Reviewer users guide

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Reactome User's Guide

Introduction

This document is an overview of the Reactome database of biological pathways and processes and its web site. This is not a comprehensive guide, but should provide you with enough information to browse the database and use its principal tools for data analysis. Please read through it and contact us with any comments or questions.

To explain some of the terms used in this User Guide, we have created a Glossary.

What is Reactome?

Reactome is a curated database of pathways and reactions (pathway steps) in human biology. The Reactome definition of a 'reaction' includes many events in biology that are changes in state, such as binding, activation, translocation and degradation, in addition to classical biochemical reactions. Information in the database is authored by expert biologist researchers, maintained by Reactome editorial staff, and extensively cross-referenced to other resources e.g. NCBI, Ensembl, UniProt, UCSC Genome Browser, HapMap, KEGG (Gene and Compound), ChEBI, PubMed and GO. Inferred orthologous reactions are available for over 20 non-human species including mouse, rat, chicken, puffer fish, worm, fly, yeast, rice, Arabidopsis and E.coli.

The Reactome Front Page

This is the normal entry point for most users of Reactome. To view this page, type: http://www.reactome.org into the URL slot on your browser.

Reactome Home Page


This page is divided into six parts:

  • The Banner contains a Reactome icon in the banner, which is interactive and when clicked from elsewhere within the website will bring the user back to the homepage.
  • The Navigation Bar just below the banner has drop down menus giving access to data and functionality available on the Reactome website.
  • Six Tool Buttons on the left-hand side of the page provides shortcut buttons to the most popular analysis tools and downloadable Reactome datasets.
  • The Main Text section includes a description of Reactome, the participating research institutions and our funding sources.
  • The Twitter feed box on the right-hand side provides up-to the minute Reactome news and a user feedback system.
  • The Homepage footer that lists all the webpages accessible throughout the Reactome website.

The Navigation Bar

Most Navigation Bar items are drop down menus. It is found on many pages of the Reactome website. Links from the Navigation Bar include:

  • About. Background information such as a description of Reactome and the people involved.
  • Content. An overview of the Reactome database, the areas of biology we cover, our plans for content expansion, the structure of our data, and statistics about the current content.
  • Documentation. Includes this User Guide, plus technical aspects of Reactome's functionality and data.
  • Tools. Tools in addition to those linked as shortcut buttons on the Sidebar. Some of these tools are covered in more detail in the Reactome Tools section.
  • Community. Details of Reactome training, publications and representation at conferences and workshops.
  • Download. Links to a page where Reactome data and code is available in various formats. See below for more details.
  • Contact Us. Opens a form page, which allow you to send your questions or comments to the Reactome helpdesk.
  • Search. Type in text (words) or identifiers to locate them in Reactome. For details see Searching Reactome section. Search Examples are listed within the Search text box.

The Six Tool Buttons

The Six Tools Buttons provides easy access to tools, the lower has shortcuts to popular Downloads, Featured tools, and Help. From top to bottom, the features are:

  • Browse Pathways ; Directly access the Reactome Pathway Browser; see The Pathway Browser and Tools
  • Analyze Data . Directly access the most popular Reactome tools; see Reactome Tools for detailed descriptions.
  • Reactome FI network. Link to a page describing how to install and use the Reactome Functional Interaction (FI) Network plugin; more details can be found at FI Network Tool
  • User Guide. Access this User Guide.
  • Downloads. Popular Reactome data downloads.
  • Contact Us. Send feedback to Reactome or ask us a question.

The Main Text

This is the text area under the Six Tool Buttons, to the right of the Twitter feed. This area contains the following:

  • About Reactome. A one paragraph statement linked to more detailed information.
  • Participating Research Institutions. Reactome is a collaboration amongst OICR, NYUMC, CSHL and EBI.
  • Funding Agencies. Acknowledging the different funding agencies that support the Reactome project.

The Pathway Browser and Tools

The Pathway Browser is the primary means of viewing and interacting with specific pathways. It includes a search tool, interactive pathway viewer and set of tools for several types of analysis including:

  • Comparison of a pathway with its equivalent in another species
  • The overlay of user-supplied expression data onto a pathway
  • The overlay of protein-protein or protein-compound data from external databases or user-supplied data onto a pathway.
  • The display of context-sensitive information from other resources in a separate panel, using widgets provided by the external resources.

The Tool bar on Reactome's Homepage gives access to extended versions of these tools that query across all Reactome pathways (see Reactome Tools).

