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*Read the introductory notes on {{ABC-PDF|BIN-PPI-Analysis|the analysis of Protein-Protein Interaction (PPI) networks}}.
 
*Read the introductory notes on {{ABC-PDF|BIN-PPI-Analysis|the analysis of Protein-Protein Interaction (PPI) networks}}.
 
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Revision as of 18:03, 9 November 2017

PPI Analysis


 

Keywords:  Analysis of PPIs; Totality, context; date- and party hubs; dynamics; Cytoscape


 



 


Caution!

This unit is under development. There is some contents here but it is incomplete and/or may change significantly: links may lead to nowhere, the contents is likely going to be rearranged, and objectives, deliverables etc. may be incomplete or missing. Do not work with this material until it is updated to "live" status.


 


Abstract

...


 


This unit ...

Prerequisites

You need the following preparation before beginning this unit. If you are not familiar with this material from courses you took previously, you need to prepare yourself from other information sources:

  • Biomolecules: The molecules of life; nucleic acids and amino acids; the genetic code; protein folding; post-translational modifications and protein biochemistry; membrane proteins; biological function.
  • Metabolism: Enzymatic catalysis and control; reaction sequences and pathways; chemiosmotic coupling; catabolic- and anabolic pathways.
  • Organelles: Compartmentalization, organelles and structures of the cell; the extracellular matrix.

You need to complete the following units before beginning this one:


 


Objectives

...


 


Outcomes

...


 


Deliverables

  • Time management: Before you begin, estimate how long it will take you to complete this unit. Then, record in your course journal: the number of hours you estimated, the number of hours you worked on the unit, and the amount of time that passed between start and completion of this unit.
  • Journal: Document your progress in your Course Journal. Some tasks may ask you to include specific items in your journal. Don't overlook these.
  • Insights: If you find something particularly noteworthy about this unit, make a note in your insights! page.


 


Evaluation

Evaluation: TBD

This unit can be submitted for evaluation for a maximum of 6 marks. Details TBD.


 


Contents

Task:


 


Working with biological graphs in R

Task:

  • Open RStudio.
  • Choose File → Recent Projects → BCH441_2016.
  • Pull the latest version of the project repository from GitHub.
  • type init()
  • Open the file BCH441_A11.R and work through the entire tutorial.
  • At the end of the tutorial, you are being asked to print R code and data on a sheet of paper and bring this to class. This will be marked by me and worth maximally 4 marks. Be careful to follow the instructions exactly, especially regarding how to use your student number as a randomization seed.
This is all that is required. There is optional material below that you may find interesting.


 


Optional: Data visualization and analysis

 

If you work a lot with interaction networks, sooner or later you will come across Cytoscape. It is more or less the standard among "professional" systems biologists. But it is not an online tool.

Task:

  • Navigate to the Cytoscape homepage and inform yourself what the program does and how to install it. There are many tutorials online available. But this is software that needs to be downloaded, and installed and it definitively has a learning curve.


Visualizing Interactions

Cytoscape is a program originally written in Trey Ideker's lab at the Institue for Systems Biology, that is now a thriving, open-source community project for the development of a biology-oriented network display and analysis tool.


Kohl et al. (2011) Cytoscape: software for visualization and analysis of biological networks. Methods Mol Biol 696:291-303. (pmid: 21063955)

[ PubMed ] [ DOI ] Substantial progress has been made in the field of "omics" research (e.g., Genomics, Transcriptomics, Proteomics, and Metabolomics), leading to a vast amount of biological data. In order to represent large biological data sets in an easily interpretable manner, this information is frequently visualized as graphs, i.e., a set of nodes and edges. Nodes are representations of biological molecules and edges connect the nodes depicting some kind of relationship. Obviously, there is a high demand for computer-based assistance for both visualization and analysis of biological data, which are often heterogeneous and retrieved from different sources. This chapter focuses on software tools that assist in visual exploration and analysis of biological networks. Global requirements for such programs are discussed. Utilization of visualization software is exemplified using the widely used Cytoscape tool. Additional information about the use of Cytoscape is provided in the Notes section. Furthermore, special features of alternative software tools are highlighted in order to assist researchers in the choice of an adequate program for their specific requirements.


