title: Gene essentiality and synthetic lethality in haploid human cells.
abstract: Although the genes essential for life have been identified in less complex model organisms, their elucidation in human cells has been hindered by technical barriers. We used extensive mutagenesis in haploid human cells to identify approximately 2000 genes required for optimal fitness under culture conditions. To study the principles of genetic interactions in human cells, we created a synthetic lethality network focused on the secretory pathway based exclusively on mutations. This revealed a genetic cross-talk governing Golgi homeostasis, an additional subunit of the human oligosaccharyltransferase complex, and a phosphatidylinositol 4-kinase β adaptor hijacked by viruses. The synthetic lethality map parallels observations made in yeast and projects a route forward to reveal genetic networks in diverse aspects of human cell biology.
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Blomen
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Májek
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
authors.forename: Lucas T
authors.initials: LT
authors.lastname: Jae
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Johannes W
authors.initials: JW
authors.lastname: Bigenzahn
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
authors.forename: Joppe
authors.initials: J
authors.lastname: Nieuwenhuis
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Staring
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sacco
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
authors.forename: Ferdy R
authors.initials: FR
authors.lastname: van Diemen
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Nadine
authors.initials: N
authors.lastname: Olk
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Alexey
authors.initials: A
authors.lastname: Stukalov
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, 299 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Caleb
authors.initials: C
authors.lastname: Marceau
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Janssen
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, 299 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Jan E
authors.initials: JE
authors.lastname: Carette
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. University of Montpellier, Institut de Recherche en Cancérologie de Montpellier Inserm U1194, Institut régional du Cancer Montpellier, 34000 Montpellier, France. jacques.colinge@inserm.fr gsuperti@cemm.at t.brummelkamp@nki.nl.
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria. jacques.colinge@inserm.fr gsuperti@cemm.at t.brummelkamp@nki.nl.
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Cancer Genomics Center (CGC.nl), Plesmanlaan 121, 1066CX, Amsterdam, Netherlands. jacques.colinge@inserm.fr gsuperti@cemm.at t.brummelkamp@nki.nl.
authors.forename: Thijn R
authors.initials: TR
authors.lastname: Brummelkamp
mesh_terms: D053263:Gene Regulatory Networks; D020043:Genes, Essential; D005804:Genes, Lethal; D056084:Genetic Fitness / Q000235:genetics*; D006056:Golgi Apparatus / Q000235:genetics; D006238:Haploidy; D006602:Hexosyltransferases / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D016254:Mutagenesis, Insertional; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D006602:Hexosyltransferases; C025620:dolichyl-diphosphooligosaccharide - protein glycotransferase