The Pathway Browser

The Pathway Browser is launched by clicking the top button on the Tool bar. The Pathway Browser has 4 panels:

Pathway Browser
  • Features bar. On the far left is a Home button that returns you to the homepage. It also includes a key to the most common pathway objects, and a link to a full Diagram Key (far right-hand side). At the top is a species selector, with drop-down list of species. The default is Homo sapiens. Change to another species and the pathway displayed will be computationally inferred from the curated human pathway. N.B. Reactome data is human-centric, data for other species is inferred from human pathways - pathway steps may be missing for other organisms if they are not identified by the inference process (described here). Currently, infectious disease pathways involving pathogen proteins are only listed under the species "Homo sapiens". This include the HIV, Influenza, and botulinum neurotoxicity pathways. Buttons for showing/hiding the hierarchy tree, details panel and the diagram key (and one for expanding the pathway diagram)
  • Pathway Hierarchy Panel. The hierarchy of Reactome pathways is listed in the panel on the left side. Similar to the Windows File Manager, sub-pathways can be revealed by clicking on the + symbol to the left of the pathway name. Click on and drag the grey line, separating the Hierarchy panel from the Pathway Diagram Panel, will adjust the width of the Pathway Hierarchy Panel.
  • Pathway Diagram Panel. This is where pathway diagrams are displayed, when selected in the Pathway Hierarchy Panel. The Pathway Diagram panel will display a brief guide to the pathway browser until you select a pathway. Top-left of this panel is a navigate/zoom tool. Click on the arrows to move across the diagram. The ‘double arrow” button resizes the pathway diagram to fit the available space. Click on the ‘+’ or ‘-‘ buttons to zoom in and out, respectively. The mouse wheel also zooms.
  • Tabbed Details Panel. It gives details of the selected pathway, reaction, complex, set or proteins, when they are selected in the pathway diagram or Pathway Hierarchy panel. This panel can be revealed/hidden using the small yellow triangle on the border with the Pathway Diagram panel. Selecting a location in the pathway diagram with your cursor, and scrolling the wheel will zoom in/out wherever the cursor is located.

The Pathway Hierarchy Panel

This contains a list of Reactome pathway topics, sorted alphabetically. Some topics, such as apoptosis, are too large to represent as a single pathway. Instead they are divided into sub-pathways, which may be further divided into sub-pathways. Most Reactome pathway topics are divided into smaller sub-pathways. Individual steps in a pathway are known as reactions. The organisation of pathways, sub-pathways and reactions is represented on the Pathway Hierarchy panel as a pathway hierarchy. This view functions in a similar manner to the Windows File Manager; sub-pathways are revealed by clicking on the + symbol to the left of the pathway name, and hidden by clicking on the – symbol. The ‘U’, ‘N’ and ‘+’ icons to the left of the pathway name identify whether a pathway is Updated, New or associated with Disease.

Pathways and reactions can be differentiated by a representative symbol to the left of the name, see the image Pathway Hierarchy Symbols below. You may also see a symbol representing 'black-box' reactions, where complete details have been omitted as unnecessary or are not completely determined.

Within a pathway, the order of reactions in the hierarchy from top to bottom usually follows their order in the pathway, so that preceding reactions are above the subsequent reaction, but note that this is not always the case. Reactome has a more formal way of identifying connected reactions called Preceding and Following Events, visible in the Reaction Details (see Details Panel below).


Pathway Hierarchy
Pathway Hierarchy Symbols

Pathway Diagrams

Pathway diagrams represent the steps of a pathway as a series of interconnected pathway steps, known in Reactome as 'reactions'. Reactions are the core unit of Reactome's data model. They encapsulate 'changes of state' in biology, such as the familiar biochemical reaction where substrates are converted into products by the action of a catalyst, but also include processes such as transport of molecules from one cellular compartment to another, binding, dissociation, phosphorylation, degradation and others.

A "pop out" diagram key is found in the upper right corner of the webpage.

Prediagramkey2.png

The diagram key provides a descriptions of the icons used in the diagrams:

Diagram Key

Objects on the diagram represent reaction inputs and outputs, and the catalyst if relevant (see A below).

