Abstract
The gene dosage inequality between females with two X-chromosomes and males with one is compensated for by X-chromosome inactivation (XCI), which ensures the silencing of one X in every somatic cell of female mammals. XCI in humans results in a mosaic of two cell populations: those expressing the maternal X-chromosome and those expressing the paternal X-chromosome. We have previously shown that the degree of mosaicism (the X-inactivation pattern) in a Canadian family is directly related to disease severity in female carriers of the X-linked recessive bleeding disorder, haemophilia A. The distribution of X-inactivation patterns in this family was consistent with a genetic trait having a co-dominant mode of inheritance, suggesting that XCI choice may not be completely random. To identify genetic elements that could be responsible for biased XCI choice, a linkage analysis was undertaken using an approach tailored to accommodate the continuous nature of the X-inactivation pattern phenotype in the Canadian family. Several X-linked regions were identified, one of which overlaps with a region previously found to be linked to familial skewed XCI. SA2, a component of the cohesin complex is identified as a candidate gene that could participate in XCI through its association with CTCF.
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Acknowledgements
We thank Drs M Dobson, C Riddell, P Avner and S Dyack for helpful discussions. We gratefully acknowledge the CIHR, Killam Trust, Canadian Hemophilia Society, CDHA, IWK Health Centre, and Dalhousie University for support. Part of this work was completed by the Australian Genome Research Facility, Victoria, Australia. We acknowledge their contribution and the support they receive from the Commonwealth.
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Renault, N., Renault, M., Copeland, E. et al. Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2. J Hum Genet 56, 390–397 (2011). https://doi.org/10.1038/jhg.2011.25
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DOI: https://doi.org/10.1038/jhg.2011.25
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