The dynamics of X-inactivation skewing as women age

Non-random X-chromosome inactivation (XCI) has been associated with X-linked diseases, neoplastic diseases, recurrent pregnancy loss, and trisomy risk. It also occurs more commonly in older female populations. To understand the etiology of non-random XCI and utilize this assay appropriately in clinical research and practice, the age-related alteration in XCI patterns in normal females needs to be clearly defined. In the present study, we evaluated the XCI status in 350 unselected women aged 0-88 years with unknown history of genetic disorders or abnormal pregnancies. DNA samples were extracted from peripheral blood and analyzed by a methylation-based assay at the androgen receptor locus. A weak but significant positive correlation was observed between age and degree of skewing in XCI over the whole age range (r = 0.23, p < 0.0001), and skewing values become non-normally distributed at older ages. However, the increase in skewed XCI appears to be more pronounced after age 30 than at younger ages. This trend supports the model of increased skewing with age as a consequence of hematopoietic stem cell senescence. An alternative possibility is that there is allele-specific loss of methylation with time that results in the appearance of increased XCI skewing using a methylation-based assay.