Escape from X inactivation varies across genes and tissues and shapes sex-biased sex chromosome gene expression

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.