The human X chromosome in sexual differentiation and reproduction: is the X still sexy?

The X chromosome (chrX) is the eighth largest human chromosome, harbouring an estimated total of 839 protein-coding genes. Historically, the chrX has been described as enriched for genes related to brain development, sexual differentiation and reproduction, earning the epithet of "smart and sexy chromosome". Many studies have confirmed that the chrX is indeed "smart", including a recent systematic analysis of human chrX genes which found an enrichment in genes relevant to brain functions. However, it is less clear whether the chrX being "sexy" still holds true. Here we reviewed the origins of this idea and we evaluated human X-linked genes in terms of their expression across several tissues, their annotated functions and their association with monogenic disorders related to sexual differentiation and reproduction (SDR). We found that sex-specific tissues show higher expression levels from chrX genes than from autosomal genes except in testis, but that X-linked genes are significantly enriched among the most highly expressed genes in testis, specifically within spermatogonia and Sertoli cells. Yet, we found no evidence for an enrichment of genes on the X with annotated functions related to male or female SDR. When analysing SDR-related monogenic disorders, we found a significant enrichment of genes on chrX associated with clinical terms related to male SDR but not with clinical terms related to female or general SDR. Overall, our results support the notion of a somewhat "sexy" X chromosome, shaped by X-linked expression patterns and clinical associations rather than current annotated gene functions.