Global genetic interaction network of a human cell maps conserved principles and informs functional interpretation of gene co-essentiality profiles

Maximilian Billmann  ¹ , Michael Costanzo  ² , Xiang Zhang  ³ , Arshia Z Hassan  ³ , Mahfuzur Rahman  ³ , Kevin R Brown  ⁴ , Katherine S Chan  ⁴ , Amy Hin Yan Tong  ² , Carles Pons  ⁵ , Henry N Ward  ⁶ , Catherine Ross  ² , Jolanda van Leeuwen  ² , Michael Aregger  ² , Keith A Lawson  ⁷ , Barbara Mair  ² , Amy F Roth  ⁸ , Nesli E Sen  ⁹ , Duncan T Forster  ⁷ , Guihong Tan  ² , Patricia Mero  ⁴ , Sanna N Masud  ¹⁰ , Yoonkyu Lee  ⁶ , Magali Aguilera-Uribe  ¹¹ , Matej Ušaj  ² , Sylvia M T Almeida  ⁷ , Kamaldeep Aulakh  ⁴ , Urvi Bhojoo  ⁷ , Saba Birkadze  ¹¹ , Nathaniel Budijono  ³ , Xunhui Cai  ¹² , Joseph J Caumanns  ² , Jordan J Chalmers  ¹¹ , Megha Chandrashekhar  ⁷ , Daniel Chang  ³ , Ryan Climie  ² , Kuheli Dasgupta  ¹¹ , Adrian Drazic  ¹³ , Jose I Rojas Echenique  ² , Rafael Gacesa  ² , Adrian Granda Farias  ¹¹ , Andrea Habsid  ⁴ , Ira Horecka  ⁷ , Kristin Kantautas  ⁷ , Fenghu Ji  ¹² , Dae-Kyum Kim  ¹⁴ , Seon Yong Lee  ⁴ , Wendy Liang  ² , Hyobin Julianne Lim  ⁷ , Kevin Lin  ⁶ , Xueyibing Lu  ³ , Michael Maier  ¹⁵ , Babak Nami  ⁴ , Allison Nixon  ⁷ , Nicholas Mikolajewicz  ⁴ , Milad Mokhtaridoost  ⁴ , Lyudmila Nedyalkova  ² , Thomas Rohde  ¹⁶ , Maria Sartori Rodrigues  ² , Martin Soste  ² , Eric Schultz  ³ , Wen Wang  ³ , Ashwin Seetharaman  ² , Ermira Shuteriqi  ² , Olga Sizova  ⁴ , David Thomson Taylor  ¹⁷ , Maria Tereshchenko  ¹⁸ , David Tieu  ⁷ , Jacob Turowec  ² , Tajinder Ubhi  ¹⁹ , Sylvia Varland  ¹³ , Kyle E Wang  ⁷ , Zi Yang Wang  ⁷ , Jiarun Wei  ¹¹ , Yu-Xi Xiao  ¹¹ , Philipp G Maass  ¹¹ , Bruno Reversade  ¹⁵ , Grant W Brown  ¹⁹ , Benjamin F Cravatt  ²⁰ , Scott J Dixon  ²¹ , Haley D M Wyatt  ¹⁸ , Hannes L Röst  ² , Frederick P Roth  ²² , Tian Xia  ²³ , Gary D Bader  ⁷ , Robbie Loewith  ⁹ , Nicholas G Davis  ⁸ , Brenda Andrews  ²⁴ , Chad L Myers  ²⁵ , Jason Moffat  ²⁶ , Charles Boone  ²⁷

Affiliations

• PMID: 42049019
• DOI: 10.1016/j.cell.2026.03.044

Abstract

Deciphering how genes interact within human cells is essential for understanding their functional wiring and for developing 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 for systematically exploring the roles of genes and their functional connections in human cell lines.

Keywords: genetic interactions; genetic network conservation; genetic suppression; genome-scale genetic interaction network; genome-wide CRISPR screens; human haploid cells; synthetic lethality.