Reassessing the "sexy" X hypothesis reveals distinct cellular and disease signatures of X-linked genes in male sexual differentiation and reproduction

The human X chromosome (chrX) has long been proposed to be enriched in genes involved in brain development, reproduction and sexual differentiation, earning the epithet of "smart and sexy" chromosome. Many studies have confirmed that the chrX is indeed "smart", but it is less clear whether "sexy" still holds true. Here, we investigated human X-linked genes with respect to their expression levels across tissues and cell types, their annotated functions, and their association with monogenic disorders affecting sexual differentiation and reproduction (SDR). We confirm that many brain and sex-specific tissues show high X-to-autosome (X:A) expression ratios; however, paradoxically, some of the corresponding main cell types, such as neurons or prostatic or endometrial cells, show X:A ratios below the average. In contrast, cell types such as blood and vascular cells have elevated X:A ratios, suggesting that they contribute to the high ratios observed at the tissue bulk level. Analysing the most highly expressed genes across tissues and cell types, we observed a significant enrichment in chrX genes for testes, spermatogonia and Sertoli cells. Interestingly, monogenic disorders with SDR phenotypes showed a significant enrichment of chrX genes only when related to male-specific conditions. Our study thus supports a male-biased view of the "sexy" human chrX, whereby it is particularly enriched in genes highly expressed in testicular cell types and in genes involved in male reproductive monogenic disorders. Intriguingly, these genes overlap very little, suggesting an important disconnect between expression levels and clinical associations, at least on the X chromosome.