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

The network identified ~550,000 negative genetic interactions.

“We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing over 23 million double mutants, identifying ~550,000 negative and ~350,000 positive genetic interactions.”

• Also stated in: § A global and quantitative genetic network for yeast · plain

  “In total, we identified nearly 1 million genetic interactions, corresponding to ~550,000 negative and ~350,000 positive genetic interactions, including ~120,000 interactions between pairs of essential genes (fig. S3).”

The current global network involves ~90% of all yeast genes as query and/or array mutants.

“The current global network involves ~90% of all yeast genes as query and/or array mutants and is accessible from http://thecellmap.org/costanzo2016/.”

The essential gene mutant collection consists of 2,001 array and/or query strains harboring TS alleles corresponding to 868 unique essential genes.

“Our essential gene mutant collection consists of 2,001 array and/or query strains harboring TS alleles corresponding to 868 unique essential genes, with ~600 of genes represented by two or more TS alleles, including strains for ~140 essential genes that were not represented in previous strain collections (11, 12).”

The collection includes strains for about 140 essential genes not represented in previous strain collections.

“Our essential gene mutant collection consists of 2,001 array and/or query strains harboring TS alleles corresponding to 868 unique essential genes, with ~600 of genes represented by two or more TS alleles, including strains for ~140 essential genes that were not represented in previous strain collections (11, 12).”

Essential genes are densely connected hubs in the network.

“This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs.”

Positive genetic interactions often mapped general regulatory connections among gene pairs, rather than shared functionality.

“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 network includes ~120,000 interactions between pairs of essential genes.

“In total, we identified nearly 1 million genetic interactions, corresponding to ~550,000 negative and ~350,000 positive genetic interactions, including ~120,000 interactions between pairs of essential genes (fig. S3).”

TS alleles mediated the majority of the essential gene genetic interactions in the network.

“Thus, TS alleles mediated the majority of the essential gene genetic interactions in our network and the analyses described exclude DAmP alleles, unless otherwise noted.”

The network identified ~350,000 positive genetic interactions.

“We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing over 23 million double mutants, identifying ~550,000 negative and ~350,000 positive genetic interactions.”

• Also stated in: § A global and quantitative genetic network for yeast · plain

  “In total, we identified nearly 1 million genetic interactions, corresponding to ~550,000 negative and ~350,000 positive genetic interactions, including ~120,000 interactions between pairs of essential genes (fig. S3).”

The global network was generated from analysis of ~23 million double mutants encompassing 5,416 different genes.

“A global genetic interaction network resulting from the combination of the NxN, ExN, and ExE networks was generated from analysis of ~23 million double mutants encompassing 5,416 different genes.”

About 600 essential genes were represented by two or more TS alleles.

“Our essential gene mutant collection consists of 2,001 array and/or query strains harboring TS alleles corresponding to 868 unique essential genes, with ~600 of genes represented by two or more TS alleles, including strains for ~140 essential genes that were not represented in previous strain collections (11, 12).”

The network identified nearly 1 million genetic interactions in total.

“In total, we identified nearly 1 million genetic interactions, corresponding to ~550,000 negative and ~350,000 positive genetic interactions, including ~120,000 interactions between pairs of essential genes (fig. S3).”

Negative genetic interactions identified pleiotropic genes.

“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 comprehensive network maps genetic interactions for essential gene pairs.

“This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs.”

The study generated a global genetic interaction network for Saccharomyces cerevisiae.

“We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing over 23 million double mutants, identifying ~550,000 negative and ~350,000 positive genetic interactions.”

Negative genetic interactions connected functionally related genes.

“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.”

Most DAmP alleles exhibited fewer interactions compared to TS alleles of essential genes.

“however, only a fraction of DAmP alleles (25%) compromised gene function enough to impact cellular fitness (> 5% fitness defect) and, consequently, most DAmP alleles exhibited fewer interactions compared to TS alleles of essential genes (fig. S1).”

The global network was constructed from over 23 million double mutants.

“We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing over 23 million double mutants, identifying ~550,000 negative and ~350,000 positive genetic interactions.”

Only a fraction of DAmP alleles (25%) compromised gene function enough to impact cellular fitness (>5% fitness defect).

“however, only a fraction of DAmP alleles (25%) compromised gene function enough to impact cellular fitness (> 5% fitness defect) and, consequently, most DAmP alleles exhibited fewer interactions compared to TS alleles of essential genes (fig. S1).”

Negative genetic interactions mapped core bioprocesses.

“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.”

Genes that encode members of the same essential protein complex exhibited significantly higher interaction profile similarity than gene pairs belonging to the same nonessential complex.

“Moreover, genes on the essential gene similarity network often showed a stronger functional relationship, because genes that encode members of the same essential protein complex exhibited significantly higher interaction profile similarity than gene pairs belonging to the same nonessential complex (fig. S5).”

These clusters were enriched for genes whose products function in the same cell compartment.

“Instead, these clusters were enriched for genes whose products function in the same cell compartment (Figs. 2A, S7; Data File S6).”

