A molecular study of X chromosome inactivation in humans

Abstract

Using DNA extracted from blood samples from 270 informative females, I determined that severely skewed X-inactivation in normal women is relatively common and increases with age (P<0.05). Samples of both buccal and urinary epithelia were also obtained from 88 of the females studied. Although there was a significant association of the X-inactivation ratios between different tissues in most individuals, wide variations were apparent in some cases, making accurate extrapolations between tissues impossible. The degree of correlation between tissues fell markedly with age. Overall, these data suggest that the major factors in the aetiology of skewed X-inactivation are secondary selection processes.

Previous studies in cases of trisomy rescue for a number of autosomes show a strong association with skewed X-inactivation. Data from the control group was used to test the hypothesis that trisomy 7 mosaicism causes Silver-Russell syndrome, a syndrome which has previously been attributed to imprinted genes. Consistent with the hypothesis, results showed a significant increase in the frequency of completely skewed X-inactivation in SRS patients (3 of 29) when compared to controls (3 of 270), suggesting the presence of undetected trisomy 7 in SRS patients.

Detailed studies of the spreading of X-inactivation into autosomal DNA in five unbalanced human X:autosome translocations were also performed. Using allele-specific RT-PCR long-range silencing of autosomal genes located up to 45Mb from the translocation breakpoint was observed, directly demonstrating the ability of X-inactivation to spread in cis through autosomal DNA. Spreading of gene silencing occurred in either a continuous or discontinuous fashion in different cases, suggesting that some autosomal DNA is resistant to the X-inactivation signal. Observations of late-replication, histone acetylation, histone methylation and XIST RNA show that X-inactivation can spread in the absence of cytogenetic features of the inactive X, although these histone modifications were found to be better cytogenetic correlates of the spread of X-inactivation than late-replication.

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