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1.  AIGO: Towards a unified framework for the Analysis and the Inter-comparison of GO functional annotations 
BMC Bioinformatics  2011;12:431.
In response to the rapid growth of available genome sequences, efforts have been made to develop automatic inference methods to functionally characterize them. Pipelines that infer functional annotation are now routinely used to produce new annotations at a genome scale and for a broad variety of species. These pipelines differ widely in their inference algorithms, confidence thresholds and data sources for reasoning. This heterogeneity makes a comparison of the relative merits of each approach extremely complex. The evaluation of the quality of the resultant annotations is also challenging given there is often no existing gold-standard against which to evaluate precision and recall.
In this paper, we present a pragmatic approach to the study of functional annotations. An ensemble of 12 metrics, describing various aspects of functional annotations, is defined and implemented in a unified framework, which facilitates their systematic analysis and inter-comparison. The use of this framework is demonstrated on three illustrative examples: analysing the outputs of state-of-the-art inference pipelines, comparing electronic versus manual annotation methods, and monitoring the evolution of publicly available functional annotations. The framework is part of the AIGO library ( for the Analysis and the Inter-comparison of the products of Gene Ontology (GO) annotation pipelines. The AIGO library also provides functionalities to easily load, analyse, manipulate and compare functional annotations and also to plot and export the results of the analysis in various formats.
This work is a step toward developing a unified framework for the systematic study of GO functional annotations. This framework has been designed so that new metrics on GO functional annotations can be added in a very straightforward way.
PMCID: PMC3237112  PMID: 22054122
2.  Large-scale Gene Ontology analysis of plant transcriptome-derived sequences retrieved by AFLP technology 
BMC Genomics  2008;9:347.
After 10-year-use of AFLP (Amplified Fragment Length Polymorphism) technology for DNA fingerprinting and mRNA profiling, large repertories of genome- and transcriptome-derived sequences are available in public databases for model, crop and tree species. AFLP marker systems have been and are being extensively exploited for genome scanning and gene mapping, as well as cDNA-AFLP for transcriptome profiling and differentially expressed gene cloning. The evaluation, annotation and classification of genomic markers and expressed transcripts would be of great utility for both functional genomics and systems biology research in plants. This may be achieved by means of the Gene Ontology (GO), consisting in three structured vocabularies (i.e. ontologies) describing genes, transcripts and proteins of any organism in terms of their associated cellular component, biological process and molecular function in a species-independent manner. In this paper, the functional annotation of about 8,000 AFLP-derived ESTs retrieved in the NCBI databases was carried out by using GO terminology.
Descriptive statistics on the type, size and nature of gene sequences obtained by means of AFLP technology were calculated. The gene products associated with mRNA transcripts were then classified according to the three main GO vocabularies. A comparison of the functional content of cDNA-AFLP records was also performed by splitting the sequence dataset into monocots and dicots and by comparing them to all annotated ESTs of Arabidopsis and rice, respectively. On the whole, the statistical parameters adopted for the in silico AFLP-derived transcriptome-anchored sequence analysis proved to be critical for obtaining reliable GO results. Such an exhaustive annotation may offer a suitable platform for functional genomics, particularly useful in non-model species.
Reliable GO annotations of AFLP-derived sequences can be gathered through the optimization of the experimental steps and the statistical parameters adopted. The Blast2GO software was shown to represent a comprehensive bioinformatics solution for an annotation-based functional analysis. According to the whole set of GO annotations, the AFLP technology generates thorough information for angiosperm gene products and shares common features across angiosperm species and families. The utility of this technology for structural and functional genomics in plants can be implemented by serial annotation analyses of genome-anchored fragments and organ/tissue-specific repertories of transcriptome-derived fragments.
PMCID: PMC2515857  PMID: 18652646
3.  The Sequence Ontology: a tool for the unification of genome annotations 
Genome Biology  2005;6(5):R44.
The goal of the Sequence Ontology (SO) project is to produce a structured controlled vocabulary with a common set of terms and definitions for parts of a genomic annotation, and to describe the relationships among them. Details of SO construction, design and use, particularly with regard to part-whole relationships are discussed and the practical utility of SO is demonstrated for a set of genome annotations from Drosophila melanogaster.
The Sequence Ontology (SO) is a structured controlled vocabulary for the parts of a genomic annotation. SO provides a common set of terms and definitions that will facilitate the exchange, analysis and management of genomic data. Because SO treats part-whole relationships rigorously, data described with it can become substrates for automated reasoning, and instances of sequence features described by the SO can be subjected to a group of logical operations termed extensional mereology operators.
PMCID: PMC1175956  PMID: 15892872
4.  Computational algorithms to predict Gene Ontology annotations 
BMC Bioinformatics  2015;16(Suppl 6):S4.
