Identification of genetic mechanisms for tissue-specific genetic effects based on CRISPR screens

Abstract A major challenge in genetic studies of complex diseases is to determine how the action of risk genes is restricted to a tissue or cell type. Here, we investigate tissue specificity of gene action using CRISPR screens from 786 cancer cell lines originating from 24 tissues. We find that the expression pattern of the gene across tissues explains only a minority of cases of tissue-specificity (9%), while gene amplification and the expression levels of paralogs account for 39.5% and 15.5%, respectively. In addition, the transfer of small molecules to mutant cells explains tissue-specific gene action in blood. The tissue-specific genes we found are not specific just for human cancer cell lines: we found that the tissue-specific genes are intolerant to functional mutations in the human population and are associated with human diseases more than genes that are essential across all cell types. Our findings offer important insights into genetic mechanisms for tissue specificity of human diseases. In this study, Dvir et al. address the problem of tissue specificity by studying genes essential for cell viability in a tissue-specific way. They find that gene amplification and the expression level of paralogs explain specificity in many more cases than the expression pattern of the gene across tissues. The tissue-specific genes identified by the authors are more likely to be associated with human diseases than common essential genes, and they are under purifying selection in the human population.