Article

The dynamics of X-inactivation skewing as women age.

Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Clinical Genetics (impact factor: 3.13). 10/2004; 66(4):327-32. DOI:10.1111/j.1399-0004.2004.00310.x pp.327-32
Source: PubMed

ABSTRACT 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.

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Keywords

350 unselected women
 
age-related alteration
 
androgen receptor locus
 
assay appropriately
 
clinical research
 
genetic disorders
 
neoplastic diseases
 
non-random XCI
 
normal females
 
older ages
 
older female populations
 
recurrent pregnancy loss
 
significant positive correlation
 
skewed XCI
 
trisomy risk
 
whole age range
 
X-linked diseases
 
XCI skewing
 
XCI status
 
younger ages
 

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