Gene function annotations, which are associations between a gene and a term of a controlled vocabulary describing gene functional features, are of paramount importance in modern biology. Datasets of these annotations, such as the ones provided by the Gene Ontology Consortium, are used to design novel biological experiments and interpret their results. Despite their importance, these sources of information have some known issues. They are incomplete, since biological knowledge is far from being definitive and it rapidly evolves, and some erroneous annotations may be present. Since the curation process of novel annotations is a costly procedure, both in economical and time terms, computational tools that can reliably predict likely annotations, and thus quicken the discovery of new gene annotations, are very useful.
We used a set of computational algorithms and weighting schemes to infer novel gene annotations from a set of known ones. We used the latent semantic analysis approach, implementing two popular algorithms (Latent Semantic Indexing and Probabilistic Latent Semantic Analysis) and propose a novel method, the Semantic IMproved Latent Semantic Analysis, which adds a clustering step on the set of considered genes. Furthermore, we propose the improvement of these algorithms by weighting the annotations in the input set.
We tested our methods and their weighted variants on the Gene Ontology annotation sets of three model organism genes (Bos taurus, Danio rerio and Drosophila melanogaster ). The methods showed their ability in predicting novel gene annotations and the weighting procedures demonstrated to lead to a valuable improvement, although the obtained results vary according to the dimension of the input annotation set and the considered algorithm.
Out of the three considered methods, the Semantic IMproved Latent Semantic Analysis is the one that provides better results. In particular, when coupled with a proper weighting policy, it is able to predict a significant number of novel annotations, demonstrating to actually be a helpful tool in supporting scientists in the curation process of gene functional annotations.
PMCID: PMC4416163  PMID: 25916950
Truncated Singular Value Decomposition; Probabilistic Latent Semantic Analysis; weighting schemes; gene clustering; Gene Ontology; biomolecular annotations; Receiver Operating Characteristic
5.  TGF-beta signaling proteins and the Protein Ontology 
BMC Bioinformatics  2009;10(Suppl 5):S3.
The Protein Ontology (PRO) is designed as a formal and principled Open Biomedical Ontologies (OBO) Foundry ontology for proteins. The components of PRO extend from a classification of proteins on the basis of evolutionary relationships at the homeomorphic level to the representation of the multiple protein forms of a gene, including those resulting from alternative splicing, cleavage and/or post-translational modifications. Focusing specifically on the TGF-beta signaling proteins, we describe the building, curation, usage and dissemination of PRO.
PRO is manually curated on the basis of PrePRO, an automatically generated file with content derived from standard protein data sources. Manual curation ensures that the treatment of the protein classes and the internal and external relationships conform to the PRO framework. The current release of PRO is based upon experimental data from mouse and human proteins wherein equivalent protein forms are represented by single terms. In addition to the PRO ontology, the annotation of PRO terms is released as a separate PRO association file, which contains, for each given PRO term, an annotation from the experimentally characterized sub-types as well as the corresponding database identifiers and sequence coordinates. The annotations are added in the form of relationship to other ontologies. Whenever possible, equivalent forms in other species are listed to facilitate cross-species comparison. Splice and allelic variants, gene fusion products and modified protein forms are all represented as entities in the ontology. Therefore, PRO provides for the representation of protein entities and a resource for describing the associated data. This makes PRO useful both for proteomics studies where isoforms and modified forms must be differentiated, and for studies of biological pathways, where representations need to take account of the different ways in which the cascade of events may depend on specific protein modifications.
PRO provides a framework for the formal representation of protein classes and protein forms in the OBO Foundry. It is designed to enable data retrieval and integration and machine reasoning at the molecular level of proteins, thereby facilitating cross-species comparisons, pathway analysis, disease modeling and the generation of new hypotheses.
PMCID: PMC2679403  PMID: 19426460
6.  annot8r: GO, EC and KEGG annotation of EST datasets 
BMC Bioinformatics  2008;9:180.
The expressed sequence tag (EST) methodology is an attractive option for the generation of sequence data for species for which no completely sequenced genome is available. The annotation and comparative analysis of such datasets poses a formidable challenge for research groups that do not have the bioinformatics infrastructure of major genome sequencing centres. Therefore, there is a need for user-friendly tools to facilitate the annotation of non-model species EST datasets with well-defined ontologies that enable meaningful cross-species comparisons. To address this, we have developed annot8r, a platform for the rapid annotation of EST datasets with GO-terms, EC-numbers and KEGG-pathways.
