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Improved functional overview of protein complexes using inferred epistatic relationships.

Ryan C, Greene D, Guénolé A, van Attikum H, Krogan NJ, Cunningham P, Cagney G - BMC Syst Biol (2011)

Bottom Line: Epistatic Miniarray Profiling(E-MAP) quantifies the net effect on growth rate of disrupting pairs of genes, often producing phenotypes that may be more (negative epistasis) or less (positive epistasis) severe than the phenotype predicted based on single gene disruptions.We constructed an expanded epistasis map for yeast cell protein complexes and show that our new interactions increase the evidence for previously proposed inter-complex connections, and predict many new links.We validated a number of these in the laboratory, including new interactions linking the SWR-C chromatin modifying complex and the nuclear transport apparatus.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Computer Science and Informatics, University College Dublin, Ireland. colm.ryan@ucd.ie.

ABSTRACT

Background: Epistatic Miniarray Profiling(E-MAP) quantifies the net effect on growth rate of disrupting pairs of genes, often producing phenotypes that may be more (negative epistasis) or less (positive epistasis) severe than the phenotype predicted based on single gene disruptions. Epistatic interactions are important for understanding cell biology because they define relationships between individual genes, and between sets of genes involved in biochemical pathways and protein complexes. Each E-MAP screen quantifies the interactions between a logically selected subset of genes (e.g. genes whose products share a common function). Interactions that occur between genes involved in different cellular processes are not as frequently measured, yet these interactions are important for providing an overview of cellular organization.

Results: We introduce a method for combining overlapping E-MAP screens and inferring new interactions between them. We use this method to infer with high confidence 2,240 new strongly epistatic interactions and 34,469 weakly epistatic or neutral interactions. We show that accuracy of the predicted interactions approaches that of replicate experiments and that, like measured interactions, they are enriched for features such as shared biochemical pathways and knockout phenotypes. We constructed an expanded epistasis map for yeast cell protein complexes and show that our new interactions increase the evidence for previously proposed inter-complex connections, and predict many new links. We validated a number of these in the laboratory, including new interactions linking the SWR-C chromatin modifying complex and the nuclear transport apparatus.

Conclusion: Overall, our data support a modular model of yeast cell protein network organization and show how prediction methods can considerably extend the information that can be extracted from overlapping E-MAP screens.

Show MeSH
Novel and Supporting Inter complex edges: A. Monochromatic interactions between complexes whose significance is increased after the addtion of our predicted epistatic interactions. B. A close up of the Swr1 complex. C. Positive interactions between the "box C/D snoRNP" complex and "Rpd3L" complex
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Figure 4: Novel and Supporting Inter complex edges: A. Monochromatic interactions between complexes whose significance is increased after the addtion of our predicted epistatic interactions. B. A close up of the Swr1 complex. C. Positive interactions between the "box C/D snoRNP" complex and "Rpd3L" complex

Mentions: The largest connected component of these 105 novel 'inter-complex' links. Is shown in Figure 4A. This figure is effectively an overview of how cellular processes are organized into modular arrangements, while operating at different hierarchical levels. At the level of the protein complex, individual proteins physically interact, while at the pathway or function level, protein complexes communicate with each other through interactions that are reflected at the epistatic level.


Improved functional overview of protein complexes using inferred epistatic relationships.

Ryan C, Greene D, Guénolé A, van Attikum H, Krogan NJ, Cunningham P, Cagney G - BMC Syst Biol (2011)

Novel and Supporting Inter complex edges: A. Monochromatic interactions between complexes whose significance is increased after the addtion of our predicted epistatic interactions. B. A close up of the Swr1 complex. C. Positive interactions between the "box C/D snoRNP" complex and "Rpd3L" complex
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117733&req=5

Figure 4: Novel and Supporting Inter complex edges: A. Monochromatic interactions between complexes whose significance is increased after the addtion of our predicted epistatic interactions. B. A close up of the Swr1 complex. C. Positive interactions between the "box C/D snoRNP" complex and "Rpd3L" complex
Mentions: The largest connected component of these 105 novel 'inter-complex' links. Is shown in Figure 4A. This figure is effectively an overview of how cellular processes are organized into modular arrangements, while operating at different hierarchical levels. At the level of the protein complex, individual proteins physically interact, while at the pathway or function level, protein complexes communicate with each other through interactions that are reflected at the epistatic level.

Bottom Line: Epistatic Miniarray Profiling(E-MAP) quantifies the net effect on growth rate of disrupting pairs of genes, often producing phenotypes that may be more (negative epistasis) or less (positive epistasis) severe than the phenotype predicted based on single gene disruptions.We constructed an expanded epistasis map for yeast cell protein complexes and show that our new interactions increase the evidence for previously proposed inter-complex connections, and predict many new links.We validated a number of these in the laboratory, including new interactions linking the SWR-C chromatin modifying complex and the nuclear transport apparatus.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Computer Science and Informatics, University College Dublin, Ireland. colm.ryan@ucd.ie.

ABSTRACT

Background: Epistatic Miniarray Profiling(E-MAP) quantifies the net effect on growth rate of disrupting pairs of genes, often producing phenotypes that may be more (negative epistasis) or less (positive epistasis) severe than the phenotype predicted based on single gene disruptions. Epistatic interactions are important for understanding cell biology because they define relationships between individual genes, and between sets of genes involved in biochemical pathways and protein complexes. Each E-MAP screen quantifies the interactions between a logically selected subset of genes (e.g. genes whose products share a common function). Interactions that occur between genes involved in different cellular processes are not as frequently measured, yet these interactions are important for providing an overview of cellular organization.

Results: We introduce a method for combining overlapping E-MAP screens and inferring new interactions between them. We use this method to infer with high confidence 2,240 new strongly epistatic interactions and 34,469 weakly epistatic or neutral interactions. We show that accuracy of the predicted interactions approaches that of replicate experiments and that, like measured interactions, they are enriched for features such as shared biochemical pathways and knockout phenotypes. We constructed an expanded epistasis map for yeast cell protein complexes and show that our new interactions increase the evidence for previously proposed inter-complex connections, and predict many new links. We validated a number of these in the laboratory, including new interactions linking the SWR-C chromatin modifying complex and the nuclear transport apparatus.

Conclusion: Overall, our data support a modular model of yeast cell protein network organization and show how prediction methods can considerably extend the information that can be extracted from overlapping E-MAP screens.

Show MeSH