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1.  Genetic resources for methane production from biomass described with the Gene Ontology 
Methane (CH4) is a valuable fuel, constituting 70–95% of natural gas, and a potent greenhouse gas. Release of CH4 into the atmosphere contributes to climate change. Biological CH4 production or methanogenesis is mostly performed by methanogens, a group of strictly anaerobic archaea. The direct substrates for methanogenesis are H2 plus CO2, acetate, formate, methylamines, methanol, methyl sulfides, and ethanol or a secondary alcohol plus CO2. In numerous anaerobic niches in nature, methanogenesis facilitates mineralization of complex biopolymers such as carbohydrates, lipids and proteins generated by primary producers. Thus, methanogens are critical players in the global carbon cycle. The same process is used in anaerobic treatment of municipal, industrial and agricultural wastes, reducing the biological pollutants in the wastes and generating methane. It also holds potential for commercial production of natural gas from renewable resources. This process operates in digestive systems of many animals, including cattle, and humans. In contrast, in deep-sea hydrothermal vents methanogenesis is a primary production process, allowing chemosynthesis of biomaterials from H2 plus CO2. In this report we present Gene Ontology (GO) terms that can be used to describe processes, functions and cellular components involved in methanogenic biodegradation and biosynthesis of specialized coenzymes that methanogens use. Some of these GO terms were previously available and the rest were generated in our Microbial Energy Gene Ontology (MENGO) project. A recently discovered non-canonical CH4 production process is also described. We have performed manual GO annotation of selected methanogenesis genes, based on experimental evidence, providing “gold standards” for machine annotation and automated discovery of methanogenesis genes or systems in diverse genomes. Most of the GO-related information presented in this report is available at the MENGO website (http://www.mengo.biochem.vt.edu/).
doi:10.3389/fmicb.2014.00634
PMCID: PMC4253957  PMID: 25520705
Gene Ontology; biomass; biodegradation; methanogenesis; methanogen; bioenergy; carbon cycle; waste treatment
2.  Genetic resources for advanced biofuel production described with the Gene Ontology 
Dramatic increases in research in the area of microbial biofuel production coupled with high-throughput data generation on bioenergy-related microbes has led to a deluge of information in the scientific literature and in databases. Consolidating this information and making it easily accessible requires a unified vocabulary. The Gene Ontology (GO) fulfills that requirement, as it is a well-developed structured vocabulary that describes the activities and locations of gene products in a consistent manner across all kingdoms of life. The Microbial ENergy processes Gene Ontology () project is extending the GO to include new terms to describe microbial processes of interest to bioenergy production. Our effort has added over 600 bioenergy related terms to the Gene Ontology. These terms will aid in the comprehensive annotation of gene products from diverse energy-related microbial genomes. An area of microbial energy research that has received a lot of attention is microbial production of advanced biofuels. These include alcohols such as butanol, isopropanol, isobutanol, and fuels derived from fatty acids, isoprenoids, and polyhydroxyalkanoates. These fuels are superior to first generation biofuels (ethanol and biodiesel esterified from vegetable oil or animal fat), can be generated from non-food feedstock sources, can be used as supplements or substitutes for gasoline, diesel and jet fuels, and can be stored and distributed using existing infrastructure. Here we review the roles of genes associated with synthesis of advanced biofuels, and at the same time introduce the use of the GO to describe the functions of these genes in a standardized way.
doi:10.3389/fmicb.2014.00528
PMCID: PMC4193338  PMID: 25346727
Gene Ontology; advanced biofuels; synthetic biology; cellulosome; advanced alcohols; fatty acid-derived fuel; isoprenoid-derived fuel
3.  An Integrated Ontology Resource to Explore and Study Host-Virus Relationships 
PLoS ONE  2014;9(9):e108075.
Our growing knowledge of viruses reveals how these pathogens manage to evade innate host defenses. A global scheme emerges in which many viruses usurp key cellular defense mechanisms and often inhibit the same components of antiviral signaling. To accurately describe these processes, we have generated a comprehensive dictionary for eukaryotic host-virus interactions. This controlled vocabulary has been detailed in 57 ViralZone resource web pages which contain a global description of all molecular processes. In order to annotate viral gene products with this vocabulary, an ontology has been built in a hierarchy of UniProt Knowledgebase (UniProtKB) keyword terms and corresponding Gene Ontology (GO) terms have been developed in parallel. The results are 65 UniProtKB keywords related to 57 GO terms, which have been used in 14,390 manual annotations; 908,723 automatic annotations and propagated to an estimation of 922,941 GO annotations. ViralZone pages, UniProtKB keywords and GO terms provide complementary tools to users, and the three resources have been linked to each other through host-virus vocabulary.
doi:10.1371/journal.pone.0108075
PMCID: PMC4169452  PMID: 25233094
4.  A method for increasing expressivity of Gene Ontology annotations using a compositional approach 
BMC Bioinformatics  2014;15:155.
