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.

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

“…Moreover, an over-abundance of 47,XXY males also develop lupus, implicating the presence of the inactive X as a risk factor for this disorder. While a full assessment of the many potential impacts of the X on [6] or with ageing [7] a See text for additional discussion and references. rstb.royalsocietypublishing.org Phil.…”

X chromosome‐linked long noncoding RNA lnc‐XLEC1 regulates c‐Myc‐dependent cell growth by collaborating with MBP‐1 in endometrial cancer

“…Theoretically, the X chromosomes from female (Xm) and male (Xp) have equal chances to be inactivated. However, the deviation that alters this ratio, termed SXCI, is a unique phenomenon in females . SXCI is usually involved in many types of cancers, particularly gynecologic tumors such as breast cancer and ovarian cancer .…”

“…However, the deviation that alters this ratio, termed SXCI, is a unique phenomenon in females. 31,32 SXCI is usually involved in many types of cancers, particularly gynecologic tumors such as breast cancer and ovarian cancer. 13,33 The development of lung cancer and esophageal cancer is also associated with SXCI.…”

The ageing genome, clonal mosaicism and chronic disease

“…Mosaicism on the X chromosome is 4 times more common than autosomal mosaicism and the female inactivated X chromosome is preferentially affected, interestingly similar to the higher rate of somatic alterations observed in the inactivated X chromosome in many cancers[19,53]. Mosaic chromosome Y loss is more common than autosomal and X mosaicism, reaching frequencies in excess of 15% in men over 80 years old[20,21].…”

“…Examples of genetic mosaicism include mosaic single nucleotide substitutions[8,9], mosaic structural deletions larger than 1 megabase (Mb)[15–17] or mosaic gains of an entire chromosome[18]. Genetic mosaicism has been described in all chromosomes, including the sex chromosomes at a higher frequency[19–21] than the autosomes[6,7,17,18]; so far, large surveys have not yet provided an accurate estimate of the frequency of mosaic mitochondrial DNA[22,23]. Current technologies permit detection of cellular fractions with alternative genotypes in between 5 and 95% of circulating leukocytes and have shown these fractions can increase by approximately 1% per year in adult cohorts[18].…”