The genetic landscape of a human cell reveals conserved topology and principles of genetic networks

We generated a genome-scale, genetic interaction network from the analysis of more than 5 million double mutants in the haploid human cell line, HAP1. The network comprises ~90,000 negative and positive 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 and pathways, biological processes, and cellular compartments. Systematic comparative analyses showed that the general principles and topology of genetic networks are conserved from yeast to humans. A genetic interaction network mapped in a single genetic background complements the DepMap cancer cell co-essentiality network, recapitulating many of the same functional connections and also capturing unique functional information to reveal roles of previously uncharacterized genes and molecular determinants of specific cancer cell line genetic dependencies.