BioPAX support in CellDesigner

Abstract

Motivation: BioPAX is a standard language for representing and exchanging models of biological processes at the molecular and cellular levels. It is widely used by different pathway databases and genomics data analysis software. Currently, the primary source of BioPAX data is direct exports from the curated pathway databases. It is still uncommon for wet-lab biologists to share and exchange pathway knowledge using BioPAX. Instead, pathways are usually represented as informal diagrams in the literature. In order to encourage formal representation of pathways, we describe a software package that allows users to create pathway diagrams using CellDesigner, a user-friendly graphical pathway-editing tool and save the pathway data in BioPAX Level 3 format.

Availability: The plug-in is freely available and can be downloaded at ftp://ftp.pantherdb.org/CellDesigner/plugins/BioPAX/

Contact: huaiyumi@usc.edu

Supplementary Information: Supplementary data are available at Bioinformatics online.

1 INTRODUCTION

Recent efforts to standardize pathway data have greatly facilitated the interpretation, exchange and integration of pathway knowledge in a rigorous and unambiguous way. The efforts have led to the creation of several widely accepted complementary community standards—Systems Biology Markup Language (SBML) (Hucka et al., 2003), Biological Pathway Exchange (BioPAX) (Demir et al., 2010) and Systems Biology Graphical Notation (SBGN) (Le Novère et al., 2009). Both SBML and BioPAX are machine-readable formats for representing cellular processes. The former is concentrated on mathematical modeling, while the latter is focused on qualitative pathway knowledge. SBGN is a standard for graphical representation of pathways and can be used for visualizing both SBML and BioPAX models. BioPAX Level 3 covers a large spectrum of qualitative information in the literature including metabolic and signaling pathways as well as molecular and genetic interactions. As a result, BioPAX is currently supported by >40 different pathway database resources (http://www.pathguide.org/), including MetaCyc (Caspi et al., 2010), PANTHER (Mi et al., 2010), PID (Schaefer et al., 2009) and Reactome (Croft et al., 2011). Most of these resources generate BioPAX-compliant exchange files from the pathway data that are curated by highly trained curators using specialized curation software. It is still rare for wet-lab biologists to create and exchange pathway data using such standards. This creates a bottleneck for pathway knowledge accumulation as the database groups can only curate a fraction of the enormous amount of knowledge that is being generated. Extending the usage of formal machine-readable models, such as BioPAX, to the wider biological community would significantly alleviate this problem and help pathway databases to cope up with the load (Mi and Thomas, 2011). Furthermore, wet-lab biologists are the end-users of the pathway databases, and thus the enrichment of pathway database content will ultimately benefit their research. The major obstacle so far is the lack of software tools that can allow biologists to easily transcribe the pathway knowledge to BioPAX format.

Cytoscape BioPAX plug-in allows users to load and graphically render BioPAX files for visualization. It has been used by a number of software to import or export BioPAX files. The plug-in does not support BioPAX Level 3 yet. CellDesigner (Funahashi et al., 2008) is a graphical, intuitive pathway-editing software, which uses controlled graphical notations for visual representation of the pathway and supports both SBML and SBGN standard (Hucka et al., 2003; Le Novère et al., 2009). It is used in the research community for generating pathway diagrams with controlled graphical notations for both wet-lab and systems biologists. Both CellDesigner and BioPAX describes pathway in terms of biochemical reaction and process, which is equivalent to SBGN Process Description (SBGN-PD) standard (Le Novère et al., 2009). The data structures in CellDesigner and BioPAX are similar but not identical, and we have developed a mapping between the two. Here, we describe a software package that allows users to draw or open a pathway diagram in CellDesigner, and save the data accurately in BioPAX format. Thus, the software provides the connection between SBML, SBGN-PD and BioPAX.