Other highly pleiotropic genes (top 30% pleiotropy scores) included those with proteostasis or signaling roles, as well as select genes with roles in fundamental cellular functions, such as translation, RNA processing, vesicle trafficking, lipid metabolism, and coenzyme-A biosynthesis.

“Other highly pleiotropic genes (top 30% pleiotropy scores) included those with proteostasis or signaling roles, as well as select genes with roles in fundamental cellular functions, such as translation, RNA processing, vesicle trafficking, lipid metabolism, and coenzyme-A biosynthesis (Fig. 4A).”

Essential gene interaction profiles provided higher accuracy gene function predictions across a diverse set of biological processes.

“By evaluating the predictive power of both essential and nonessential genetic interaction profiles (8), we found that essential gene interaction profiles provided higher accuracy gene function predictions across a diverse set of biological processes (14), and this increased accuracy was correlated with the fraction of essential genes annotated to specific bioprocesses (fig. S6; Data File S4).”

• cites [8] Materials and Methods are available as supporting online material.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [14] Ashburner M Gene ontology: tool for the unification of biology. The Gene Ontology Consortium Nat Genet 25 25 2000 10802651 PMC3037419 sourceNot checked yet

  Not checked in the free run.

Ipa1 physically interacted with CPF complex members, Mpe1 and Ysh1.

“We also found that Ipa1 physically interacted with CPF complex members, Mpe1 and Ysh1 (Data File S8)(8) further supporting a role for IPA1 in this process.”

• cites [8] Materials and Methods are available as supporting online material.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

SAFE identified 28 gene clusters corresponding to 123 specific protein complexes.

“At a higher level of functional resolution, SAFE identified 28 gene clusters corresponding to 123 specific protein complexes (Fig 2B, Complexes; Data File S5).”

Gene clusters enriched for GO terms related to cell polarity, protein degradation, and rRNA processing were specifically detected in the essential gene similarity network.

“Gene clusters enriched for GO terms related to cell polarity, protein degradation, and rRNA processing, were specifically detected in the essential gene similarity network (Fig. 1D), whereas the nonessential gene similarity network identified clusters enriched for mitochondrial and peroxisomal functions (Fig. 1E).”

Interactions involving either essential or nonessential genes can predict function.

“Nevertheless, interactions involving either essential or nonessential genes can predict function.”

SAFE identified 487 significantly enriched GO bioprocess terms that mapped to 17 unique network regions and covered 1343 genes on the global network.

“SAFE identified 487 significantly enriched GO bioprocess terms that mapped to 17 unique network regions and covered 1343 genes on the global network (Fig. 1F).”

Functional relationships between protein complexes were resolved in greater detail by extracting biological process-enriched clusters from the global network and visualizing them in isolation.

“Functional relationships between protein complexes were also resolved in greater detail by extracting biological process-enriched clusters from the global network and visualizing them in isolation (Fig. 3; Data File S5).”

IPA1 shares many genetic interactions in common with genes encoding members of the CPF and CF IA protein complexes.

“IPA1 shares many genetic interactions in common with genes encoding members of the Cleavage/Polyadenylation factor (CPF) and Cleavage Factor IA (CF IA) protein complexes (Fig. 4B, C), which along with HRP1, are essential for mRNA 3′ end processing (19).”

• cites [19] Chan S Choi EA Shi Y Pre-mRNA 3′-end processing complex assembly and function Wiley interdisciplinary reviews RNA 2 321 2011 21957020 PMC3980678 sourceNot checked yet

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Sibling clusters detected at an intermediate range of profile similarity (0.2 < PCC < 0.4), which combined into a relatively smaller set of larger parent clusters at a lower range of profile similarity (0.05 < PCC < 0.2), did not share enrichment for the same GO biological process, pathways or protein complex annotations.

“However, sibling clusters detected at an intermediate range of profile similarity (0.2 < PCC < 0.4), which combined into a relatively smaller set of larger parent clusters at a lower range of profile similarity (0.05 < PCC < 0.2), did not share enrichment for the same GO biological process, pathways or protein complex annotations.”

Optimal functional prediction performance was achieved with a global similarity network that combined the majority of all nonessential and essential protein coding genes in the S. cerevisiae genome.

“Nevertheless, optimal functional prediction performance was achieved with a global similarity network that combined the majority of all nonessential and essential protein coding genes in the S. cerevisiae genome.”

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.

“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).”

Genes encoding Hsp90, IRA2, and RSP5 ranked among the most highly pleiotropic genes observed.

“Genes encoding Hsp90 (hsc82Δhsp82-5001 TS double mutant query strain; Data File S1), IRA2, a negative regulator of RAS signaling, and RSP5, an E3 ubiquitin ligase, ranked among the most highly pleiotropic genes observed (Data File S7).”

High pleiotropy genes tended not to belong to densely connected network clusters, but rather were more often positioned outside the functionally enriched clusters, scattered in the sparser regions of the global network.

“Because they share genetic interactions with many functionally diverse genes, high pleiotropy genes tended not to belong to densely connected network clusters, but rather were more often positioned outside the functionally enriched clusters, scattered in the sparser regions of the global network (Fig. 4A).”

