An Introduction to the Gene Ontology
What does the Gene Ontology Consortium do?
Biologists currently waste a lot of time and effort in searching for all of the available information about each small area of research. This is hampered further by the wide variations in terminology that may be common usage at any given time, which inhibit effective searching by both computers and people. For example, if you were searching for new targets for antibiotics, you might want to find all the gene products that are involved in bacterial protein synthesis, and that have significantly different sequences or structures from those in humans. If one database describes these molecules as being involved in 'translation', whereas another uses the phrase 'protein synthesis', it will be difficult for you - and even harder for a computer - to find functionally equivalent terms.
The Gene Ontology (GO) project is a collaborative effort to address the need for consistent descriptions of gene products in different databases. The project began as a collaboration between three model organism databases, FlyBase (Drosophila), the Saccharomyces Genome Database (SGD) and the Mouse Genome Database (MGD), in 1998. Since then, the GO Consortium has grown to include many databases, including several of the world's major repositories for plant, animal and microbial genomes. See the GO Consortium page for a full list of member organizations.
The GO project has developed three structured controlled vocabularies (ontologies) that describe gene products in terms of their associated biological processes, cellular components and molecular functions in a species-independent manner. There are three separate aspects to this effort: first, the development and maintenance of the ontologies themselves; second, the annotation of gene products, which entails making associations between the ontologies and the genes and gene products in the collaborating databases; and third, development of tools that facilitate the creation, maintenance and use of ontologies.
The use of GO terms by collaborating databases facilitates uniform queries across them. The controlled vocabularies are structured so that they can be queried at different levels: for example, you can use GO to find all the gene products in the mouse genome that are involved in signal transduction, or you can zoom in on all the receptor tyrosine kinases. This structure also allows annotators to assign properties to genes or gene products at different levels, depending on the depth of knowledge about that entity.
The Gene Ontology project provides an ontology of defined terms representing gene product properties. The ontology covers three domains: cellular component, the parts of a cell or its extracellular environment; molecular function, the elemental activities of a gene product at the molecular level, such as binding or catalysis; and biological process, operations or sets of molecular events with a defined beginning and end, pertinent to the functioning of integrated living units: cells, tissues, organs, and organisms.
For example, the gene product cytochrome c can be described by the molecular function term oxidoreductase activity, the biological process terms oxidative phosphorylation and induction of cell death, and the cellular component terms mitochondrial matrix and mitochondrial inner membrane.
The GO ontology is structured as a directed acyclic graph, and each term has defined relationships to one or more other terms in the same domain, and sometimes to other domains. The GO vocabulary is designed to be species-neutral, and includes terms applicable to prokaryotes and eukaryotes, single and multicellular organisms.
A cellular component is just that, a component of a cell, but with the proviso that it is part of some larger object; this may be an anatomical structure (e.g. rough endoplasmic reticulum or nucleus) or a gene product group (e.g. ribosome, proteasome or a protein dimer). See the Documentation on the cellular component ontology for more details.
A biological process is series of events accomplished by one or more ordered assemblies of molecular functions. Examples of broad biological process terms are cellular physiological process or signal transduction. Examples of more specific terms are pyrimidine metabolic process or alpha-glucoside transport. It can be difficult to distinguish between a biological process and a molecular function, but the general rule is that a process must have more than one distinct steps.
A biological process is not equivalent to a pathway; at present, GO does not try to represent the dynamics or dependencies that would be required to fully describe a pathway.
Further information can be found in the process ontology documentation.
Molecular function describes activities, such as catalytic or binding activities, that occur at the molecular level. GO molecular function terms represent activities rather than the entities (molecules or complexes) that perform the actions, and do not specify where or when, or in what context, the action takes place. Molecular functions generally correspond to activities that can be performed by individual gene products, but some activities are performed by assembled complexes of gene products. Examples of broad functional terms are catalytic activity, transporter activity, or binding; examples of narrower functional terms are adenylate cyclase activity or Toll receptor binding.
It is easy to confuse a gene product name with its molecular function, and for that reason many GO molecular functions are appended with the word "activity". The documentation on the function ontology explains more about GO functions and the rules governing them.
The Scope of GO
It is important to clearly state the scope of GO, and what it does and does not cover. The preceding section explained the domains covered by GO; the following areas are outside the scope of GO, and terms in these domains would not appear in the ontologies.
