ArticleBMC genomics2026
Escape from X inactivation varies across genes and tissues and shapes sex-biased sex chromosome gene expression.
Article in BMC genomics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Sex differences in human health and disease are shaped by complex interactions between hormones, environment, and genetic factors - including those associated with sex chromosomes. While X chromosome inactivation (XCI) in females generally silences one copy of the X to equalize dosage with males, a subset of genes "escape" XCI and remain expressed from both X chromosomes. In this study, I integrate allele-specific expression data from three females with non-mosaic XCI, sex-biased expression profiles from over 40 tissues, and enhancer activity data from GTEx to explore how variation in the magnitude of XCI escape contributes to sex-biased gene expression across the human body. I confirm that female-biased expression on the X chromosome is a poor proxy for escape from XCI. I find that XCI extends into the pseudoautosomal region (PAR) and that the extent of inactivation strongly predicts male-biased expression of PAR genes. Conversely, stronger escape from XCI in non-PAR X-linked (NPX) genes is associated with more pronounced female-biased expression. Across both PAR and NPX genes, escape patterns are shaped by topologically associating domains (TADs) and sex-biased expression is supported by proximity to sex-biased enhancer activity. These findings reveal a direct, tissue-specific relationship between the strength of XCI escape and the magnitude of sex-biased gene expression, providing a mechanistic framework for understanding how the X chromosome contributes to sex-biased biology.
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