A global genetic interaction network maps a wiring diagram of cellular function

Michael Costanzo ,Benjamin Vandersluis ,Nydia Van Dyk ,Vicent Pelechano ,Li Z ,Raamesh Deshpande ,Susan D Lee ,Chad L Myers ,Guihong Tan ,Nataša Pržulj ,Jamie Snider ,Tian Xia ,Vuk Janjić ,Maximilian Billmann ,Adam P Rosebrock ,Sheena C Li ,Emira Shuteriqi ,Tharan Srikumar ,Julia Hanchard ,Harsha Garadi Suresh ,Zhen Yuan Lin ,Matej Ušaj ,Christoph F Kurat ,Michael Boutros ,Brenda Andrews ,Elizabeth N Koch ,Hiroki Okada ,Brian Raught ,Igor Štagljar ,Wen Wang ,Olga G Troyanskaya ,Sara Sharifpoor ,Scott W Simpkins ,Lars M Steinmetz ,Elena Kuzmin ,Bryan Joseph San Luis ,Hongwei Zhu ,Carles Pons ,Claire Moore ,Amy A Caudy ,Erin B Styles ,Mojca Mattiazzi Ušaj ,J Daniel Nelson ,Anastasia Baryshnikova ,Sondra Bahr ,Yoshikazu Ohya ,Jolanda Van Leeuwen ,Yiqun Chen ,Yizhao Tan ,Noël Malod-Dognin ,Jeff S Piotrowski ,Anne‐Claude Gingras ,Natasha Pascoe ,Charles Boone

doi:10.1126/science.aaf1420

Abstract

We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing more than 23 million double mutants, identifying about 550,000 negative and about 350,000 positive genetic interactions. This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs. 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. Negative interactions connected functionally related genes, mapped core bioprocesses, and identified pleiotropic genes, whereas positive interactions often mapped general regulatory connections among gene pairs, rather than shared functionality. The global network illustrates how coherent sets of genetic interactions connect protein complex and pathway modules to map a functional wiring diagram of the cell.

Highlights

Genetic interaction networks highlight mechanistic connections between genes and their corresponding pathways [1]
We examined the topology of genetic interactions occurring between protein complexes and found a large number of complex-complex pairs that were both enriched for genetic interactions (P < 0.001, hypergeometric) and strongly biased towards either negative or positive interactions [8]
A global network based on genetic interaction profile similarity resolves a hierarchy of modules, enriched for sets of genes within specific pathways and protein complexes, biological processes, or subcellular compartments

Summary

Introduction

Genetic interaction networks highlight mechanistic connections between genes and their corresponding pathways [1]. Genetic profile similarities map a hierarchy of gene and cellular function The relative positioning of biological process clusters appeared to reflect shared functionality because distinct, but related processes such as DNA Replication & Repair and Mitosis & Chromosome Segregation, were positioned next to each other in the global similarity network (Fig. 1F) To explore this functional organization more rigorously, we considered only those genes with at least one highly similar gene partner, resulting in a set of 515 nonessential and 421 essential array mutants [8]. The majority of positive interacting gene pairs in both the essential (ExE, 78%) and nonessential (NxN, 75%) genetic interaction networks occurred between distantly connected genes whose products appeared to function in different cell compartments (Fig. 6C). We observed hundreds of instances of both coherent negative [470] and positive [192] interactions connecting pairs of essential and nonessential complexes emphasizing the highly organized topology of genetic interaction networks (Fig. 7B; Data File S13). Genes with cell cycle progression-related roles accounted for 30% of essential gene positive interactions, which combined with genes involved in proteostasis, explain 46% of the positive interactions among essential genes

Discussion

Findings

Summary