Cytoscape is now available as version 3 and should be straightforward to download and install.

Cytoscape 3 tutorials ([1])


Cytoscape tutorials ([2])
Montojo et al. (2010) GeneMANIA Cytoscape plugin: fast gene function predictions on the desktop. Bioinformatics 26:2927-8. (pmid: 20926419)

[ PubMed ] [ DOI ] UNLABELLED: The GeneMANIA Cytoscape plugin brings fast gene function prediction capabilities to the desktop. GeneMANIA identifies the most related genes to a query gene set using a guilt-by-association approach. The plugin uses over 800 networks from six organisms and each related gene is traceable to the source network used to make the prediction. Users may add their own interaction networks and expression profile data to complement or override the default data. AVAILABILITY AND IMPLEMENTATION: The GeneMANIA Cytoscape plugin is implemented in Java and is freely available at http://www.genemania.org/plugin/.

Merico et al. (2011) Visualizing gene-set enrichment results using the Cytoscape plug-in enrichment map. Methods Mol Biol 781:257-77. (pmid: 21877285)

[ PubMed ] [ DOI ] Gene-set enrichment analysis finds functionally coherent gene-sets, such as pathways, that are statistically overrepresented in a given gene list. Ideally, the number of resulting sets is smaller than the number of genes in the list, thus simplifying interpretation. However, the increasing number and redundancy of -gene-sets used by many current enrichment analysis resources work against this ideal. "Enrichment Map" is a Cytoscape plug-in that helps overcome gene-set redundancy and aids in the interpretation of enrichment results. Gene-sets are organized in a network, where each set is a node and links represent gene overlap between sets. Automated network layout groups related gene-sets into -network clusters, enabling the user to quickly identify the major enriched functional themes and more easily interpret enrichment results.

The Cytoscape wiki and manual, and the Cytoscape manual page on network formats.
Platform
Shannon et al. (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498-504. (pmid: 14597658)

[ PubMed ] [ DOI ] Cytoscape is an open source software project for integrating biomolecular interaction networks with high-throughput expression data and other molecular states into a unified conceptual framework. Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunction with large databases of protein-protein, protein-DNA, and genetic interactions that are increasingly available for humans and model organisms. Cytoscape's software Core provides basic functionality to layout and query the network; to visually integrate the network with expression profiles, phenotypes, and other molecular states; and to link the network to databases of functional annotations. The Core is extensible through a straightforward plug-in architecture, allowing rapid development of additional computational analyses and features. Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models.

Cline et al. (2007) Integration of biological networks and gene expression data using Cytoscape. Nat Protoc 2:2366-82. (pmid: 17947979)

[ PubMed ] [ DOI ] Cytoscape is a free software package for visualizing, modeling and analyzing molecular and genetic interaction networks. This protocol explains how to use Cytoscape to analyze the results of mRNA expression profiling, and other functional genomics and proteomics experiments, in the context of an interaction network obtained for genes of interest. Five major steps are described: (i) obtaining a gene or protein network, (ii) displaying the network using layout algorithms, (iii) integrating with gene expression and other functional attributes, (iv) identifying putative complexes and functional modules and (v) identifying enriched Gene Ontology annotations in the network. These steps provide a broad sample of the types of analyses performed by Cytoscape.

Killcoyne et al. (2009) Cytoscape: a community-based framework for network modeling. Methods Mol Biol 563:219-39. (pmid: 19597788)

[ PubMed ] [ DOI ] Cytoscape is a general network visualization, data integration, and analysis software package. Its development and use has been focused on the modeling requirements of systems biology, though it has been used in other fields. Cytoscape's flexibility has encouraged many users to adopt it and adapt it to their own research by using the plugin framework offered to specialize data analysis, data integration, or visualization. Plugins represent collections of community-contributed functionality and can be used to dynamically extend Cytoscape functionality. This community of users and developers has worked together since Cytoscape's initial release to improve the basic project through contributions to the core code and public offerings of plugin modules. This chapter discusses what Cytoscape does, why it was developed, and the extensions numerous groups have made available to the public. It also describes the development of a plugin used to investigate a particular research question in systems biology and walks through an example analysis using Cytoscape.

