X-chromosome inactivation (XCI) is controlled by expression of the Tsix gene and its regulation of Xist mRNA accumulation. Deleting one copy of Tsix results in skewed XCI towards the mutated X chromosome in female soma. In an Advanced Online Publication in Nature Genetics Jeannie Lee reports the generation of homozygous Tsix-null mice by breeding heterozygote animals (Nat Genet 2002, DOI:10.1038/ng939).

The frequency of homozygote offspring was 20–40% of that expected. Furthermore, homozygous mutation caused a significant sex-ratio distortion favoring male births. Homozygous null females had extremely low fertility and were often sterile. The sex-ratio distortion seems to be linked to female-specific defects in trophoblast and inner cell mass (ICM) growth. Lee generated hybrid mice with polymorphic X chromosomes to monitor XCI. She demonstrated that the loss of both copies of Tsix randomizes XCI. Lee proposes a "chaotic" choice model to explain these observations.

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