A global genetic interaction network of a human cell maps conserved principles and informs functional interpretation of gene co-essentiality profiles. Billmann et al.

Deciphering how genes interact within human cells is essential for understanding their functional wiring and the development of targeted therapeutic strategies. In this study, we present a genome-scale map of genetic interactions in the human haploid cell line HAP1, based on CRISPR-based perturbation of ~ 4 million gene pairs. The resulting network comprises ~89,000 high-confidence gene-gene interactions, organizing genes into hierarchical modules corresponding to protein complexes and pathways, biological processes, and cellular compartments, mirroring principles observed in yeast and highlighting the functional architecture of a human cell. This large-scale genetic network complements the DepMap gene co-essentiality network by capturing unique functional information, uncovering roles of previously uncharacterized genes, and identifying molecular determinants of cancer cell line-specific genetic dependencies. This study presents a general data-driven strategy analysis for systematically exploring the roles of genes and their functional connections in human cell lines.