Genetic diseases often manifest in a specific tissue despite the genetic risk variant being present in all the cells. The most commonly assumed mechanism for this tissue-specificity is the selective expression of the causal gene in the pathogenic tissue, but other possible mechanisms are less explored. Here, using genome-scale CRISPR screens and expression data from approximately 800 cancer cell lines, we identified 1274 tissue-specific essential genes (TSEGs) and show that only a minority of these genes can be explained by preferential expression. To elucidate the mechanisms for the TSEGs we analyzed their association with gene expression. The expression of 115 TSEGs was consistent with preferential expression in the vulnerable tissues. Counterintuitively, for 509 TSEGs we observe a decrease in expression in the vulnerable tissues, which is mainly explained by the increase in gene copy number. Analyzing the expression level of all other genes in the genome identified three other suggested mechanisms for TSEGs. First, based on the expression of paralogs, we observed reduced functional redundancy for 273 TSEGs out of the 741 with known paralogs. Second, in another 118 TSEGs, we found a surprisingly significantly higher expression of their paralogs in the vulnerable tissues, implying functional codependency. Finally, using gene set enrichment analyses, we provide evidence for the remaining 466 TSEGs that the transfer of small molecules to mutant cells by non-mutant cells could explain blood-specific essentiality. Our findings indicate that reliance only on the preferential expression of disease genes may bias views of the disease-relevant tissues.
