine P. Shown

  2. Department of Epidemiology and Biostatistics and Department of Genetics, Case Western Reserve University, Cleveland, Ohio, 44106, USA

    Nicholas J. Schork

  3. Howard Hughes Medical Institute, Whitehead Institute, and Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, Massachusetts, 02142, USA

    Xiaoling Xu, Robert D. Dredge, M. Todeane Pringle & David C. Page

Authors
  1. Eva M. Eicher
    View author publications

    Search author on:PubMed Google Scholar

  2. Linda L. Washburn
    View author publications

    Search author on:PubMed Google Scholar

  3. Nicholas J. Schork
    View author publications

    Search author on:PubMed Google Scholar

  4. Barbara K. Lee
    View author publications

    Search author on:PubMed Google Scholar

  5. Elaine P. Shown
    View author publications

    Search author on:PubMed Google Scholar

  6. Xiaoling Xu
    View author publications

    Search author on:PubMed Google Scholar

  7. Robert D. Dredge
    View author publications

    Search author on:PubMed Google Scholar

  8. M. Todeane Pringle
    View author publications

    Search author on:PubMed Google Scholar

  9. David C. Page
    View author publications

    Search author on:PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eicher, E., Washburn, L., Schork, N. et al. Sex–determining genes on mouse autosomes identified by linkage analysis of C57BL/6J–YPOS sex reversal . Nat Genet 14, 206–209 (1996). https://doi.org/10.1038/ng1096-206

Download citation

  • Received:

  • Accepted:

  • Issue date:

  • DOI: https://doi.org/10.1038/ng1096-206

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing