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

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

doi:10.1126/science.aaf1420

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

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

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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.

Original language	English (US)
Article number	1420
Journal	Science
Volume	353
Issue number	6306
DOIs	https://doi.org/10.1126/science.aaf1420
State	Published - Sep 23 2016

Bibliographical note

Funding Information:
We thank D. Botstein, H. Bussey, A. Fraser, H. Friesen, M. Meneghini, and M. Tyers for critical comments. This work was primarily supported by the National Institutes of Health (R01HG005853) (C.B., B.A., and C.L.M.), Canadian Institutes of Health Research (FDN-143264 and FDN-143265) (C.B. and B.A.), RIKEN Strategic Programs for R&D (C.B.), JSPS Kakenhi (15H04483) (C.B.), National Institutes of Health (R01HG005084 and R01GM104975) (C.L.M), and the National Science Foundation (DBI\0953881) (C.L.M.). Computing resources and data storage services were partially provided by the Minnesota Supercomputing Institute and the UMN Office of Information Technology, respectively. Additional support was provided by the Canadian Institutes of Health Research (A.A.C.), National Science Foundation (MCB\1244043) (C.M.), European Research Council (ERC) Advanced Investigator Grant (AdG-294542) (L.M.S), ERC Advanced Grant (European Commission) (M.B.), Ministry of Education, Culture, Sports, Sciences and Technology, MEXT (15H04402) (Y.O.), Canadian Institutes of Health Research (FDN143301), Genome Canada Genome Innovation network (through the Ontario Genomics Institute) (A.-C.G), the Ontario Genomics Institute, Canadian Cystic Fibrosis Foundation, Canadian Cancer Society, Pancreatic Cancer Canada, University Health Network (I.S.), National Science Foundation, Cyber-Enabled Discover and Innovation (CDI) (OIA-1028394), ERC Starting Independent Researcher Grant (278212), ARRS project (J1-5424), Serbian Ministry of Education and Science Project 11144006 (N.P.), National Natural Science Foundation of China (T.X), RIKEN Foreign Postdoctoral Researcher Program (J.S.P., S.C.L.), National Science Foundation Graduate Research Fellowship (NSF 00039202) (E.N.K. and S.W.S), U. of Minnesota Doctoral Dissertation Fellowship (B.V. and E.N.K.). O.G.T, C.L.M, B.A., and C.B are fellows of the Canadian Institute for Advanced Research (CIFAR). All data files (Data Files S1 to 17) associated with this study are described in detail in the supplementary materials and can be downloaded from http://boonelab.ccbr.utoronto.ca/supplement/costanzo2016. Data Files S1 to S17 were also deposited in the DRYAD Digital Repository (doi:10.5061/dryad.4291s). Raw mass spectrometry data and downloadable identification and SAINTexpress results tables were deposited in the MassIVE repository housed at the Center for Computational Mass Spectrometry at UCSD (http://proteomics.ucsd.edu/ProteoSAFe/datasets.jsp). The endogenously tagged GFP and Gal-inducible hemagglutinin data sets have been assigned the MassIVE IDs MSV000079157 and MSV000079368 and are available for FTP download at ftp://[email protected] and ftp://[email protected], respectively. The data sets were assigned the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) identifiers PXD002368 and PXD003147 (data set password: SGA).

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Costanzo, M., VanderSluis, B., Koch, E. N., Baryshnikova, A., Pons, C., Tan, G., Wang, W., Usaj, M., Hanchard, J., Lee, S. D., Pelechano, V., Styles, E. B., Billmann, M., Van Leeuwen, J., Van Dyk, N., Lin, Z. Y., Kuzmin, E., Nelson, J., Piotrowski, J. S., ... Boone, C. (2016). A global genetic interaction network maps a wiring diagram of cellular function. Science, 353(6306), Article 1420. https://doi.org/10.1126/science.aaf1420

Costanzo, M, VanderSluis, B, Koch, EN, Baryshnikova, A, Pons, C, Tan, G, Wang, W, Usaj, M, Hanchard, J, Lee, SD, Pelechano, V, Styles, EB, Billmann, M, Van Leeuwen, J, Van Dyk, N, Lin, ZY, Kuzmin, E, Nelson, J, Piotrowski, JS, Srikumar, T, Bahr, S, Chen, Y, Deshpande, R, Kurat, CF, Li, SC, Li, Z, Usaj, MM, Okada, H, Pascoe, N, Luis, BJS, Sharifpoor, S, Shuteriqi, E, Simpkins, SW, Snider, J, Suresh, HG, Tan, Y, Zhu, H, Malod-Dognin, N, Janjic, V, Przulj, N, Troyanskaya, OG, Stagljar, I, Xia, T, Ohya, Y, Gingras, AC, Raught, B, Boutros, M, Steinmetz, LM, Moore, CL, Rosebrock, AP, Caudy, AA, Myers, CL, Andrews, B & Boone, C 2016, 'A global genetic interaction network maps a wiring diagram of cellular function', Science, vol. 353, no. 6306, 1420. https://doi.org/10.1126/science.aaf1420