Applying SAFE with a protein localization standard detected 14 network regions enriched for genes whose products localize to 11 different subcellular compartments.

“Applying SAFE with a protein localization standard (17), we detected 14 network regions enriched for genes whose products localize to 11 different subcellular compartments (Fig. 2B, Localization).”

• cites [17] Koh JL CYCLoPs: A Comprehensive Database Constructed from Automated Analysis of Protein Abundance and Subcellular Localization Patterns in Saccharomyces cerevisiae G3 (Bethesda) 5 1223 2015 26048563 PMC4478550 sourceNot checked yet

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Implementing SAFE with 4373 biological process terms from GO detected gene clusters in each similarity network that were enriched for unique sets of related GO terms.

“Implementing SAFE with 4373 biological process terms from Gene Ontology (GO)(14), we detected gene clusters in each similarity network that were enriched for unique sets of related GO terms (Fig. 1D–F; Data File S5).”

• cites [14] Ashburner M Gene ontology: tool for the unification of biology. The Gene Ontology Consortium Nat Genet 25 25 2000 10802651 PMC3037419 sourceNot checked yet

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Unbiased metabolomics analysis revealed that the MTC pathway mutants exhibited elevated levels of kyurenine biosynthetic pathway metabolites, including NAD+.

“Furthermore, unbiased metabolomics analysis revealed that the MTC pathway mutants exhibited elevated levels of kyurenine biosynthetic pathway metabolites, including NAD+ (Fig. 4J)(8).”

• cites [8] Materials and Methods are available as supporting online material.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The essential gene similarity network was more than 25-fold more densely connected compared to the corresponding nonessential network at the same PCC threshold.

“When evaluated at the same Pearson correlation coefficient (PCC) threshold, the essential gene similarity network (Fig. 1A) was more than 25-fold more densely connected compared to the corresponding nonessential network (Fig. 1B).”

The nonessential gene similarity network identified clusters enriched for mitochondrial and peroxisomal functions.

“Gene clusters enriched for GO terms related to cell polarity, protein degradation, and rRNA processing, were specifically detected in the essential gene similarity network (Fig. 1D), whereas the nonessential gene similarity network identified clusters enriched for mitochondrial and peroxisomal functions (Fig. 1E).”

The ARO1 genetic interaction profile revealed strong negative interactions with genes involved in amino acid metabolism, the entire MTC pathway and the aromatic amino acid transporters, BAP2 and TAT1.

“For example, the ARO1 genetic interaction profile revealed strong negative interactions with genes involved in amino acid metabolism, the entire MTC pathway and the aromatic amino acid transporters, BAP2 and TAT1 (Figs. 4G, S9), suggesting that the MTC pathway may control amino acid metabolism or affect trafficking of Bap2 and Tat1 permeases.”

All ten sibling clusters were enriched for gene products that exhibit nuclear localization patterns.

“Instead, all ten sibling clusters were enriched for gene products that exhibit nuclear localization patterns (Data File S6).”

Bioprocess clusters such as DNA synthesis, Mitosis, Nuclear Transport and Transcription combined into a single module encompassing genes localized to the cell nucleus.

“For example, bioprocess clusters such as DNA synthesis, Mitosis, Nuclear Transport and Transcription (Fig. 2B, GO BP; Data File S5) combined into a single module encompassing genes localized to the cell nucleus (Fig. 2B, Localization).”

The increased accuracy of essential gene interaction profiles was correlated with the fraction of essential genes annotated to specific bioprocesses.

“By evaluating the predictive power of both essential and nonessential genetic interaction profiles (8), we found that essential gene interaction profiles provided higher accuracy gene function predictions across a diverse set of biological processes (14), and this increased accuracy was correlated with the fraction of essential genes annotated to specific bioprocesses (fig. S6; Data File S4).”

• cites [8] Materials and Methods are available as supporting online material.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [14] Ashburner M Gene ontology: tool for the unification of biology. The Gene Ontology Consortium Nat Genet 25 25 2000 10802651 PMC3037419 sourceNot checked yet

  Not checked in the free run.

The network uncovered a role for a previously uncharacterized essential gene, YJR141W, which we named IPA1, in the highly conserved process of mRNA 3′-end processing and polyadenylation.

“Notably, while most essential genes are relatively well studied, our network uncovered a role for a previously uncharacterized essential gene, YJR141W, which we named IPA1 (Important for cleavage and PolyAdenylation), in the highly conserved process of mRNA 3′-end processing and polyadenylation.”

The 10% most connected genes in the genetic interaction network participated in 3.5-fold more genetic interactions than the average gene.

“For example, the 10% most connected genes (i.e. high interaction degree genes or hub genes) in the genetic interaction network participated in 3.5-fold more genetic interactions than the average gene.”

The most distantly related essential gene pairs were more frequently connected by positive interactions than gene pairs mapping to the same biological process-level clusters.

“In fact, the most distantly related essential gene pairs were more frequently connected by positive interactions than gene pairs mapping to the same biological process-level clusters (Fig. 6B).”

Essential genes participated in ~5-fold more negative and positive interactions than nonessential genes.

