Sex-biased gene expression shapes sex differences in gene essentiality

Abstract

Sex differences in disease incidence and progression are well documented, yet their underlying molecular mechanisms remain poorly understood. Multiple models suggest that baseline gene expression levels shape the impact of gene disruption, raising the possibility that sex-biased expression itself contributes to sex differences in cellular vulnerability. Here, we test this hypothesis by integrating sex-biased transcriptomic profiles with large-scale CRISPR loss-of-function screens to determine whether sex-biased expression predicts sex-biased gene essentiality across the genome. We find that gene expression level and sex chromosome dosage each explain a modest fraction of variance in essentiality, with substantially larger effects for sex chromosome genes than for autosomes. Across genes, sex effects on expression and essentiality are small in magnitude but directionally aligned, suggesting that sex differences in transcription can influence functional dependency. To resolve how these relationships arise, we applied gene-level mediation analyses to decompose sex effects on essentiality into expression-mediated and expression-independent components. This approach revealed multiple mechanistic architectures. On autosomes, most genes exhibited either sex-biased essentiality from direct sex effects (independent of expression) or sex-biased expression without functional consequence, while expression-mediated sex differences accounted for a smaller but substantial fraction of genes. In contrast, X chromosome genes were dominated by direct, expression-independent sex differences, consistent with strong effects of sex chromosome dosage, but also showed enrichment of expression-mediated architectures, particularly among X gametologs. Together, our results demonstrate that while sex-biased expression can generate sex-biased gene essentiality, this mechanism is not the default. Instead, sex-biased functional dependency is often driven by direct, expression-independent effects, particularly on the X chromosome, where dosage and compensatory mechanisms play a dominant role.