Genetic mechanisms for tissue-specific essential genes

Abstract

Genetic diseases often manifest in specific tissues despite having the genetic risk variants in all cells. The most commonly assumed mechanism is selective expression of the causal gene in the pathogenic tissues, but other mechanisms are less explored. Using CRISPR screens from 789 cell lines and 27 lineages, we identified 1274 lineage-specific essential genes (LSEGs). We show that only a minority of LSEGs are explained by preferential expression (n = 115), and a big proportion of them (n = 509) is explained by lineage-specific gene amplification. Three other mechanisms were identified by genome-wide expression analysis. First, lineage-specific expression of paralogs leads to reduced functional redundancy and can account for 153 LSEGs. Second, for 45 LSEGs, the paralog expression increases vulnerability, implying functional codependency. Third, we suggest that the transfer of small molecules to mutant cells could explain blood-specific essentiality. Overall, LSEGs were more likely to be associated with human diseases than common essential genes, were highly intolerant to mutations and function in developmental pathways. Analysis of diverse human cell types found that the expression specificity of LSEGs and their paralogs is consistent with preferential expression and functional redundancy being a general phenomenon. Our findings offer important insights into genetic mechanisms for tissue specificity of human diseases.