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Homozygous Tsix mutant mice reveal a sex-ratio distortion and revert to random X-inactivation

Abstract

Tsix1 controls X-chromosome inactivation (XCI) by blocking the accumulation of Xist2,3,4 RNA on the future active X chromosome5,6,7. Deleting Tsix on one X chromosome (XΔX) skews XCI toward the mutated X chromosome in the female soma. Here I have generated homozygous Tsix-null mice (XΔXΔ) to test how deleting the second allele affects the choice of XCI. Homozygosity leads to extremely low fertility and reveals two previously unknown non-mendelian patterns of inheritance. First, the sex ratio is skewed against female births so that one daughter is born for every two to three sons. Second, the pattern of XCI unexpectedly returns to random in surviving XΔXΔ mice. Thus, with respect to choice, mutation of Tsix yields a phenotypic abnormality in heterozygotes but not homozygotes. To reconcile the paradox of female loss with apparent reversion to random choice, I propose that deleting both Tsix alleles results in chaotic choice and that randomness in XΔXΔ survivors reflects a fortuitous selection of distinct X chromosomes as active and inactive.

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Figure 1: Homozygosity at Tsix reveals a sex-ratio distortion.
Figure 2: Extremely low fertility of XΔXΔ females.
Figure 3: Effects of Tsix homozygosity on trophoblast and ICM growth.
Figure 4: A reversion to random X-chromosome choice.
Figure 5: Three models that could explain sex-ratio distortion and apparent reversion to random choice.

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References

  1. Lee, J.T., Davidow, L.S. & Warshawsky, D. Tsix, a gene antisense to Xist at the X-inactivation center. Nature Genet. 21, 400–404 (1999).

    Article  CAS  Google Scholar 

  2. Brown, C.J. et al. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349, 38–44 (1991).

    Article  CAS  Google Scholar 

  3. Brown, C.J. et al. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71, 527–542 (1992).

    Article  CAS  Google Scholar 

  4. Brockdorff, N. et al. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71, 515–526 (1992).

    Article  CAS  Google Scholar 

  5. Lee, J.T. & Lu, N. Targeted mutagenesis of Tsix leads to nonrandom X-inactivation. Cell 99, 47–57 (1999).

    Article  CAS  Google Scholar 

  6. Stavropoulos, N., Lu, N. & Lee, J.T. A functional role for Tsix transcription in blocking Xist RNA accumulation but not in X-chromosome choice. Proc. Natl Acad. Sci. USA 98, 10232–10237 (2001).

    Article  CAS  Google Scholar 

  7. Luikenhuis, S., Wutz, A. & Jaenisch, R. Antisense transcription through the Xist locus mediates Tsix function in embryonic stem cells. Mol. Cell. Biol. 21, 8512–8520 (2001).

    Article  CAS  Google Scholar 

  8. Lyon, M.F. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190, 372–373 (1961).

    Article  CAS  Google Scholar 

  9. Avner, P. & Heard, E. X-chromosome inactivation: counting, choice, and initiation. Nature Rev. Genet. 2, 59–67 (2001).

    Article  CAS  Google Scholar 

  10. Boumil, R.M. & Lee, J.T. 40 years of decoding the silence in X-chromosome inactivation. Hum. Mol. Genet. 10, 2225–2232 (2001).

    Article  CAS  Google Scholar 

  11. Takagi, N. & Sasaki, M. Preferential inactivation of the paternally derived X-chromosome in the extraembryonic membranes of the mouse. Nature 256, 640–642 (1975).

    Article  CAS  Google Scholar 

  12. Huynh, K.D. & Lee, J.T. Imprinted X inactivation in eutherians: a model of gametic execution and zygotic relaxation. Curr. Opin. Cell. Biol. 13, 690–697 (2001).

    Article  CAS  Google Scholar 

  13. Penny, G.D., Kay, G.F., Sheardown, S.A., Rastan, S. & Brockdorff, N. Requirement for Xist in X chromosome inactivation. Nature 379, 131–137 (1996).

