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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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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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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DOI: https://doi.org/10.1038/ng939
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