  • Inputs, outputs and catalysts are represented as boxes or ovals.
  • Green ovals are small molecules or sets of small molecules.
  • Green boxes with rounded off corners are individual proteins or sets of proteins or mixed sets.
  • Green boxes with square corners are proteins that have no Uniprot accession (or did not at the time the reaction was created).
  • Blue boxes are complexes, i.e. proteins and/or small molecules that are bound to each other.
  • Green boxes with white inner boxes are sub-pathways.
  • Input and output molecules are joined by lines to a central 'reaction node' (surrounded by a green box in Reaction Objects A, below). Clicking this node selects the reaction.
  • The outputs of a reaction have an arrowhead on the line connecting them to the reaction node.
  • Numbered boxes on the line between an input/output and the reaction node indicate the number of units of this input/output in the reaction (when n >1).
  • Reaction input/output molecules are often connected by arrows to molecules that take part in preceding or subsequent reactions (i.e. the preceding/subsequent steps in the pathway).
  • Catalysts are connected to the reaction node by a line ending in an open circle.
  • Molecules that regulate a reaction are connected to the reaction node by a line ending in an open triangle for positive regulation or a 'T'-shaped head for negative regulation (see B below).


Reaction Objects A
Reaction Objects B

Reactions are superimposed onto pink boxes that represent cellular compartments - a typical diagram has a box representing the cytoplasm, bounded by a double-line representing the plasma membrane. The white background beyond this represents the extracellular space. Other organelles are represented as additional labeled boxes within the cytoplasm. Reaction objects are placed in the physiologically correct cellular compartment, or span the boundary of a compartment to indicate they are in the corresponding membrane, e.g. the boundary of the cytosol is the plasma membrane.

The reaction node has 5 subtypes, indicating subclasses of reaction (see Reaction Objects C, below):

  • Open squares represent a 'transition'
  • Filled circles represent 'association', i.e. binding
  • Double-circles represent 'dissociation'
  • Squares with two slashes represent 'omitted process'. This is used to denote a reaction where the full details have been deliberately omitted. This is most commonly used for events that include specific members of a protein family to illustrate the general behaviour of the larger group. It is used for reactions that occur with no fixed order or stoichiometry, and for degradation where the output is a random set of peptide fragments.
  • Squares containing a question mark represent 'uncertain process', where some details of the reaction are known, but the process is thought to be more complex than it is represented. Explanatory details are typically included in the Description.


Reaction Objects C

Navigating Pathway Diagrams

Clicking on a pathway or reaction name in the Pathway Hierarchy panel causes it to be highlighted in green, opens the corresponding pathway diagram in the Pathway Diagram panel and populates the Details panel.

When a pathway diagram is visible in the Pathway Diagram panel, moving the mouse pointer over the name of one of it's sub-pathways or reactions on the Pathway Hierarchy panel will highlight the reaction node(s) for that sub-pathway/reaction in green on the diagram. If the sub-pathway or reaction name is selected (clicked) on the Pathway Hierarchy panel, it is highlighted in green, it's parent pathway or pathways are highlighted in yellow-green, and the reaction node(s) corresponding to the sub-pathway or reaction are surrounded by a green box in the pathway diagram. In addition, the Details panel will update to show details of the sub-pathway or reaction selected. If the selected sub-pathway or reaction is not currently visible in the pathway diagram, it will re-centre on the selected object(s).

Selecting a reaction in the Pathway Diagram will cause it's name and the name of parent pathway(s) in the hierarchy to be highlighted on the Pathway Hierarchy panel.

Highlighted reactions are also visible in the thumbnail diagram and can be used to navigate quickly to the region of interest in the diagram using the thumbnail window, bottom left of the Pathway Diagram. The blue box outline represents the current view. Click and drag blue box will reposition the pathway diagram. To centre the diagram at the point, click outside the blue outline. Moving the cursor out of thumbnail box while dragging will stops the pathway repositioning.

Hovering over a protein, complex or small molecule node shows a tooltip with node's name and type. An information icon to the top left of the node is displayed. Clicking the ‘info’ icon will display a context sensitive menu, providing access to more information about the pathway node.

There is a navigation tool top-left of the Pathway Diagram. With this you can navigate left, right up or down and zoom in or out of the diagram. You can also zoom using the mouse wheel, and click and drag the diagram.

Located at the top right of the Pathway diagram is the Pathway Options button, will display the pathway diagram settings, allowing the user to configure different aspects viewing the pathway diagram and to download the pathway diagram.