    Article  CAS  Google Scholar 

  14. Lee, J.T. Disruption of imprinted X inactivation by parent-of-origin effects at Tsix. Cell 103, 17–27 (2000).

    Article  CAS  Google Scholar 

  15. Sado, T., Wang, Z., Sasaki, H. & Li, E. Regulation of imprinted X-chromosome inactivation in mice by Tsix. Development 128, 1275–1286 (2001).

    CAS  PubMed  Google Scholar 

  16. Okamoto, I., Tan, S.S. & Takagi, N. X-chromosome inactivation in XX androgenetic mouse embryos surviving implantation. Development 127, 4137–4145 (2000).

    CAS  PubMed  Google Scholar 

  17. Bell, A.C., West, A.G. & Felsenfeld, G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell 98, 387–396 (1999).

    Article  CAS  Google Scholar 

  18. Bell, A. & Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482–485 (2000).

    Article  CAS  Google Scholar 

  19. Hark, A.T. et al. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405, 486–489 (2000).

    Article  CAS  Google Scholar 

  20. Kanduri, C. et al. Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr. Biol. 10, 853–856 (2000).

    Article  CAS  Google Scholar 

  21. Chao, W., Huynh, K.D., Spencer, R.J., Davidow, L.S. & Lee, J.T. CTCF, a candidate trans-acting factor for X-inactivation choice. Science 295, 345–347 (2002).

    Article  CAS  Google Scholar 

  22. Percec, I., Plenge, R.M., Nadeau, J.H., Bartolomei, M.S. & Willard, H.F. Autosomal dominant mutations affecting X inactivation choice in the mouse. Science 296, 1136–1139 (2002).

    Article  CAS  Google Scholar 

  23. Carrel, L. et al. X inactivation analysis and DNA methylation studies of the ubiquitin activating enzyme E1 and PCTAIRE-1 genes in human and mouse. Hum. Mol. Genet. 5, 391–401 (1996).

    Article  CAS  Google Scholar 

  24. Charlier, C. et al. The callipyge mutation enhances the expression of coregulated imprinted genes in cis without affecting their imprinting status. Nature Genet. 27, 367–369 (2001).

    Article  CAS  Google Scholar 

  25. Pardo-Manuel de Villena, F., Naumova, A.K., Verner, A.E., Jin, W.H. & Sapienza, C. Confirmation of maternal transmission ratio distortion at Om and direct evidence that the maternal and paternal 'DDK syndrome' genes are linked. Mamm. Genome 8, 642–646 (1997).

    Article  CAS  Google Scholar 

  26. Cattanach, B.M. & Papworth, D. Controlling elements in the mouse. V. Linkage tests with X-linked genes. Genet. Res. 38, 57–70 (1981).

    Article  CAS  Google Scholar 

  27. Marahrens, Y., Loring, J. & Jaenisch, R. Role of the Xist gene in X chromosome choosing. Cell 92, 657–664 (1998).

    Article  CAS  Google Scholar 

  28. Plenge, R.M. et al. A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Nature Genet. 17, 353–356 (1997).

    Article  CAS  Google Scholar 

  29. Marahrens, Y. X-inactivation by chromosomal pairing events. Genes Dev. 13, 2624–2632 (1999).

    Article  CAS  Google Scholar 

  30. Kay, G.F. et al. Expression of Xist during mouse development suggests a role in the initiation of X chromosome inactivation. Cell 72, 171–182 (1993).

    Article  CAS  Google Scholar 

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Acknowledgements

I thank N. Stavropoulos for identifying the HinfI SNP in Hprt; C. Sapienza for sharing views on polar overdominance; and D. Altshuler, D. Cohen, M. Donohoe, K. Huynh, J. Kirby and B. Sun for comments on the manuscript. This work was funded by the US National Institutes of Health and the Pew Scholars Program. The author is an assistant investigator of the Howard Hughes Medical Institute.

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Correspondence to Jeannie T. Lee.

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Lee, J. Homozygous Tsix mutant mice reveal a sex-ratio distortion and revert to random X-inactivation. Nat Genet 32, 195–200 (2002). https://doi.org/10.1038/ng939

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