Skewed X-inactivation is common in the general female population

Ekaterina Shvetsova, Peter A C 't Hoen, D.I. Boomsma, R. Pool, J. van Dongen, J.J. Hottenga, Gonneke Willemsen, BIOS Consortium

Research output: Contribution to JournalArticleAcademicpeer-review


X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.

Original languageEnglish
Pages (from-to)455-465
Number of pages11
JournalEuropean Journal of Human Genetics
Issue number3
Publication statusPublished - Mar 2019


Acknowledgements LUMC’s Sequence Analysis Support Core for assistance with pipeline development and RNA-seq data submission. We thank Andrew Sharp (Mount Sinai, NY, USA) for critically reviewing the manuscript. The study was supported by the Moscow State University – Leiden University Medical Center Bioinformatics summer exchange program in bioinformatics (MoBiLe). This work was partially funded by BBMRI-NL, a research infrastructure financed by the Netherlands Organization for Scientific Research (NWO project 184.021.007).

FundersFunder number
Leiden University Medical Center Bioinformatics
Netherlands Organization for Scientific Research
Nederlandse Organisatie voor Wetenschappelijk Onderzoek184.021.007
Bauman Moscow State Technical University

    Cohort Studies

    • Netherlands Twin Register (NTR)


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