Smoot et al. (2011) Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 27:431-2. (pmid: 21149340)

[ PubMed ] [ DOI ] UNLABELLED: Cytoscape is a popular bioinformatics package for biological network visualization and data integration. Version 2.8 introduces two powerful new features--Custom Node Graphics and Attribute Equations--which can be used jointly to greatly enhance Cytoscape's data integration and visualization capabilities. Custom Node Graphics allow an image to be projected onto a node, including images generated dynamically or at remote locations. Attribute Equations provide Cytoscape with spreadsheet-like functionality in which the value of an attribute is computed dynamically as a function of other attributes and network properties. AVAILABILITY AND IMPLEMENTATION: Cytoscape is a desktop Java application released under the Library Gnu Public License (LGPL). Binary install bundles and source code for Cytoscape 2.8 are available for download from http://cytoscape.org.

Plugins
Rivera et al. (2010) NeMo: Network Module identification in Cytoscape. BMC Bioinformatics 11 Suppl 1:S61. (pmid: 20122237)

[ PubMed ] [ DOI ] BACKGROUND: As the size of the known human interactome grows, biologists increasingly rely on computational tools to identify patterns that represent protein complexes and pathways. Previous studies have shown that densely connected network components frequently correspond to community structure and functionally related modules. In this work, we present a novel method to identify densely connected and bipartite network modules based on a log odds score for shared neighbours. RESULTS: To evaluate the performance of our method (NeMo), we compare it to other widely used tools for community detection including kMetis, MCODE, and spectral clustering. We test these methods on a collection of synthetically constructed networks and the set of MIPS human complexes. We apply our method to the CXC chemokine pathway and find a high scoring functional module of 12 disconnected phospholipase isoforms. CONCLUSION: We present a novel method that combines a unique neighbour-sharing score with hierarchical agglomerative clustering to identify diverse network communities. The approach is unique in that we identify both dense network and dense bipartite network structures in a single approach. Our results suggest that the performance of NeMo is better than or competitive with leading approaches on both real and synthetic datasets. We minimize model complexity and generalization error in the Bayesian spirit by integrating out nuisance parameters. An implementation of our method is freely available for download as a plugin to Cytoscape through our website and through Cytoscape itself.

Montojo et al. (2010) GeneMANIA Cytoscape plugin: fast gene function predictions on the desktop. Bioinformatics 26:2927-8. (pmid: 20926419)

[ PubMed ] [ DOI ] UNLABELLED: The GeneMANIA Cytoscape plugin brings fast gene function prediction capabilities to the desktop. GeneMANIA identifies the most related genes to a query gene set using a guilt-by-association approach. The plugin uses over 800 networks from six organisms and each related gene is traceable to the source network used to make the prediction. Users may add their own interaction networks and expression profile data to complement or override the default data. AVAILABILITY AND IMPLEMENTATION: The GeneMANIA Cytoscape plugin is implemented in Java and is freely available at http://www.genemania.org/plugin/.

Oesper et al. (2011) WordCloud: a Cytoscape plugin to create a visual semantic summary of networks. Source Code Biol Med 6:7. (pmid: 21473782)

[ PubMed ] [ DOI ] BACKGROUND: When biological networks are studied, it is common to look for clusters, i.e. sets of nodes that are highly inter-connected. To understand the biological meaning of a cluster, the user usually has to sift through many textual annotations that are associated with biological entities. FINDINGS: The WordCloud Cytoscape plugin generates a visual summary of these annotations by displaying them as a tag cloud, where more frequent words are displayed using a larger font size. Word co-occurrence in a phrase can be visualized by arranging words in clusters or as a network. CONCLUSIONS: WordCloud provides a concise visual summary of annotations which is helpful for network analysis and interpretation. WordCloud is freely available at http://baderlab.org/Software/WordCloudPlugin.