Background
The Gene Ontology project integrates data about the function of gene products across a diverse range of organisms, allowing the transfer of knowledge from model organisms to humans, and enabling computational analyses for interpretation of high-throughput experimental and clinical data. The core data structure is the annotation, an association between a gene product and a term from one of the three ontologies comprising the GO. Historically, it has not been possible to provide additional information about the context of a GO term, such as the target gene or the location of a molecular function. This has limited the specificity of knowledge that can be expressed by GO annotations.
Results
The GO Consortium has introduced annotation extensions that enable manually curated GO annotations to capture additional contextual details. Extensions represent effector–target relationships such as localization dependencies, substrates of protein modifiers and regulation targets of signaling pathways and transcription factors as well as spatial and temporal aspects of processes such as cell or tissue type or developmental stage. We describe the content and structure of annotation extensions, provide examples, and summarize the current usage of annotation extensions.
Conclusions
The additional contextual information captured by annotation extensions improves the utility of functional annotation by representing dependencies between annotations to terms in the different ontologies of GO, external ontologies, or an organism’s gene products. These enhanced annotations can also support sophisticated queries and reasoning, and will provide curated, directional links between many gene products to support pathway and network reconstruction.
doi:10.1186/1471-2105-15-155
PMCID: PMC4039540  PMID: 24885854
Gene Ontology; Functional annotation; Annotation extension; Manual curation
5.  Interdisciplinary perspectives on the development, integration, and application of cognitive ontologies 
We discuss recent progress in the development of cognitive ontologies and summarize three challenges in the coordinated development and application of these resources. Challenge 1 is to adopt a standardized definition for cognitive processes. We describe three possibilities and recommend one that is consistent with the standard view in cognitive and biomedical sciences. Challenge 2 is harmonization. Gaps and conflicts in representation must be resolved so that these resources can be combined for mark-up and interpretation of multi-modal data. Finally, Challenge 3 is to test the utility of these resources for large-scale annotation of data, search and query, and knowledge discovery and integration. As term definitions are tested and revised, harmonization should enable coordinated updates across ontologies. However, the true test of these definitions will be in their community-wide adoption which will test whether they support valid inferences about psychological and neuroscientific data.
doi:10.3389/fninf.2014.00062
PMCID: PMC4064452  PMID: 24999329
ontology; cognition; mental functioning; neuroscience; annotation; integration; big data; brain science
6.  The Gene Ontology (GO) Cellular Component Ontology: integration with SAO (Subcellular Anatomy Ontology) and other recent developments 
Background
The Gene Ontology (GO) (http://www.geneontology.org/) contains a set of terms for describing the activity and actions of gene products across all kingdoms of life. Each of these activities is executed in a location within a cell or in the vicinity of a cell. In order to capture this context, the GO includes a sub-ontology called the Cellular Component (CC) ontology (GO-CCO). The primary use of this ontology is for GO annotation, but it has also been used for phenotype annotation, and for the annotation of images. Another ontology with similar scope to the GO-CCO is the Subcellular Anatomy Ontology (SAO), part of the Neuroscience Information Framework Standard (NIFSTD) suite of ontologies. The SAO also covers cell components, but in the domain of neuroscience.
Description
Recently, the GO-CCO was enriched in content and links to the Biological Process and Molecular Function branches of GO as well as to other ontologies. This was achieved in several ways. We carried out an amalgamation of SAO terms with GO-CCO ones; as a result, nearly 100 new neuroscience-related terms were added to the GO. The GO-CCO also contains relationships to GO Biological Process and Molecular Function terms, as well as connecting to external ontologies such as the Cell Ontology (CL). Terms representing protein complexes in the Protein Ontology (PRO) reference GO-CCO terms for their species-generic counterparts. GO-CCO terms can also be used to search a variety of databases.