- Gene products: e.g. cytochrome c is not in the ontologies, but attributes of cytochrome c, such as oxidoreductase activity, are.
- Processes, functions or components that are unique to mutants or diseases: e.g. oncogenesis is not a valid GO term because causing cancer is not the normal function of any gene.
- Attributes of sequence such as intron/exon parameters: these are not attributes of gene products and will be described in a separate sequence ontology (see the OBO website for more information).
- Protein domains or structural features.
- Protein-protein interactions.
- Environment, evolution and expression.
- Anatomical or histological features above the level of cellular components, including cell types.
GO is not a database of gene sequences, nor a catalog of gene products. Rather, GO describes how gene products behave in a cellular context.
GO is not a dictated standard, mandating nomenclature across databases. Groups participate because of self-interest, and cooperate to arrive at a consensus.
GO is not a way to unify biological databases (i.e. GO is not a 'federated solution'). Sharing vocabulary is a step towards unification, but is not, in itself, sufficient. Reasons for this include the following:
- Knowledge changes and updates lag behind.
- Individual curators evaluate data differently. While we can agree to use the word 'kinase', we must also agree to support this by stating how and why we use 'kinase', and consistently apply it. Only in this way can we hope to compare gene products and determine whether they are related.
- GO does not attempt to describe every aspect of biology; its scope is limited to the domains described above.
Annotation and tools
Annotation is the practice of capturing the activities and localization of a gene product with GO terms, providing references and indicating what kind of evidence is available to support the annotations. More information on how this is done can be found in the GO Annotation Guide. Members of the GO Consortium make their annotation data freely available to the public as part of the data accessed by AmiGO, the GO browser and search engine. Annotation data sets from individual databases can found on the GO annotations page.
You can browse the ontologies using a range of web-based browsers. A full list of these, and other tools for analyzing gene function using GO, is available on the GO Tools section.
In addition, the GO consortium has prepared GO slims, 'slimmed down' versions of the ontologies that allow you to annotate genomes or sets of gene products to gain a high-level view of gene functions. Using GO slims you can, for example, work out what proportion of a genome is involved in signal transduction, biosynthesis or reproduction. See the GO Slim Guide for more information.
All data from the GO project is freely available. You can download the ontology data in a number of different formats, including XML and mySQL. The GO file format guide has more information on these formats.
A If you need lists of the genes or gene products that have been associated with a particular GO term, the current Annotations table tracks the number of annotations and provides links to the gene association files for each of the collaborating databases is available.
GO allows us to annotate genes and their products with a limited set of attributes. For example, GO does not allow us to describe genes in terms of which cells or tissues they're expressed in, which developmental stages they're expressed at, or their involvement in disease. It is not necessary for GO to do these things because other ontologies are being developed for these purposes. The GO consortium supports the development of other ontologies and makes its tools for editing and curating ontologies freely available. A list of freely available ontologies that are relevant to genomics and proteomics and are structured similarly to GO can be found at the Open Biomedical Ontologies website. A larger list, which includes the ontologies listed at OBO and also other controlled vocabularies that do not fulfill the OBO criteria is available at the Ontology Working Group section of the Microarray Gene Expression Data (MGED) Network site.
The existence of several ontologies will also allow us to create 'cross-products' that maximize the utility of each ontology while avoiding redundancy. For example, by combining the developmental terms in the GO process ontology with a second ontology that describes Drosophila anatomical structures, we could create an ontology of fly development. We could repeat this process for other organisms without having to clutter up GO with large numbers of species-specific terms. Similarly, we could create an ontology of biosynthetic pathways by combining the biosynthesis terms in the GO process ontology with a chemical ontology.
Mappings to other classification systems
GO is not the only attempt to build structured controlled vocabularies for genome annotation, nor is it the only such series of catalogs in current use. The GO project provides mappings between GO and these other systems, although we caution that these mappings are neither complete nor exact and should only to be used as a guide.
Contributing to GO
The GO project is constantly evolving, and we welcome feedback from all users. If you need a new term or definition, or would like to suggest that we reorganize a section of one of the ontologies, please do so through the GO curator requests tracker. Any errors or omissions in annotations should be reported to the GO annotation mailing list.
Any other questions or suggestions should be addressed to the GO helpdesk.