Pathway Browser showing a selected sub-pathway highlighted in green and parent pathways highlighted in yellow-green, reaction nodes for all reactions in the sub-pathway are surrounded by green squares in the Pathway Diagram


Sub-pathway Diagrams

Large topics such as apoptosis contain too much information to be displayed as a single pathway or diagram. Where this is the case, the topic is divided into sub-pathways in the pathway hierarchy, and sub-pathway diagrams in the Pathway Diagram Panel. If you select a pathway in the Pathway Hierarchy panel that only has sub-pathways diagrams, the Pathway Diagram displays an overview diagram, containing boxes with green borders, the symbol for a sub-pathway diagram. This symbol indicates that a detailed diagram is available but is not part of the currently displayed Pathway Diagram. The sub-pathway diagram symbol can also be used within a pathway diagram if the details of a sub-pathway are too complicated for inclusion, to indicate that the sub-pathway has it's own, separate diagram.

There are two ways to access a sub-pathway diagram. The simplest is to right-click on the sub-pathway diagram symbol. This produces a menu, select the option 'Go To Pathway'. Alternatively, left-click to select the sub-pathway diagram symbol - the corresponding sub-pathway name will be highlighted on the Pathway Hierarchy panel. In the example shown below, the sub-pathway diagram symbol for 'Intrinsic Pathway for Apoptosis' is selected (boxed in green) causing the corresponding sub-pathway and it's parent pathway to be highlighted green on the Pathway tab. The sub-pathway name has not been clicked. Clicking on the sub-pathway name in the hierarchy causes the corresponding pathway diagram to open in the Pathway Diagram panel.

Pathway Browser showing a selected sub-pathway diagram symbol surrounded by green square, corresponding sub-pathway and parent pathway are highlighted in green on the Pathway Hierarchy panel.

Details Panel

The Details Panel is at the bottom of the Pathway Browser. It gives details of the selected pathway, reaction, complex, set or proteins, when they are selected in the Pathway Diagram or Pathway Hierarchy panel. The height of the Details panel can be adjusted by clicking on and dragging the grey line, separating the Details Panel from the Pathway Diagram, to the intended depth.

The different tabs within the “Details" panel, provides alternative displays of graphical and textual information depending on whether a pathway, reaction, or physical entity node is selected:

  • Overview. Displays summary information relating to the selected pathway, reaction or entity.
  • Molecules. Displays external annotations and links outs to other bioinformatics resources describing the selected molecule. Molecule information can be downloaded as a csv, tsv, xml or excel file.
  • Structures. Displays 3D structural data and citations from PDB.
  • Expression. Feeds condition-specific gene expression data from the Gene Expression Atlas.
  • Processes. Displays the associated Reactome pathways and reactions associated with the selected pathway node or events.
  • Download. Allows users to download a variety of compatible with third-party tools

Pathway Details Panel

The Overview tab of the Pathway Details Panel typically includes, the pathway name, the species, a stable identifier, a description of the pathway (summation), the GO biological process term for the pathway, the GO cellular compartment term (if applicable), and references linked to PubMed providing background information relevant to the pathway.

If the pathway is not supported directly by human experimental data but has been inferred from another species, this is indicated by the phrase 'This event is deduced on the basis of event(s)' and a link to that pathway. The ‘Computationally inferred to' drop down menu lists species that have been computationally predicted to have the same pathway. There is also information that reflects the authors and reviewers that have contributed to the curation of this pathway.

Clicking a ‘+’ or ‘-‘ icon associated with the different displayed fields within the Overview tab will show or hide more information about the pathway overview.

The molecules that participate in a pathway can be displayed and/or downloaded by clicking on the ‘Molecules’ tab of the Pathways Details Panel. The user can select the type(s) of molecules to download, the type of information desired for each molecule type, and the format of the download file.

The 'Expression' tab displays gene expression data derived from transcription profiling of individual and mixture of 16 human tissues RNA (Illumina Body Map). The heat map employs a two-dimensional matrix where rows correspond to genes (encoding pathway components) and columns correspond to 16 human tissues, such as adipose, brain, colon, etc. Filled boxes indicate genes expressed. Click 'Display levels' to show expression. A human anatomogram provides a graphical display of the gene expression data as a user clicks on the different tissues or gene expression data presented in the table. Clicking the gender symbols denoting male and female will update the anatomogram with sex-specific gene expression data.

The user can select to display the other Reactome pathways for the selected sub-pathway by clicking the Process tab. Clicking a ‘+’ or ‘-‘ icon next to ‘Involved in pathways’ within the Process tab will show or hide more information about the associated pathway and literature citations.

The Download tab provides options for the user to download different files types for the selected pathways. These files include:

  • [SBML]. An exchange format used by systems biologists for their models.
  • [SBGN]. An exchange format used to represent pathway and network diagrams.
  • [BioPAX2]. An exchange format used by systems biologists for their models.
  • [BioPAX3]. An exchange format used by systems biologists for their models.
  • [PDF]. Text dump of the pathway, organized to look like a research report.
  • [Word]. A document format compatible with Microsoft and other word processor software.
  • [Protege]. A format used for ontology exchange.