2 MAPPING CELLDESIGNER TO BIOPAX LEVEL 3

In this work, the mapping is done between CellDesigner 4.1 and BioPAX Level 3, and refer to them as CellDesigner and BioPAX, respectively, throughout the rest of the article. Since CellDesigner supports SBML, our mapping is greatly facilitated by the existing SBML to BioPAX mappings developed by other groups (Ruebenacker et al., 2009). The detailed mapping is described in the Supplementary Data 1 and Table S1. Here we will only discuss briefly our general approach of the mapping and our solutions to some of the issues that we encountered during the mapping. For the convenience of describing the mapping, all the CellDesigner terms are in italic, and the BioPAX terms are in italic and underline.

The mapping described here is designed to support the current development to export CellDesigner symbols to BioPAX ontology classes. One of our long-term goals is to import BioPAX pathways to CellDesigner. Although the general principle of the mapping is to ensure accurate translation of CellDesigner symbols to BioPAX ontology terms, we are also mindful about the accuracy of the reverse mapping.

The three main categories of symbols in CellDeigner, Model, State node symbol (also known as species) and Arcs can be mapped to Pathway, PhysicialEntity and Interaction in BioPAX, respectively. The symbols in each category in CellDesigner are mapped to the corresponding BioPAX subclasses in the following three approaches. First, a CellDesigner symbol has an exact (or one-to-one) match to a corresponding BioPAX subclass. Although each system uses different names, their underlying context and concept may be identical, e.g. Heteromultimer and State Transition in CellDeisgner versus Complex and BiochemicalReaction in BioPAX, respectively. Therefore, a one-to-one mapping can be created. Second, multiple CellDesigner symbols are mapped to a single BioPAX subclass, e.g. Ion channel and Generic protein symbols in CellDesigner are both mapped to Protein in BioPAX. Although there is loss of data in this case, most of the information can still be captured through the names (for entities) and the reactions involved (for transitions arcs). Third, the CellDesigner symbols cannot be mapped to any corresponding BioPAX subclasses, and therefore they have to be mapped to the parent class term. For example, Inhibition and Physical Stimulation in CellDesigner are mapped to Control in BioPAX, with values such as Inhibition or Activation associated to ControlType. Loss of data could be an issue in this type of mapping. In many cases, we tried to find ways within BioPAX to capture the information to minimize the information loss. The current implementation in the mapping has minimum loss of data going from CellDesigner to BioPAX. However, we do realize that the reverse map from BioPAX to CellDesigner is still ambiguous. The developers of this project are both involved in CellDesigner and BioPAX development. We are aware of the issues and are actively working toward a solution to resolve this problem (see Supplementary Data 1 for more detailed discussions on each case).

3 IMPLEMENTATION

The preliminary work has been implemented in CellDesigner 4.1 release in 2010. Due to the different release cycles of CellDesigner, BioPAX and our mapping updates, we have decided to implement the BioPAX translator as a CellDesigner plug-in, so that timely updates can be released. The existing implementation will be obsoleted in the next CellDesigner release.

CellDesigner includes an extensible plug-in system that allows third-party software to register as plug-ins for additional functionality. The interface allows any plug-in to retrieve information such as model, compartments, components and relationships between components as well as the relationships between the components and the compartments.

The BioPAX plug-in first reads the CellDesigner components via the Java plug-in API. It then maps them to the corresponding BioPAX Level 3 objects defined in the Paxtools, a Java library that can be used to create BioPAX objects and output the corresponding model in the OWL/RDF-XML format. The mapping between CellDesigner and BioPAX is not always one-to-one and the translator employs some rules and heuristics to resolve ambiguous mappings. See Supplementary Data 1 for details.

Importantly, the translator also adds cross-references to facilitate mapping to the external data sources. The translator uses web services provided by the Ontology Lookup Service to search for terms such as cellular component (GO database) (Gene Ontology Consortium, 2010), protein modification (PSI-MI) (Kerrien et al., 2007) and small molecule description (ChEBI) (Degtyarenko et al., 2008).

The BioPAX files produced by the plug-in are valid and error-free (Supplementary Data 1). The plug-in supports CellDesigner 4.1 and the recently released 4.2. It is freely available and can be downloaded at: ftp://ftp.pantherdb.org/CellDesigner/plugins/BioPAX/.

See Supplement Data 2 and Figure S3 for details about installation and use of the tool.