Razick et al. (2011) iRefScape. A Cytoscape plug-in for visualization and data mining of protein interaction data from iRefIndex. BMC Bioinformatics 12:388. (pmid: 21975162)

[ PubMed ] [ DOI ] BACKGROUND: The iRefIndex consolidates protein interaction data from ten databases in a rigorous manner using sequence-based hash keys. Working with consolidated interaction data comes with distinct challenges: data are redundant, overlapping, highly interconnected and may be collected and represented using different curation practices. These phenomena were quantified in our previous studies. RESULTS: The iRefScape plug-in for the Cytoscape graphical viewer addresses these challenges. We show how these factors impact on data-mining tasks and how our solutions resolve them in a simple and efficient manner. A uniform accession space is used to limit redundancy and support search expansion and searching on multiple accession types. Multiple node and edge features support data filtering and mining. Node colours and features supply information about search result provenance. Overlapping evidence is presented using a multi-graph and a bi-partite representation is used to distinguish binary and n-ary source data. Searching for interactions between sets of proteins is supported and specifically includes searches on disease-related genes found in OMIM. Finally, a synchronized adjacency-matrix view facilitates visualization of relationships between sets of user defined groups. CONCLUSIONS: The iRefScape plug-in will be of interest to advanced users of interaction data. The plug-in provides access to a consolidated data set in a uniform accession space while remaining faithful to the underlying source data. Tools are provided to facilitate a range of tasks from a simple search to knowledge discovery. The plug-in uses a number of strategies that will be of interest to other plug-in developers.

Morris et al. (2011) clusterMaker: a multi-algorithm clustering plugin for Cytoscape. BMC Bioinformatics 12:436. (pmid: 22070249)

[ PubMed ] [ DOI ] BACKGROUND: In the post-genomic era, the rapid increase in high-throughput data calls for computational tools capable of integrating data of diverse types and facilitating recognition of biologically meaningful patterns within them. For example, protein-protein interaction data sets have been clustered to identify stable complexes, but scientists lack easily accessible tools to facilitate combined analyses of multiple data sets from different types of experiments. Here we present clusterMaker, a Cytoscape plugin that implements several clustering algorithms and provides network, dendrogram, and heat map views of the results. The Cytoscape network is linked to all of the other views, so that a selection in one is immediately reflected in the others. clusterMaker is the first Cytoscape plugin to implement such a wide variety of clustering algorithms and visualizations, including the only implementations of hierarchical clustering, dendrogram plus heat map visualization (tree view), k-means, k-medoid, SCPS, AutoSOME, and native (Java) MCL. RESULTS: Results are presented in the form of three scenarios of use: analysis of protein expression data using a recently published mouse interactome and a mouse microarray data set of nearly one hundred diverse cell/tissue types; the identification of protein complexes in the yeast Saccharomyces cerevisiae; and the cluster analysis of the vicinal oxygen chelate (VOC) enzyme superfamily. For scenario one, we explore functionally enriched mouse interactomes specific to particular cellular phenotypes and apply fuzzy clustering. For scenario two, we explore the prefoldin complex in detail using both physical and genetic interaction clusters. For scenario three, we explore the possible annotation of a protein as a methylmalonyl-CoA epimerase within the VOC superfamily. Cytoscape session files for all three scenarios are provided in the Additional Files section. CONCLUSIONS: The Cytoscape plugin clusterMaker provides a number of clustering algorithms and visualizations that can be used independently or in combination for analysis and visualization of biological data sets, and for confirming or generating hypotheses about biological function. Several of these visualizations and algorithms are only available to Cytoscape users through the clusterMaker plugin. clusterMaker is available via the Cytoscape plugin manager.



 


Further reading, links and resources

 


Notes


 


Self-evaluation

 



 



 

If in doubt, ask! If anything about this learning unit is not clear to you, do not proceed blindly but ask for clarification. Post your question on the course mailing list: others are likely to have similar problems. Or send an email to your instructor.


 

About ...
 
Author:

Boris Steipe <boris.steipe@utoronto.ca>

Created:

2017-08-05

Modified:

2017-08-05

Version:

0.1

Version history:

  • 0.1 First stub

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