Hierarchical organization of the human cell from a cancer coessentiality network

Abstract Genetic interactions mediate the emergence of phenotype from genotype. Systematic survey of genetic interactions in yeast showed that genes operating in the same biological process have highly correlated genetic interaction profiles, and this observation has been exploited to infer gene function in model organisms. Systematic surveys of digenic perturbations in human cells are also highly informative, but are not scalable, even with CRISPR-mediated methods. As an alternative, we developed an indirect method of deriving functional interactions. We show that genes having correlated knockout fitness profiles across diverse, non-isogenic cell lines are analogous to genes having correlated genetic interaction profiles across isogenic query strains, and similarly implies shared biological function. We constructed a network of genes with correlated fitness profiles across 400 CRISPR knockout screens in cancer cell lines into a “coessentiality network,” with up to 500-fold enrichment for co-functional gene pairs, enabling strong inference of human gene function. Modules in the network are connected in a layered web that gives insight into the hierarchical organization of the cell.