“In general, essential genes participated in ~5-fold more negative and positive interactions than nonessential genes, confirming previous estimates (Fig. 5A)(24).”

• cites [24] Mnaimneh S Exploration of essential gene functions via titratable promoter alleles Cell 118 31 2004 15242642 sourceNot checked yet

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In the nonessential genetic interaction network (NxN), negative and positive interaction hubs were enriched for biological processes including chromatin organization, transcription and vesicle trafficking.

“In the nonessential genetic interaction network (NxN), negative and positive interaction hubs were enriched for biological processes including chromatin organization, transcription and vesicle trafficking (Data File S11).”

Positive interactions tended to connect essential genes with roles in highly distinct biological processes.

“Instead, positive interactions tended to connect essential genes with roles in highly distinct biological processes.”

We did not detect any overlap between essential gene positive interactions and other molecular or functional relationships, including physical interactions.

“In contrast, we did not detect any overlap between essential gene positive interactions and other molecular or functional relationships, including physical interactions (Figs. 5B, C, S15).”

ABC transporters, which belong to functionally redundant gene families and thus are extensively buffered, exhibited fewer genetic interactions.

“For example, ABC transporters, which belong to functionally redundant gene families and thus are extensively buffered, exhibited fewer genetic interactions (figs. S11–S14; Table S2).”

For both nonessential and essential genetic interactions, stronger interactions tended to connect genes with closer functional relationships.

“For both nonessential and essential genetic interactions, stronger interactions tended to connect genes with closer functional relationships (Fig. 6D).”

Genes encoding proteins involved in specific biochemical functions, or those that contain specific functional domains, such as an SH3 domain, were also associated with a higher number of genetic interactions.

“Genes encoding proteins involved in specific biochemical functions, or those that contain specific functional domains, such as an SH3 (SRC Homology 3) protein-protein interaction domain, were also associated with a higher number of genetic interactions (figs. S13, S14).”

We observed significant enrichment for positive interactions that connected essential genes with nuclear-related functions to essential genes required for vesicle traffic-dependent functions.

“In particular, we observed significant enrichment for positive interactions that connected essential genes with nuclear-related functions to essential genes required for vesicle traffic-dependent functions (Figs. 5D, S17).”

Genes that exhibited relatively few genetic interactions were also associated with specific features.

“Genes that exhibited relatively few genetic interactions were also associated with specific features (figs. S11–S14; Table S2; Data File S10).”

Negative interactions were also enriched between deletion alleles of nonessential genes in different biological processes.

“Negative interactions were also enriched between deletion alleles of nonessential genes in different biological processes (Fig. 5D, off-diagonal).”

Protein complexes exhibited highly organized patterns of genetic interactions.

“Consistent with previous findings (1, 5, 28, 29), we found that protein complexes exhibited highly organized patterns of genetic interactions.”

• cites [1] Costanzo M The genetic landscape of a cell Science 327 425 2010 20093466 PMC5600254 sourceNot checked yet

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• cites [5] Baryshnikova A Quantitative analysis of fitness and genetic interactions in yeast on a genome scale Nat Methods 7 1017 2010 21076421 PMC3117325 sourceNot checked yet

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• cites [28] Segre D Deluna A Church GM Kishony R Modular epistasis in yeast metabolism Nat Genet 37 77 2005 15592468 sourceNot checked yet

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• cites [29] Bandyopadhyay S Kelley R Krogan NJ Ideker T Functional maps of protein complexes from quantitative genetic interaction data PLoS Comput Biol 4 e1000065 2008 18421374 PMC2289880 sourceNot checked yet

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Negative genetic interactions were significantly enriched among genes belonging to the same biological process in both the nonessential (NxN) and essential (ExE) genetic interaction networks.

“Negative genetic interactions were significantly enriched (P < 0.05, hypergeometric) among genes belonging to the same biological process in both the nonessential (NxN) and essential (ExE) genetic interaction networks (Fig. 5D, on-diagonal).”

The density of negative interactions, among genes in both the nonessential (NxN) and essential (ExE) genetic interaction networks, increased with the functional specificity of a given cluster.

“The density (i.e. number of observed interactions relative to the total number of gene pairs screened) of negative interactions, among genes in both the nonessential (NxN) and essential (ExE) genetic interaction networks, increased with the functional specificity of a given cluster.”

We did not observe a relationship between functional similarity and the magnitude of positive interactions between essential gene pairs.

“Moreover, we did not observe a relationship between functional similarity and the magnitude of positive interactions between essential gene pairs (Fig. 6D).”

Positive genetic interactions between nonessential genes also overlapped with protein-protein interactions, albeit to a lesser extent (0.5%, 3.7-fold enrichment).

“Consistent with previous observations (1), positive genetic interactions between nonessential genes also overlapped with protein-protein interactions, albeit to a lesser extent (0.5%, 3.7-fold enrichment; Figs. 5C, S15).”

• cites [1] Costanzo M The genetic landscape of a cell Science 327 425 2010 20093466 PMC5600254 sourceNot checked yet

  Not checked in the free run.