Conclusions
In this publication we provide an overview of the GO-CCO, its overall design, and some recent extensions that make use of additional spatial information. One of the most recent developments of the GO-CCO was the merging in of the SAO, resulting in a single unified ontology designed to serve the needs of GO annotators as well as the specific needs of the neuroscience community.
doi:10.1186/2041-1480-4-20
PMCID: PMC3852282  PMID: 24093723
Gene ontology; Cellular component ontology; Subcellular anatomy ontology; Neuroscience; Annotation; Ontology language; Ontology integration; Neuroscience information framework
7.  Dovetailing biology and chemistry: integrating the Gene Ontology with the ChEBI chemical ontology 
BMC Genomics  2013;14:513.
Background
The Gene Ontology (GO) facilitates the description of the action of gene products in a biological context. Many GO terms refer to chemical entities that participate in biological processes. To facilitate accurate and consistent systems-wide biological representation, it is necessary to integrate the chemical view of these entities with the biological view of GO functions and processes. We describe a collaborative effort between the GO and the Chemical Entities of Biological Interest (ChEBI) ontology developers to ensure that the representation of chemicals in the GO is both internally consistent and in alignment with the chemical expertise captured in ChEBI.
Results
We have examined and integrated the ChEBI structural hierarchy into the GO resource through computationally-assisted manual curation of both GO and ChEBI. Our work has resulted in the creation of computable definitions of GO terms that contain fully defined semantic relationships to corresponding chemical terms in ChEBI.
Conclusions
The set of logical definitions using both the GO and ChEBI has already been used to automate aspects of GO development and has the potential to allow the integration of data across the domains of biology and chemistry. These logical definitions are available as an extended version of the ontology from http://purl.obolibrary.org/obo/go/extensions/go-plus.owl.
doi:10.1186/1471-2164-14-513
PMCID: PMC3733925  PMID: 23895341
8.  Cross-Product Extensions of the Gene Ontology 
The Gene Ontology (GO) consists of nearly 30,000 classes for describing the activities and locations of gene products. Manual maintenance of an ontology of this size is a considerable effort, and errors and inconsistencies inevitably arise. Reasoners can be used to assist with ontology development, automatically placing classes in a subsumption hierarchy based on their properties. However, the historic lack of computable definitions within the GO has prevented the user of these tools.
In this paper we present preliminary results of an ongoing effort to normalize the GO by explicitly stating the definitions of compositional classes in a form that can be used by reasoners. These definitions are partitioned into mutually exclusive cross-product sets, many of which reference other OBO Foundry candidate ontologies for chemical entities, proteins, biological qualities and anatomical entities. Using these logical definitions we are gradually beginning to automate many aspects of ontology development, detecting errors and filling in missing relationships. These definitions also enhance the GO by weaving it into the fabric of a wider collection of interoperating ontologies, increasing opportunities for data integration and enhancing genomic analyses.
doi:10.1016/j.jbi.2010.02.002
PMCID: PMC2910209  PMID: 20152934
9.  Unifying Themes in Microbial Associations with Animal and Plant Hosts Described Using the Gene Ontology 
Summary: Microbes form intimate relationships with hosts (symbioses) that range from mutualism to parasitism. Common microbial mechanisms involved in a successful host association include adhesion, entry of the microbe or its effector proteins into the host cell, mitigation of host defenses, and nutrient acquisition. Genes associated with these microbial mechanisms are known for a broad range of symbioses, revealing both divergent and convergent strategies. Effective comparisons among these symbioses, however, are hampered by inconsistent descriptive terms in the literature for functionally similar genes. Bioinformatic approaches that use homology-based tools are limited to identifying functionally similar genes based on similarities in their sequences. An effective solution to these limitations is provided by the Gene Ontology (GO), which provides a standardized language to describe gene products from all organisms. The GO comprises three ontologies that enable one to describe the molecular function(s) of gene products, the biological processes to which they contribute, and their cellular locations. Beginning in 2004, the Plant-Associated Microbe Gene Ontology (PAMGO) interest group collaborated with the GO consortium to extend the GO to accommodate terms for describing gene products associated with microbe-host interactions. Currently, over 900 terms that describe biological processes common to diverse plant- and animal-associated microbes are incorporated into the GO database. Here we review some unifying themes common to diverse host-microbe associations and illustrate how the new GO terms facilitate a standardized description of the gene products involved. We also highlight areas where new terms need to be developed, an ongoing process that should involve the whole community.
doi:10.1128/MMBR.00017-10
PMCID: PMC3008171  PMID: 21119014
10.  How the gene ontology evolves 
BMC Bioinformatics  2011;12:325.
