Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

Abstract

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.

Figure 1. Adjusted mean rate of events by chromosome.

A comparison of detected mosaic events >2 Mb in size in the autosomes to the X chromosome (X events=124, Autosomal events=430).

Figure 2. Detected mosaic events on the X chromosome.

Mosaic losses (N=59) are in red, mosaic gains (N=22) are green, and mosaic copy-neutral events (N=43) are in blue.

Figure 3. Unadjusted age relationship with X mosaicism.

Dashed line represents the mean overall proportion with mosaic X events across all age groups and error pars represent 95% Wilson confidence intervals (N=31,982).

Figure 4. Chromosome X methylation beta values by estimated mosaic proportion.

Average beta values (range: 0.0–1.0) indicate amount of methylation at a genomic locus where low values indicate hypomethylation and high values indicate hypermethylation. X methylation beta values are plotted for promoter probes spanning a mosaic X event and points are sized for the number of probes. The estimated mosaic proportion is calculated from the mosaic proportion estimate of the SNP microarrays and direction (positive versus negative) is determined from average probe beta z-scores. Control men (N=1,665) and women (N=136) are shown as light grey squares and circles. Mosaic females (N=48) are plotted as green, blue and red circles for mosaic gains, copy-neutral events and losses, respectively. Solid and dashed black lines are median and interquartile range for control men (left) and women (right) beta values.