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title = "A global genetic interaction network maps a wiring diagram of cellular function",

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.",

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

note = "Funding Information: We thank D. Botstein, H. Bussey, A. Fraser, H. Friesen, M. Meneghini, and M. Tyers for critical comments. This work was primarily supported by the National Institutes of Health (R01HG005853) (C.B., B.A., and C.L.M.), Canadian Institutes of Health Research (FDN-143264 and FDN-143265) (C.B. and B.A.), RIKEN Strategic Programs for R&D (C.B.), JSPS Kakenhi (15H04483) (C.B.), National Institutes of Health (R01HG005084 and R01GM104975) (C.L.M), and the National Science Foundation (DBI\0953881) (C.L.M.). Computing resources and data storage services were partially provided by the Minnesota Supercomputing Institute and the UMN Office of Information Technology, respectively. Additional support was provided by the Canadian Institutes of Health Research (A.A.C.), National Science Foundation (MCB\1244043) (C.M.), European Research Council (ERC) Advanced Investigator Grant (AdG-294542) (L.M.S), ERC Advanced Grant (European Commission) (M.B.), Ministry of Education, Culture, Sports, Sciences and Technology, MEXT (15H04402) (Y.O.), Canadian Institutes of Health Research (FDN143301), Genome Canada Genome Innovation network (through the Ontario Genomics Institute) (A.-C.G), the Ontario Genomics Institute, Canadian Cystic Fibrosis Foundation, Canadian Cancer Society, Pancreatic Cancer Canada, University Health Network (I.S.), National Science Foundation, Cyber-Enabled Discover and Innovation (CDI) (OIA-1028394), ERC Starting Independent Researcher Grant (278212), ARRS project (J1-5424), Serbian Ministry of Education and Science Project 11144006 (N.P.), National Natural Science Foundation of China (T.X), RIKEN Foreign Postdoctoral Researcher Program (J.S.P., S.C.L.), National Science Foundation Graduate Research Fellowship (NSF 00039202) (E.N.K. and S.W.S), U. of Minnesota Doctoral Dissertation Fellowship (B.V. and E.N.K.). O.G.T, C.L.M, B.A., and C.B are fellows of the Canadian Institute for Advanced Research (CIFAR). All data files (Data Files S1 to 17) associated with this study are described in detail in the supplementary materials and can be downloaded from http://boonelab.ccbr.utoronto.ca/supplement/costanzo2016. Data Files S1 to S17 were also deposited in the DRYAD Digital Repository (doi:10.5061/dryad.4291s). Raw mass spectrometry data and downloadable identification and SAINTexpress results tables were deposited in the MassIVE repository housed at the Center for Computational Mass Spectrometry at UCSD (http://proteomics.ucsd.edu/ProteoSAFe/datasets.jsp). The endogenously tagged GFP and Gal-inducible hemagglutinin data sets have been assigned the MassIVE IDs MSV000079157 and MSV000079368 and are available for FTP download at ftp://[email protected] and ftp://[email protected], respectively. The data sets were assigned the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) identifiers PXD002368 and PXD003147 (data set password: SGA).",

year = "2016",

month = sep,

day = "23",

doi = "10.1126/science.aaf1420",

language = "English (US)",

volume = "353",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6306",

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TY - JOUR

T1 - A global genetic interaction network maps a wiring diagram of cellular function

AU - Costanzo, Michael

AU - VanderSluis, Benjamin

AU - Koch, Elizabeth N.

AU - Baryshnikova, Anastasia

AU - Pons, Carles

AU - Tan, Guihong

AU - Wang, Wen

AU - Usaj, Matej

AU - Hanchard, Julia

AU - Lee, Susan D.

AU - Pelechano, Vicent

AU - Styles, Erin B.

AU - Billmann, Maximilian

AU - Van Leeuwen, Jolanda

AU - Van Dyk, Nydia

AU - Lin, Zhen Yuan

AU - Kuzmin, Elena

AU - Nelson, Justin

AU - Piotrowski, Jeff S.