SBML, SBGN and BioPAX are exchange formats of interest to bioinformaticians. Word and PDF are familiar document formats, providing you with a convenient "document" of the pathway. Protégé is an extensible, platform-independent environment for creating and editing ontologies and knowledge bases, this download is likely to be of interest to those wishing to extend Reactome functionality.

The complete Reactome textbook of biological processes in PDF or RTF format, the complete set of human reactions in Reactome (in SBML or BioPAX level 2 or 3 format), and a list of human protein-protein interaction pairs are available to download from the Download page, linked to the Menu Bar on the Reactome homepage.

To find out about how Reactome generates SBML, see SBML At Reactome.

For general information about SBML, click here. For more information about BioPAX click here.

Reaction Details Panel

Included in the Overview tab of the Reactions Details Panel is a reaction name, a stable identifier, and a summary of the reaction. Reactions must contain literature references that contain experimental data verifying the reaction, or an 'Inferred From' link if the reaction has been manually inferred from experimental data from model organisms. For pathway details see the previous section.

Other details within the Overview section include:

  • Input/Output. Identifies the input/output molecules, sets or complexes for this reaction. Icons to the right of these named items link to further information in Reactome.
  • Authors. The expert biologists that contributed materials that allowed this reaction to be created in Reactome.
  • Reviewers. The expert biologists that verified the content for this pathway.
  • Preceding event(s). A list of events that occur immediately before the event being viewed.
  • Following event(s). A list of events that occur immediately after the event being viewed.
  • Catalyst (when relevant). The protein or complex that catalyzes the reaction. The Gene Ontology molecular function term that represents the activity of a catalyst or transporter within the reaction will be listed. If the catalyst is a complex, the component, or domain in a simple catalyst, that enables the reaction to occur will be listed.
  • Inferred from another species (when relevant). This indicates that event has not been experimentally demonstrated in humans, but has been inferred on the basis of data acquired for another species. The link points to a web page containing the experimental data for the reaction in that species.
  • Positively (or Negatively) regulated by. The protein or complex that regulates the reactions.
  • References. The research publications that describe the evidence supporting the reaction, each hyperlinked to its PubMed abstract (when applicable).
  • Taxon. The species in which the event occurs.
  • Computationally inferred to. Links to descriptions of the events in other species that are either confirmed to occur in a very similar way in both species, or have been electronically inferred .

The molecules that participate in a reaction can be displayed and/or downloaded by clicking on the ‘Molecules’ tab of the Reaction Details Panel. The user can select the type(s) of molecules to download, the type of information desired for each molecule type, and the format of the download file.

The 'Expression' tab displays gene expression data derived from the Illumina Body Map for the proteins associated with the selected reaction.

The user can display the other Reactome pathways for the selected reaction by clicking the Process tab. Clicking a ‘+’ or ‘-‘ icon next to ‘Involved in pathways’ within the Process tab will show or hide more information about the associated events and literature citations.

The Download tab provides reaction in one of the formats:SBML, SBGN, BioPAX2, BioPAX3, PDF, Word and Protege {Need to Check this is correct}.

Protein, Small Molecule, Complex and Set Details

The details of any protein, small molecule, complex or set represented in the pathway diagrams can be displayed in the Details panel by selecting the object within the diagram. These views are all very similar, an example of protein details is represented below. Clicking a ‘+’ or ‘-‘ icon associated with the different displayed fields within the Detail panel tabs will show or hide more information about the protein, small molecule, complex and set.

The Overview tab will display the following information depending whether the selected node is a :

  • Links to corresponding entries in other databases. Cross-reference to identifiers used for this molecule in external reference databases, with hyperlinks to the record.
  • Cellular compartment. The cellular compartment that contains this molecule, with hyperlink to the corresponding GO term.
  • Computationally inferred orthologues. Lists equivalent molecules in other species if these have been inferred to exist. A description of the inference process can be found here.
  • Components. If this molecule is part of any complexes, they are listed here
  • Produced by. If this molecule is 'created', e.g. becomes incorporated into a complex or degraded, the appropriate reactions are listed.
  • Consumed by events. If this molecule is 'consumed', e.g. becomes incorporated into a complex or degraded, the appropriate reactions are listed.
  • Post-translational modification. If this molecule exists within Reactome in an alternate, post-translationally modified form, the appropriate molecules are listed.

