Systematic analysis of ~4 million gene pairs in HAP1 cells reveals ~90,000 genetic interactions that organize into a hierarchical functional network mirroring protein complexes, pathways, and cellular compartments, demonstrating that fundamental principles of genetic network topology are conserved from yeast to human cells and that genetic interactions provide orthogonal functional information to cancer cell line co-essentiality networks for revealing molecular mechanisms underlying disease gene dependencies.

We generated a genome-scale, genetic interaction network from the analysis of more than 4 million double mutants in the haploid human cell line, HAP1. The network maps ∼90,000 genetic interactions, including thousands of extreme synthetic lethal and genetic suppression interactions. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes, pathways, biological processes, and cellular compartments. Comparative analyses showed that general principles of genetic networks are conserved from yeast to human cells. A genetic interaction network mapped in a single genetic background complements the DepMap gene co-essentiality network, recapitulating many of the same biological connections and also capturing unique functional information to reveal roles of uncharacterized genes and molecular determinants of specific cancer cell line genetic dependencies.