AU - Srikumar, Tharan

AU - Bahr, Sondra

AU - Chen, Yiqun

AU - Deshpande, Raamesh

AU - Kurat, Christoph F.

AU - Li, Sheena C.

AU - Li, Zhijian

AU - Usaj, Mojca Mattiazzi

AU - Okada, Hiroki

AU - Pascoe, Natasha

AU - Luis, Bryan Joseph San

AU - Sharifpoor, Sara

AU - Shuteriqi, Emira

AU - Simpkins, Scott W.

AU - Snider, Jamie

AU - Suresh, Harsha Garadi

AU - Tan, Yizhao

AU - Zhu, Hongwei

AU - Malod-Dognin, Noel

AU - Janjic, Vuk

AU - Przulj, Natasa

AU - Troyanskaya, Olga G.

AU - Stagljar, Igor

AU - Xia, Tian

AU - Ohya, Yoshikazu

AU - Gingras, Anne Claude

AU - Raught, Brian

AU - Boutros, Michael

AU - Steinmetz, Lars M.

AU - Moore, Claire L.

AU - Rosebrock, Adam P.

AU - Caudy, Amy A.

AU - Myers, Chad L.

AU - Andrews, Brenda

AU - Boone, Charles

N1 - Funding Information: We thank D. Botstein, H. Bussey, A. Fraser, H. Friesen, M. Meneghini, and M. Tyers for critical comments. This work was primarily supported by the National Institutes of Health (R01HG005853) (C.B., B.A., and C.L.M.), Canadian Institutes of Health Research (FDN-143264 and FDN-143265) (C.B. and B.A.), RIKEN Strategic Programs for R&D (C.B.), JSPS Kakenhi (15H04483) (C.B.), National Institutes of Health (R01HG005084 and R01GM104975) (C.L.M), and the National Science Foundation (DBI\0953881) (C.L.M.). Computing resources and data storage services were partially provided by the Minnesota Supercomputing Institute and the UMN Office of Information Technology, respectively. Additional support was provided by the Canadian Institutes of Health Research (A.A.C.), National Science Foundation (MCB\1244043) (C.M.), European Research Council (ERC) Advanced Investigator Grant (AdG-294542) (L.M.S), ERC Advanced Grant (European Commission) (M.B.), Ministry of Education, Culture, Sports, Sciences and Technology, MEXT (15H04402) (Y.O.), Canadian Institutes of Health Research (FDN143301), Genome Canada Genome Innovation network (through the Ontario Genomics Institute) (A.-C.G), the Ontario Genomics Institute, Canadian Cystic Fibrosis Foundation, Canadian Cancer Society, Pancreatic Cancer Canada, University Health Network (I.S.), National Science Foundation, Cyber-Enabled Discover and Innovation (CDI) (OIA-1028394), ERC Starting Independent Researcher Grant (278212), ARRS project (J1-5424), Serbian Ministry of Education and Science Project 11144006 (N.P.), National Natural Science Foundation of China (T.X), RIKEN Foreign Postdoctoral Researcher Program (J.S.P., S.C.L.), National Science Foundation Graduate Research Fellowship (NSF 00039202) (E.N.K. and S.W.S), U. of Minnesota Doctoral Dissertation Fellowship (B.V. and E.N.K.). O.G.T, C.L.M, B.A., and C.B are fellows of the Canadian Institute for Advanced Research (CIFAR). All data files (Data Files S1 to 17) associated with this study are described in detail in the supplementary materials and can be downloaded from http://boonelab.ccbr.utoronto.ca/supplement/costanzo2016. Data Files S1 to S17 were also deposited in the DRYAD Digital Repository (doi:10.5061/dryad.4291s). Raw mass spectrometry data and downloadable identification and SAINTexpress results tables were deposited in the MassIVE repository housed at the Center for Computational Mass Spectrometry at UCSD (http://proteomics.ucsd.edu/ProteoSAFe/datasets.jsp). The endogenously tagged GFP and Gal-inducible hemagglutinin data sets have been assigned the MassIVE IDs MSV000079157 and MSV000079368 and are available for FTP download at ftp://[email protected] and ftp://[email protected], respectively. The data sets were assigned the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) identifiers PXD002368 and PXD003147 (data set password: SGA).

PY - 2016/9/23

Y1 - 2016/9/23

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84989216655&partnerID=8YFLogxK

U2 - 10.1126/science.aaf1420

DO - 10.1126/science.aaf1420

M3 - Article

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AN - SCOPUS:84989216655

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VL - 353

JO - Science

JF - Science

IS - 6306

M1 - 1420

ER -

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

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