The ‘Molecules’ tab will show more information and link outs to external bioinformatics resources. The user can select the type(s) of molecules to download, the type of information desired for each molecule type, and the format of the download file.

The ‘Structures’ tab will displays 3D structural data and citations from PDB. The most relevant (best) crystal structure for the selected node will be shown. Clicking the "All structures..." will display other associated crystal structure. Users can also explore additional crystal structure infromation at PDB by clicking the different icons:

  • Book. A paper describing the PDB entry.
  • Person/Multi-Cladogram. The taxon or source of the biomolecule.
  • Circular plasmid/Multi. The expermental technique used to create the crystal.
  • NMR/X-RAY. The technique that was used to determine the 3D structure.
  • Protein Domain. The protein sequence and domain information associated with protein.
  • DNA helix. Nucleic acids (DNA, RNA) are associated (green-highlighted) or not associated (grey-highlighted) with the crystal structure.
  • Benzene ring. Ligand is associated (green-highlighted) or not associated (grey-highlighted) with the crystal structure.

The 'Expression' tab displays gene expression data derived from transcription profiling of individual and mixture of 16 human tissues RNA (Illumina Body Map). The heat map employs a two-dimensional matrix where rows correspond to genes (encoding pathway components) and columns correspond to 16 human tissues, such as adipose, brain, colon, etc. Filled boxes indicate genes expressed. Click 'Display levels' to show expression. A human anatomogram provides a graphical display of the gene expression data as a user clicks on the different tissues or gene expression data presented in the table. Clicking the gender symbols denoting male and female will update the anatomogram with sex-specific gene expression data.

The ‘Process’ tab shows the Reactome events associated with the selected node. Clicking a ‘+’ or ‘-‘ icon next to ‘Involved in pathways’ will show or hide more information about the associated events and literature citations. "Is present in sets" displays information about the Reactome sets that the selected node participates in.

Pathway Options Menu

This button, located on the top-right of the Pathway diagram, opens a control panel that has several functions:

Search Diagram (ctrl-f).
Search the diagram nodes and reactions for a word or phrase. The search tab appears with by pressing the 'ctrl-f' key combination.
Snapshot Current View.
Take a screenshot of the current pathway diagram view, which will be opened in a new window.
Download Diagram.
Will open the entire pathway diagram in a new window, ready for download.
Interaction Overlay Options…
Allows configuration of Molecular Interactions onto the pathway diagram.

Navigating Disease Pathway Diagrams

Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human disease pathways have three mechanistic causes:

  • the inclusion of microbially-expressed proteins
  • altered functions of human proteins
  • changed expression levels of otherwise functionally normal human proteins

For some Reactome disease pathways, such as "Signaling by EGFR in cancer" it is helpful to describe the effects of disease related reactions and entities on the normal human pathway. In this case, disease related events and normal events are grouped together in the pathway hierarchy and the disease events (reactions and associated molecular entities) are overlaid on top of the diagram of the normal human pathway that they affect. This “merged" diagram can be viewed by clicking on the "parent" disease pathway. Disease related entities and reactions are outlined in red whereas the normal events and entities are “greyed out”. In the event hierarchy, the parent pathway contains both the normal pathway (Signaling by EGFR) and a pathway containing uniquely the disease associated reactions (Signaling by constitutively active EGFR).

Parent Disease pathway

Clicking on the “normal" subpathway hides the diseased entities and reactions entirely from the diagram allowing the user to browse just the normal events.

Normal pathway

Clicking on the “disease" subpathway shows the merged (disease/normal) diagram again. The disease reaction nodes are highlighted with green boxes. Disease related pathways, reactions, and entities may be flagged, in the details section, with the most relevant EBI Human disease ontology term. *Please note that it is not currently possible to link to the Human disease ontology website directly from the disease tagged entity/event, but this feature will appear in the V40 release.

Disease pathway


Some disease pathways in Reactome have not been grouped, in the hierarchy, with a separately annotated "normal" pathway and diagram. These include infectious disease pathways (and the Amyloids pathway) in which the majority of annotated reactions involve pathogen (abnormal) proteins only and/or involve interactions among pathogen (abnormal) and human proteins. These disease pathways have each been placed in a single diagram. Red lines are used to emphasize disease events. Reactions involved in disease or disease progression are highlighted in red as are any entities that are disease-associated or derived from another species (pathogen). Host/human or normal entities are black. Complexes that contain both host and disease associated/pathogen derived entities are colored red.

Disease single ELV1.png