Negative interactions among essential genes showed a striking overlap with protein-protein interactions.

“In particular, negative interactions among essential genes showed a striking overlap with protein-protein interactions (Figs. 5C, S15).”

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.

“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).”

Fitness defects associated with both deletion alleles of nonessential genes and TS alleles of essential genes were highly correlated with the degree of genetic interaction.

“As observed previously (1), fitness defects associated with both deletion alleles of nonessential genes and TS alleles of essential genes were highly correlated with the degree of genetic interaction (figs. S11–S12; Table S1; Data File S10).”

• cites [1] Costanzo M The genetic landscape of a cell Science 327 425 2010 20093466 PMC5600254 sourceNot checked yet

  Not checked in the free run.

The density of positive interactions detected in the essential network was not related to functional specificity.

“In contrast, the density of positive interactions detected in the essential network was not related to functional specificity.”

A wide range of connectivity exists in the genetic interaction network.

“Although the average gene participated in ~100 negative interactions (2% of genes tested) and ~65 positive interactions (1% of genes tested), when assessed at an intermediate confidence threshold (8), a wide range of connectivity exists in the genetic interaction network (fig. S10; Data File S9).”

• cites [8] Materials and Methods are available as supporting online material.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The magnitude of a given negative interaction was also associated with the extent of functional similarity shared between genes.

“The magnitude of a given negative interaction was also associated with the extent of functional similarity shared between genes (Fig. 6D).”

~1000 of the 5,400 yeast genes examined showed relatively few genetic interactions and remain sparsely connected.

“~1000 of the 5,400 yeast genes we examined showed relatively few genetic interactions and remain sparsely connected”

A large number of complex-complex pairs were both enriched for genetic interactions (P < 0.001, hypergeometric) and strongly biased towards either negative or positive interactions.

“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”

• cites [8] Materials and Methods are available as supporting online material.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

We discovered a genetic background in which an additional ~3,300 genes are essential for viability.

“we discovered a genetic background in which an additional ~3,300 genes are essential for viability (8)”

• cites [8] Materials and Methods are available as supporting online material.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Negative interactions associated with the 19S proteasome highlighted diverse functions that are particularly important when proteasome activity is compromised, including interactions with genes encoding the APC.

“negative interactions associated with the 19S proteasome highlighted diverse functions that are particularly important when proteasome activity is compromised (Fig. 8B), including interactions with genes encoding the APC”

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The type of interaction observed within protein complexes depended on essentiality.

“The type of interaction observed within protein complexes depended on essentiality.”

Essential genes that showed negative interactions with the proteasome were enriched for multidomain proteins.

“essential genes that showed negative interactions with the proteasome were enriched for multidomain proteins”

Extreme negative or synthetic lethal interactions among essential genes often occur between genes within the same protein complex, or between genes in different protein complexes but within the same biological process or subcellular compartment.

“Second, the extreme negative or synthetic lethal interactions among essential genes often occur between genes within the same protein complex, or between genes in different protein complexes but within the same biological process or subcellular compartment”

None of the essential complexes in the dataset were enriched for positive interactions.

“none of the essential complexes in our dataset were enriched for positive interactions”

• AssumptionRests on an assumption: The set of protein complexes tested is representative of all protein complexes in yeast.

Protein complexes biased for positive interactions with essential genes exhibited many negative interactions with checkpoint genes.

“Protein complexes biased for positive interactions with essential genes also exhibited many negative interactions with checkpoint genes (P < 4×10−56, Fisher’s exact test; fig. S22)”

Relatively severe deletion alleles of nonessential genes or TS alleles of essential genes often show extensive digenic interaction profiles.

“Our analysis revealed that relatively severe deletion alleles of nonessential genes or TS alleles of essential genes often show extensive digenic interaction profiles.”

Genes encoding components of the same proteasome subunit (e.g., within 19S or within 20S) interact more frequently with one another than genes belonging to different subunits (between 19S and 20S).

“genes encoding components of the same subunit (e.g. within 19S or within 20S) interact more frequently with one another than genes belonging to different subunits (between 19S and 20S; fig. S19)”

More complex-complex pairs were connected by coherent sets of negative than positive interactions.

“More complex-complex pairs were connected by coherent sets of negative than positive interactions”

The positive interactions of these biased complexes were more functionally diverse compared to their negative interactions.

“The positive interactions of these biased complexes, were also more functionally diverse compared to their negative interactions.”

Extracting all genetic interactions for specific protein complexes generated functional wiring diagrams that revealed the set of genes, pathways, and bioprocesses modulated by mutation of a particular complex.

“Extracting all genetic interactions for specific protein complexes generated functional wiring diagrams that revealed the set of genes, pathways, and bioprocesses, modulated by mutation of a particular complex”

Most essential protein complexes (>75% essential genes) were enriched for negative interactions among their members (82%; 35/44 complexes).

“most essential protein complexes (> 75% essential genes; Data File S12) were enriched for negative interactions among their members (82%; 35/44 complexes)”

• AssumptionRests on an assumption: The set of protein complexes tested is representative of all protein complexes in yeast.

