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Alfredo Ferro, Rosalba Giugno, Alessandro Laganà, Misael Mongiovì, Giuseppe PigolA, Alfredo PulvirentI

Dipartimento di Matematica e Informatica, UniversitA’ di Catania, Viale A. Doria 6, I-95125 Catania, Italy{ferro, giugno, lagana, mongiovi, pigola, apulvirenti}@dmi.unict.it

Gary Bader

Banting and Best Department of Medical Research and Department of Medical Genetics and Microbiology,University of Toronto, 160 College St, Toronto, Ontario, CanadA M5S 3E1gary.bader@utoronto.ca

Dennis Shasha

Courant Institute of Mathematical, Sciences, New York University, 251 Mercer Street New York, NY 10012, USAshasha@cs.nyu.edu

miRScape: A Cytoscape Plug-in to Annotate Biological Networks with

microRNAs

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Introduction and Motivations

In the last few years there has been an increasing interest in mining biological networks involving miRNAs;

Recent works proved the existence of functional interactions among miRNAs;

miRScape is the first Cytoscape plugin (www.cytoscape.org) to mine biological networks annotated with microRNAs;

It makes use of miRo’, a knowledge base (available at the following web site http://ferrolab.dmi.unict.it), which introduces a new layer of associations among genes (functions, processes, diseases related) based on miRNAs annotations;

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microRNAs (miRNA) are single stranded RNA molecules of 21-23 nucleotides which regulate gene expression;

They are involved in several processes, functions and diseases;

The knockout of a single miRNA may dramatically affect the phenotype of an organism [Couzin J. Erasing microRNAs reveals their powerful punch. Science 2007;316(5824):530];

A miRNA may target more than one gene, often in several sites, and one gene may be targeted by many miRNAs acting cooperatively [Ambros V. The functions of animal microRNAs. Nature 2004;431:350-355];

Mining on gene networks annotated with miRNAs is needed;

Moreover, analyzing network of interactions between genes and miRNAs may be useful;

Introduction and Motivations

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miRScape

mirScape plug-in

Cytoscape

Annotate

Interaction netwoks

Retrieve data about genes,miRNAs, Diseases, Functions, Processes

miRò web pages

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Mirò: the miR-Ontology database www.ferrolab.dmi.unict.it

● Using miRScape the user is able to identify and highlight relations involving genes present in the network with specific functions, process and diseases through the selected miRNAs;

● The miRò knowledge base stores miRNAs annotated with additional information coming from miRBase;

● It also includes experimentally supported miRNA targets coming from miRecords and predicted targets taken from the TargetScan , PicTar, and miRanda;

● The target ontologies (processes and functions) are obtained from the Gene Ontology Database (GO);

● The gene-disease relations come from the Genetic Association Database (GAD), which is a database of human genetic association studies of complex diseases and disorders;

● All the data are collected and maintained up-to-date in a MySQL database accessible through a web interface;

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Cytoscapewww.cytoscape.org

Cytoscape is an open source bioinformatics software platform for visualizing and analyzing biological interaction networks;

It is multiplatform (Java);

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Cytoscape: Featureswww.cytoscape.org

Cytoscape supports a lot of standard network and annotation file formats including: SIF (Simple Interaction Format), GML, XGMML, BioPAX, PSI-MI, SBML, OBO, and Gene Association;

Filter the network to select subsets of nodes and/or interactions;

Search nodes and edges;

Customize network data display using powerful Visual Styles;

Different visualization layouts;

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Cytoscape: Pluginswww.cytoscape.org

Additional features are available as plug-ins:  

In Cytoscape you can write your own plug-in for data analysis/import/visualization by writing Java code;

Several plug-ins are available for network and molecular profiling analyses, new layouts, additional file format support, scripting, graph matching and connection with databases;

Plug-ins can easily installed by just one click from Plugin Manager;

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Cytoscape: Pluginswww.cytoscape.org

Topology analysis:Network Analyzer, ShortestPaths CentiscaPe;

Find clusters (highly interconnected regions):

MCODE;

Motif Finder: Motif Finder Plugin;Metabolica Plugin;

Graph Matching:NetMatch;

…………………..

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miRScape: Search by Genehttp://ferrolab.dmi.unict.it

There are two different ways to query miRò database: by gene or by miRNA;

Selecting a set of genes in a network it is possible to retrieve all miRNAs, Functions, Processes and Diseases correlated with selected genes;

The gene searching in miRò is done by NCBI id, Official name and aliases;

All results are linked to the miRò web site;

Highlight relations: it is possible to build a network of interactions between genes and miRNAs;

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Moreover, it is possible to annotate the network with information about related miRNAs, Functions, Diseases, and Processes;

Eventually the network can be saved with these additional information.

miRScape: Annotating Networkshttp://ferrolab.dmi.unict.it

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It is possible to retrieve information about all genes correlated to selected miRNAs;

The process can be done searching only for miRNAs:

1. Validated (Experimentally by miRecords);

1. TargetScan (Lewis BP et al. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005;120:15-20);

1. Pictar (Krek A et al. Combinatorial microRNA target predictions. Nat Genetics 2005;37:495-500);

1. MiRanda;

It is also possible getting information about: Functions,Processes, and Diseases related to miRNAs;

Genes in the network correlated with selected miRNAs will be highlighted;

miRScape: Search by miRNAhttp://ferrolab.dmi.unict.it

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Example: Search by Gene and annotate Networkshttp://ferrolab.dmi.unict.it

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Example: Create a network genes-miRNAshttp://ferrolab.dmi.unict.it

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Example: Highlight Specific Interactionshttp://ferrolab.dmi.unict.it

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Example: Search by miRNAhttp://ferrolab.dmi.unict.it

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Conclusions

miRScape represents the first tool able to annotate networks with miRNAs related information coming from several distributed databases. This was achieved by making use of miRò which can be viewed as a unified access point to these remote databases.

One of the crucial functions available on mirScape is the possibility to highlight hidden relations among clusters of genes at miRNA level. This capability represent the basic step for any analysis requiring mining.

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miRScape: Future Workhttp://ferrolab.dmi.unict.it

● Using different kinds of attribute in order to query miRò database;

● Adding datamining facilities: Association rules etc…;

● New visualization layouts for very large networks;

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Download miRScapehttp://ferrolab.dmi.unict.it

● Download Cytoscape: www.cytoscape.org

● miRò web site: http://ferrolab.dmi.unict.it

● Plugin download and bugs report: contact ferro@dmi.unict.it

Thank You……