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

## TL;DR

This study shows how some genes on the X chromosome escape inactivation in females, leading to sex differences in gene expression across tissues.

## Contribution

The study reveals how variation in XCI escape contributes to sex-biased gene expression in a tissue-specific manner.

## Key findings

- Female-biased expression on the X chromosome is not a reliable indicator of escape from XCI.
- XCI extends into the pseudoautosomal region (PAR), and inactivation strength predicts male-biased expression of PAR genes.
- Escape from XCI in non-PAR X-linked genes correlates with stronger female-biased 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.

The online version contains supplementary material available at 10.1186/s12864-026-12611-3.