Background
Maintaining a bio-ontology in the long term requires improving and updating its contents so that it adequately captures what is known about biological phenomena. This paper illustrates how these processes are carried out, by studying the ways in which curators at the Gene Ontology have hitherto incorporated new knowledge into their resource.
Results
Five types of circumstances are singled out as warranting changes in the ontology: (1) the emergence of anomalies within GO; (2) the extension of the scope of GO; (3) divergence in how terminology is used across user communities; (4) new discoveries that change the meaning of the terms used and their relations to each other; and (5) the extension of the range of relations used to link entities or processes described by GO terms.
Conclusion
This study illustrates the difficulties involved in applying general standards to the development of a specific ontology. Ontology curation aims to produce a faithful representation of knowledge domains as they keep developing, which requires the translation of general guidelines into specific representations of reality and an understanding of how scientific knowledge is produced and constantly updated. In this context, it is important that trained curators with technical expertise in the scientific field(s) in question are involved in supervising ontology shifts and identifying inaccuracies.
doi:10.1186/1471-2105-12-325
PMCID: PMC3166943  PMID: 21819553
Gene Ontology; knowledge; maintenance; curation; ontology shifts
11.  Survey-based naming conventions for use in OBO Foundry ontology development 
BMC Bioinformatics  2009;10:125.
Background
A wide variety of ontologies relevant to the biological and medical domains are available through the OBO Foundry portal, and their number is growing rapidly. Integration of these ontologies, while requiring considerable effort, is extremely desirable. However, heterogeneities in format and style pose serious obstacles to such integration. In particular, inconsistencies in naming conventions can impair the readability and navigability of ontology class hierarchies, and hinder their alignment and integration. While other sources of diversity are tremendously complex and challenging, agreeing a set of common naming conventions is an achievable goal, particularly if those conventions are based on lessons drawn from pooled practical experience and surveys of community opinion.
Results
We summarize a review of existing naming conventions and highlight certain disadvantages with respect to general applicability in the biological domain. We also present the results of a survey carried out to establish which naming conventions are currently employed by OBO Foundry ontologies and to determine what their special requirements regarding the naming of entities might be. Lastly, we propose an initial set of typographic, syntactic and semantic conventions for labelling classes in OBO Foundry ontologies.
Conclusion
Adherence to common naming conventions is more than just a matter of aesthetics. Such conventions provide guidance to ontology creators, help developers avoid flaws and inaccuracies when editing, and especially when interlinking, ontologies. Common naming conventions will also assist consumers of ontologies to more readily understand what meanings were intended by the authors of ontologies used in annotating bodies of data.
doi:10.1186/1471-2105-10-125
PMCID: PMC2684543  PMID: 19397794
12.  Relations in biomedical ontologies 
Genome Biology  2005;6(5):R46.
To enhance the treatment of relations in biomedical ontologies we advance a methodology for providing consistent and unambiguous formal definitions of the relational expressions used in such ontologies in a way designed to assist developers and users in avoiding errors in coding and annotation.
To enhance the treatment of relations in biomedical ontologies we advance a methodology for providing consistent and unambiguous formal definitions of the relational expressions used in such ontologies in a way designed to assist developers and users in avoiding errors in coding and annotation. The resulting Relation Ontology can promote interoperability of ontologies and support new types of automated reasoning about the spatial and temporal dimensions of biological and medical phenomena.
doi:10.1186/gb-2005-6-5-r46
PMCID: PMC1175958  PMID: 15892874
13.  Mapping the Gene Ontology Into the Unified Medical Language System 
We have recently mapped the Gene Ontology (GO), developed by the Gene Ontology Consortium, into the National Library of Medicine's Unified Medical Language System (UMLS). GO has been developed for the purpose of annotating gene products in genome databases, and the UMLS has been developed as a framework for integrating large numbers of disparate terminologies, primarily for the purpose of providing better access to biomedical information sources. The mapping of GO to UMLS highlighted issues in both terminology systems. After some initial explorations and discussions between the UMLS and GO teams, the GO was integrated with the UMLS. Overall, a total of 23% of the GO terms either matched directly (3%) or linked (20%) to existing UMLS concepts. All GO terms now have a corresponding, official UMLS concept, and the entire vocabulary is available through the web-based UMLS Knowledge Source Server. The mapping of the Gene Ontology, with its focus on structures, processes and functions at the molecular level, to the existing broad coverage UMLS should contribute to linking the language and practices of clinical medicine to the language and practices of genomics.
doi:10.1002/cfg.407
PMCID: PMC2447454  PMID: 18629164

Results 1-13 (13)