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

Tsix(1) controls X-chromosome inactivation (XCI) by blocking the accumulation of Xist(2-4) RNA on the future active X chromosome(5-7). Deleting Tsix on one X chromosome ((XX)-X-Delta) skews XCI toward the mutated X chromosome in the female soma. Here 1 have generated homozygous Tsix-null mice ((XXDelta)-X-Delta) 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 (XXDelta)-X-Delta 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 (XXDelta)-X-Delta survivors reflects a fortuitous selection of distinct X chromosomes as active and inactive.