Positive genetic interactions connected the proteasome and other proteostasis-related complexes to genes involved in various functions, including vesicle trafficking and transcription.

“Positive genetic interactions connected the proteasome and other proteostasis-related complexes to genes involved in various functions, including vesicle trafficking and transcription”

The ORC-Translocon connection reflects enrichment for cross-compartment positive interactions observed between genes encoding essential, nuclear and vesicle traffic-dependent functions.

“The ORC-Translocon connection reflects enrichment for cross-compartment positive interactions observed between genes encoding essential, nuclear and vesicle traffic-dependent functions”

Protein complexes involved in proteostasis, including several chaperones and the proteasome, exhibited among the strongest enrichment for positive genetic interactions, especially in the essential gene network.

“Protein complexes involved in proteostasis, including several chaperones and the proteasome, exhibited among the strongest enrichment for positive genetic interactions, especially in the essential gene network”

Positive interactions were enriched between genes involved in mRNA decay and essential gene DAmP alleles.

“positive interactions were also enriched between genes involved in mRNA decay and essential gene DAmP alleles (13)”

• cites [13] Schuldiner M Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile Cell 123 507 2005 16269340 sourceNot checked yet

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Coherent sets of negative interactions involving the ORC linked functionally related complexes, including the MCM and GINS complexes.

“coherent sets of negative interactions involving the ORC, which specifies sites of initiation of DNA replication throughout the genome (31), linked functionally related complexes, including the MCM (Mini-Chromosome Maintenance) and the GINS (Go, Ichi, Ni, San) complexes”

• cites [31] Bell SP The origin recognition complex: from simple origins to complex functions Genes Dev 16 659 2002 11914271 sourceNot checked yet

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Hundreds of instances of both coherent negative (470) and positive (192) interactions connecting pairs of essential and nonessential complexes were observed.

“we observed hundreds of instances of both coherent negative (470) and positive (192) interactions connecting pairs of essential and nonessential complexes”

ORC subunits were connected by coherent sets of positive interactions to genes with roles in several different functions including members of the ER-associated Translocon complex.

“ORC subunits were connected by coherent sets of positive interactions to genes with roles in several different functions including members of the ER-associated Translocon complex”

Complexes composed primarily of nonessential genes (>75% nonessential) were more often enriched for positive (21%, 20/97) compared to negative (5%, 5/97) interactions among their members.

“complexes composed primarily of nonessential genes (> 75% nonessential genes; Data File S12) were more often enriched for positive (21%, 20/97 complexes) compared to negative (5%, 5/97 complexes) interactions among their members”

• AssumptionRests on an assumption: The set of protein complexes tested is representative of all protein complexes in yeast.

16% of positive interactions with essential genes appear to be associated with proteostasis.

“In total, 16% of positive interactions with essential genes appear to be associated with proteostasis.”

~30% of proteasome positive interactions represent genetic suppression, where a fitness defect associated with a hypomorphic TS allele of an essential gene is suppressed by a second mutation in a proteasome encoding gene.

“we further tested a subset of these positive interactions (8) and, based on this analysis, we estimated that ~30% of proteasome positive interactions represent genetic suppression, where a fitness defect associated with a hypomorphic TS allele of an essential gene is suppressed by a second mutation in a proteasome encoding gene”

• cites [8] Materials and Methods are available as supporting online material.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• AssumptionRests on an assumption: The subset of positive interactions tested is representative of all proteasome positive interactions.
• AssumptionRests on an assumption: The proteasome plays a direct role in controlling protein turnover.

A subset of protein complexes exhibited more positive interactions compared to negative interactions with essential genes.

“a subset of protein complexes, in addition to being enriched for positive interactions (Fig. 8C), also exhibited more positive interactions compared to negative interactions with essential genes”

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.

“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.”

Mutations that compromise the cellular proteostasis network often suppressed TS alleles of essential genes.

“mutations that compromise the cellular proteostasis network often suppressed TS alleles of essential genes”

Genes belonging to similar biological processes tend to share common genetic interactions.

“Genes belonging to similar biological processes tend to share common genetic interactions, and genes encoding proteins that function together within the same pathway or complex display similar genetic interaction profiles (fig. S4)(1).”

• cites [1] Costanzo M The genetic landscape of a cell Science 327 425 2010 20093466 PMC5600254 sourceNot checked yet

  Not checked in the free run.

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.

“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.”

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.

“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.”

Genetic interaction profiles provide a quantitative measurement of functional similarity.

“Thus, genetic interaction profiles provide a quantitative measurement of functional similarity, and similarity networks generated from the large-scale mapping correlated genetic interaction profiles organizes genes into clusters that highlight biological processes (1).”

• cites [1] Costanzo M The genetic landscape of a cell Science 327 425 2010 20093466 PMC5600254 sourceNot checked yet

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The location of numerous previously uncharacterized genes either within or in close proximity to functionally enriched regions of the genetic profile similarity network allows us to predict functions for these genes.

“The location of numerous previously uncharacterized genes either within or in close proximity to functionally enriched regions of the genetic profile similarity network allows us to predict functions for these genes (Fig. 4B)(8).”

