Gene essentiality in cancer cell lines is modified by the sex chromosomes

Human sex differences arise from gonadal hormones and sex chromosomes. Studying the direct effects of sex chromosomes in humans is still challenging. Here we studied how the sex chromosomes can modulate gene expression and the outcome of mutations across the genome by exploiting the tendency of cancer cell lines to lose or gain sex chromosomes. We inferred the dosage of the sex chromosomes in 355 female and 408 male cancer cell lines and used it to dissect the contributions of the Y and X Chromosomes to sex-biased gene expression. Furthermore, based on genome-wide CRISPR screens, we identified genes whose essentiality is different between male and female cells depending on the sex chromosomes. The most significant genes were X-linked genes compensated by Y-linked paralogs. Our sex-based analysis identifies genes that, when mutated, can affect male and female cells differently and reinforces the roles of the X and Y Chromosomes in sex-specific cell function.