X chromosome-inactivation patterns of 1,005 phenotypically unaffected females

Abstract

X-chromosome inactivation is widely believed to be random in early female development and to result in a mosaic distribution of cells, approximately half with the paternally derived X chromosome inactive and half with the maternally derived X chromosome inactive. Significant departures from such a random pattern are hallmarks of a variety of clinical states, including being carriers for severe X-linked diseases or X-chromosome cytogenetic abnormalities. To evaluate the significance of skewed patterns of X inactivation, we examined patterns of X inactivation in a population of >1,000 phenotypically unaffected females. The data demonstrate that only a very small proportion of unaffected females show significantly skewed inactivation, especially during the neonatal period. By comparison with this data set, the degree of skewed inactivation in a given individual can now be quantified and evaluated for its potential clinical significance.

Figure 1.

The X-inactivation patterns of 1,005 females were assigned to 21 “bins” with a range of <2:98 to >98:2, with increments of 5%. These are normally distributed, with the mean of the distribution residing at 49:51 and the median at 50:50 (SD of the mean = 17).

Figure 2.

Distributions of X-inactivation ratios of both newborn samples (n=590) and unaffected adult females (n=415).

Figure 3.

Comparison of the newborn distribution with predicted normal distributions of varying stem-cell pool size. The solid black curve follows a normal distribution with use of the actual SD of the newborn samples (15.4 [fig. 2]). The estimated number of precursor stem cells predicted by the newborn SD is between 10 and 12 cells.