• cites [8] Materials and Methods are available as supporting online material.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Similarity networks generated from correlated genetic interaction profiles organize genes into clusters that highlight biological processes.

“Thus, genetic interaction profiles provide a quantitative measurement of functional similarity, and similarity networks generated from the large-scale mapping correlated genetic interaction profiles organizes genes into clusters that highlight biological processes (1).”

• cites [1] Costanzo M The genetic landscape of a cell Science 327 425 2010 20093466 PMC5600254 sourceNot checked yet

  Not checked in the free run.

Novel functional organization is embedded within large-scale, unbiased datasets, which may not be captured completely by functional standards, including GO as it is currently organized.

“As observed previously (16), this indicates that novel functional organization is embedded within large-scale, unbiased datasets, which may not be captured completely by functional standards, including GO as it is currently organized (14).”

• cites [16] Dutkowski J A gene ontology inferred from molecular networks Nat Biotechnol 31 38 2013 23242164 PMC3654867 sourceNot checked yet

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• cites [14] Ashburner M Gene ontology: tool for the unification of biology. The Gene Ontology Consortium Nat Genet 25 25 2000 10802651 PMC3037419 sourceNot checked yet

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All of these genes were identified as important for growth in high-pressure and cold environments.

“Interestingly, all of these genes were identified as important for growth in high-pressure and cold environments (21).”

• cites [21] Abe F Minegishi H Global screening of genes essential for growth in high-pressure and cold environments: searching for basic adaptive strategies using a yeast deletion library Genetics 178 851 2008 18245339 PMC2248370 sourceNot checked yet

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Genes encoding proteins that function together within the same pathway or complex display similar genetic interaction profiles.

“Genes belonging to similar biological processes tend to share common genetic interactions, and genes encoding proteins that function together within the same pathway or complex display similar genetic interaction profiles (fig. S4)(1).”

• cites [1] Costanzo M The genetic landscape of a cell Science 327 425 2010 20093466 PMC5600254 sourceNot checked yet

  Not checked in the free run.

MTC2, MTC4, and MTC6 mutants were previously shown to enhance the mutant phenotype associated with perturbation of CDC13, which controls the maintenance of telomere capping.

“MTC2, MTC4, and MTC6 mutants were previously shown to enhance the mutant phenotype associated with perturbation of CDC13, which controls the maintenance of telomere capping (22).”

• cites [22] Addinall SG A genomewide suppressor and enhancer analysis of cdc13-1 reveals varied cellular processes influencing telomere capping in Saccharomyces cerevisiae Genetics 180 2251 2008 18845848 PMC2600956 sourceNot checked yet

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The connectivity for some genes will only be revealed under different environmental or genetic conditions.

“Approximately 1000 genes (~20%), the majority of which are nonessential genes, displayed few genetic interactions and had profiles that generally displayed a relatively low level of functional information, suggesting that the connectivity for some genes will only be revealed under different environmental or genetic conditions.”

Positive interactions between essential genes generally appear to reflect more functionally distant relationships.

“Thus, positive interactions between essential genes generally appear to reflect more functionally distant relationships.”

Simultaneous perturbation of two genes encoding members of the same nonessential protein complex often show a fitness defect resembling the corresponding single mutants.

“This reflects that simultaneous perturbation of two genes encoding members of the same nonessential protein complex often show a fitness defect resembling the corresponding single mutants.”

The lack of a functional signal could not be explained by differences in data quality because replicate analysis confirmed that SGA-derived positive and negative interactions showed similar levels of reproducibility.

“The lack of a functional signal could not be explained by differences in data quality because replicate analysis confirmed that SGA-derived positive and negative interactions showed similar levels of reproducibility (fig. S2).”

On the basis of the strength of negative genetic interaction, we can predict if two genes share an intimate relationship and possibly function in the same pathway or complex.

“Thus, on the basis of the strength of negative genetic interaction, we can predict if two genes share an intimate relationship and possibly function in the same pathway or complex.”

This observation highlights the reduced ability of a cell to tolerate multiple partial loss-of-function mutations in the same essential pathway or complex.

“This observation highlights the reduced ability of a cell to tolerate multiple partial loss-of-function mutations in the same essential pathway or complex (Figs. 5C, S15).”

Coherent sets of negative and positive genetic interactions connect both within and between the highly resolved complex and pathway modules to map a functional wiring diagram of the cell.

“In the context of this functional organization, coherent sets of negative and positive genetic interactions connect both within and between the highly resolved complex and pathway modules to map a functional wiring diagram of the cell.”

A cell cycle delay may result when a mutation activates a checkpoint pathway which slows cell cycle progression, allowing the cell to correct an otherwise rate-limiting defect to mask the phenotypic effect normally associated with a second mutation.

“A cell cycle delay may result when a mutation activates a checkpoint pathway which slows cell cycle progression, allowing the cell to correct an otherwise rate-limiting defect to mask the phenotypic effect normally associated with a second mutation (36).”

