Escape from X inactivation drives sex differences in gene expression

Abstract

X chromosome inactivation (XCI) partially balances gene dosage between sexes, yet many genes are expressed from the inactive X (Xi) to a variable degree. In this study, we investigate whether variation in Xi expression among genes predicts transcriptional and phenotypic consequences of X-linked variation. We find that Xi expression levels are a strong linear predictor of female-male expression differences, suggesting that other compensatory or regulatory mechanisms play a more minor role in sex differences in X-linked gene expression. Among females, we identify traits--including BMI, estradiol, and testosterone levels--for which higher Xi expression correlates with the strength of evidence for either additive or dominance effects on the trait. We hypothesize that an underappreciated mechanism could generate dominance effects of X-linked variants on a trait--specifically when the variant influences skew in X inactivation. The work establishes Xi expression as important for understanding transcriptional sex differences and the physiological variation among females.