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Epigenetics and Complex Traits pp 63–88Cite as

X-Chromosome Inactivation

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Abstract

The dimorphism of the sex chromosomes has led to some of the most dramatic epigenetic phenomena known in order to achieve dosage compensation between the sexes. Mammalian X-chromosome inactivation (XCI) requires the differential treatment of two essentially identical chromosomes in the same nuclear environment. XCI has thus been the subject of considerable study in mouse as a paradigm for epigenetic choice, although less is known about the timing and initial events of XCI in humans and other species. XCI, as can be visualized by the spots on a calico cat, is also a dramatic example of the stability of epigenetic silencing, since the inactivation state of an X chromosome (X) is faithfully inherited through subsequent somatic cell divisions. Studies to understand the layering of epigenetic modifications that result in such stable silencing have been reviewed elsewhere, and in this review we focus instead on the translation of our growing understanding of the epigenetic phenomena of XCI to human disease.

X-linked disease is epitomized by an excess of affected males, but the characterization as dominant or recessive belies the complexity of the contribution of XCI. Notably, whether or not X-linked disease is apparent in females is considerably impacted by the extent of skewing of XCI in the individual. Furthermore, the unique biology of the sex chromosomes impacts the likelihood of X-linked disease in females due to de novo mutation rates. In addition, XCI does not result in complete dosage equivalence between males and females; however, the extent to which there are sex, and even interindividual differences due to XCI has not yet been well elucidated. Overall, while it is the Y chromosome (Y) that determines sex, the X contributes in a complex fashion to the sex differences in disease frequency and severity.

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Authors and Affiliations

  1. Department of Medical Genetics, Molecular Epigenetics Group, University of British Columbia, Vancouver, BC, Canada, V6T 1Z3

    Wendy P. Robinson, Allison M. Cotton, Maria S. Peñaherrera, Samantha B. Peeters & Carolyn J. Brown

  2. Child & Family Research Institute, 950 West 28th Avenue, Vancouver, BC, Canada, V5Z 4H4

    Wendy P. Robinson & Maria S. Peñaherrera

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  1. Wendy P. Robinson
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  2. Allison M. Cotton
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  3. Maria S. Peñaherrera
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  1. Departments of Obstetrics and Gynecology and Human Genetics, McGill University, Montreal, Canada

    Anna K. Naumova

  2. Lady Davis Institute for Medical Research Centre for Clinical Epidemiology, Jewish General Hospital, Montreal, Canada

    Celia M.T. Greenwood

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Robinson, W.P., Cotton, A.M., Peñaherrera, M.S., Peeters, S.B., Brown, C.J. (2013). X-Chromosome Inactivation. In: Naumova, A., Greenwood, C. (eds) Epigenetics and Complex Traits. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8078-5_3

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