• cites [36] Li R Murray AW Feedback control of mitosis in budding yeast Cell 66 519 1991 1651172 sourceNot checked yet

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The global network has the potential for digenic interactions to compound the phenotypes associated with single gene mutations.

“An important property associated with the global network is the potential for digenic interactions to compound the phenotypes associated with single gene mutations.”

Only ~1000 genes in the yeast genome are individually essential in standard growth conditions and cause lethality when mutated.

“While only ~1000 genes in the yeast genome are individually essential in standard growth conditions and cause lethality when mutated (9, 10)”

• cites [9] Winzeler EA Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis Science 285 901 1999 10436161 sourceNot checked yet

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• cites [10] Giaever G Functional profiling of the Saccharomyces cerevisiae genome Nature 418 387 2002 12140549 sourceNot checked yet

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An ORC-dependent S-phase cell cycle delay may mask growth defects associated with perturbation of genes required for polarized secretion during budding, thereby resulting in positive interactions.

“Thus, an ORC-dependent S-phase cell cycle delay may mask growth defects associated with perturbation of genes required for polarized secretion during budding, thereby resulting in positive interactions.”

Genetic interactions occurring within protein complexes can resolve the structural organization of large, multi-subunit complexes.

“The genetic interactions occurring within protein complexes can even resolve the structural organization of large, multi-subunit complexes.”

The global genetic network was mapped under a particular condition in a specific genetic background.

“Our global genetic network was mapped under a particular condition in a specific genetic background”

Cell viability depends on an active checkpoint response in the absence of these complexes.

“suggesting that cell viability depends on an active checkpoint response in the absence of these complexes”

The topology of genetic networks connecting genes within protein complexes by uniform sets of genetic interactions is conserved in higher eukaryotes.

“suggesting that the topology of genetic networks connecting genes within protein complexes by uniform sets of genetic interactions is conserved in higher eukaryotes”

• cites [30] Hoepfner D High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions Microbiol Res 169 107 2014 24360837 sourceNot checked yet

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• cites [8] Materials and Methods are available as supporting online material.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Mutations in many different pairs of genes may lead to the same phenotype, such as a disease state, in humans.

“mutations in many different pairs of genes may lead to the same phenotype, such as a disease state, in humans”

Many different pairs of mutations may lead to the same terminal synthetic lethal/sick phenotype.

“many different pairs of mutations may lead to same terminal synthetic lethal/sick phenotype”

Digenic interactions mapped in yeast can be conserved in different yeast species over hundreds of millions of years of evolution.

“It is clear that the digenic interactions we have mapped in yeast can be conserved in different yeast species over hundreds of millions of years of evolution (49, 50).”

• cites [49] Dixon SJ Significant conservation of synthetic lethal genetic interaction networks between distantly related eukaryotes Proc Natl Acad Sci U S A 105 16653 2008 18931302 PMC2575475 sourceNot checked yet

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• cites [50] Roguev A Conservation and rewiring of functional modules revealed by an epistasis map in fission yeast Science 322 405 2008 18818364 PMC2753251 sourceNot checked yet

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The regulatory mechanisms associated with positive genetic interactions among essential genes, which include genetic suppression interactions, are potentially relevant to human genetics.

“The regulatory mechanisms associated with positive genetic interactions among essential genes, which include genetic suppression interactions, are also potentially relevant to human genetics”

• cites [46] Buchovecky CM A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome Nature genetics 45 1013 2013 23892605 PMC3837522 sourceNot checked yet

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• cites [47] Keeling KM Xue X Gunn G Bedwell DM Therapeutics based on stop codon readthrough Annu Rev Genomics Hum Genet 15 371 2014 24773318 PMC5304456 sourceNot checked yet

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The general topology of genetic networks will also be conserved.

“it is reasonable to expect that the general topology of genetic networks will also be conserved (25)”

• cites [25] Koch EN Conserved rules govern genetic interaction degree across species Genome biology 13 R57 2012 22747640 PMC3491379 sourceNot checked yet

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Scanning disease cohorts for genetic variation that corresponds to coherent sets of mutations that connect genes within or between protein complexes and pathways may reveal genetic networks underlying diseases.

“scanning disease cohorts for genetic variation that corresponds to coherent sets of mutations that connect genes within or between protein complexes and pathways (e.g. see functional wiring diagrams for the ORC the 19S proteasome, Fig. 8) may reveal genetic networks underlying diseases”

Conservation of genetic interactions from yeast to human cells has been observed, particularly within fundamental bioprocesses like DNA synthesis and repair and chromosome segregation.

“conservation of genetic interactions from yeast to human cells has been observed (51, 52), particularly within fundamental bioprocesses like DNA synthesis and repair and chromosome segregation”

• cites [51] Deshpande R A comparative genomic approach for identifying synthetic lethal interactions in human cancer Cancer research 73 6128 2013 23980094 PMC3809957 sourceNot checked yet

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• cites [52] McManus KJ Barrett IJ Nouhi Y Hieter P Specific synthetic lethal killing of RAD54B-deficient human colorectal cancer cells by FEN1 silencing Proc Natl Acad Sci U S A 106 3276 2009 19218431 PMC2651317 sourceNot checked yet

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