annot8r automatically downloads all files relevant for the annotation process and generates a reference database that stores UniProt entries, their associated Gene Ontology (GO), Enzyme Commission (EC) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) annotation and additional relevant data. For each of GO, EC and KEGG, annot8r extracts a specific sequence subset from the UniProt dataset based on the information stored in the reference database. These three subsets are then formatted for BLAST searches. The user provides the protein or nucleotide sequences to be annotated and annot8r runs BLAST searches against these three subsets. The BLAST results are parsed and the corresponding annotations retrieved from the reference database. The annotations are saved both as flat files and also in a relational postgreSQL results database to facilitate more advanced searches within the results. annot8r is integrated with the PartiGene suite of EST analysis tools.
annot8r is a tool that assigns GO, EC and KEGG annotations for data sets resulting from EST sequencing projects both rapidly and efficiently. The benefits of an underlying relational database, flexibility and the ease of use of the program make it ideally suited for non-model species EST-sequencing projects.
PMCID: PMC2324097  PMID: 18400082
7.  The Gene Ontology (GO) Cellular Component Ontology: integration with SAO (Subcellular Anatomy Ontology) and other recent developments 
The Gene Ontology (GO) ( 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.
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.
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.
PMCID: PMC3852282  PMID: 24093723
Gene ontology; Cellular component ontology; Subcellular anatomy ontology; Neuroscience; Annotation; Ontology language; Ontology integration; Neuroscience information framework
8.  A method for increasing expressivity of Gene Ontology annotations using a compositional approach 
BMC Bioinformatics  2014;15:155.
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.
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.
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.
PMCID: PMC4039540  PMID: 24885854
Gene Ontology; Functional annotation; Annotation extension; Manual curation
9.  Enriching a biomedical event corpus with meta-knowledge annotation 
BMC Bioinformatics  2011;12:393.
Biomedical papers contain rich information about entities, facts and events of biological relevance. To discover these automatically, we use text mining techniques, which rely on annotated corpora for training. In order to extract protein-protein interactions, genotype-phenotype/gene-disease associations, etc., we rely on event corpora that are annotated with classified, structured representations of important facts and findings contained within text. These provide an important resource for the training of domain-specific information extraction (IE) systems, to facilitate semantic-based searching of documents. Correct interpretation of these events is not possible without additional information, e.g., does an event describe a fact, a hypothesis, an experimental result or an analysis of results? How confident is the author about the validity of her analyses? These and other types of information, which we collectively term meta-knowledge, can be derived from the context of the event.
We have designed an annotation scheme for meta-knowledge enrichment of biomedical event corpora. The scheme is multi-dimensional, in that each event is annotated for 5 different aspects of meta-knowledge that can be derived from the textual context of the event. Textual clues used to determine the values are also annotated. The scheme is intended to be general enough to allow integration with different types of bio-event annotation, whilst being detailed enough to capture important subtleties in the nature of the meta-knowledge expressed in the text. We report here on both the main features of the annotation scheme, as well as its application to the GENIA event corpus (1000 abstracts with 36,858 events). High levels of inter-annotator agreement have been achieved, falling in the range of 0.84-0.93 Kappa.
By augmenting event annotations with meta-knowledge, more sophisticated IE systems can be trained, which allow interpretative information to be specified as part of the search criteria. This can assist in a number of important tasks, e.g., finding new experimental knowledge to facilitate database curation, enabling textual inference to detect entailments and contradictions, etc. To our knowledge, our scheme is unique within the field with regards to the diversity of meta-knowledge aspects annotated for each event.
PMCID: PMC3222636  PMID: 21985429
10.  AISO: Annotation of Image Segments with Ontologies 
Large quantities of digital images are now generated for biological collections, including those developed in projects premised on the high-throughput screening of genome-phenome experiments. These images often carry annotations on taxonomy and observable features, such as anatomical structures and phenotype variations often recorded in response to the environmental factors under which the organisms were sampled. At present, most of these annotations are described in free text, may involve limited use of non-standard vocabularies, and rarely specify precise coordinates of features on the image plane such that a computer vision algorithm could identify, extract and annotate them. Therefore, researchers and curators need a tool that can identify and demarcate features in an image plane and allow their annotation with semantically contextual ontology terms. Such a tool would generate data useful for inter and intra-specific comparison and encourage the integration of curation standards. In the future, quality annotated image segments may provide training data sets for developing machine learning applications for automated image annotation.
We developed a novel image segmentation and annotation software application, “Annotation of Image Segments with Ontologies” (AISO). The tool enables researchers and curators to delineate portions of an image into multiple highlighted segments and annotate them with an ontology-based controlled vocabulary. AISO is a freely available Java-based desktop application and runs on multiple platforms. It can be downloaded at
AISO enables curators and researchers to annotate digital images with ontology terms in a manner which ensures the future computational value of the annotated images. We foresee uses for such data-encoded image annotations in biological data mining, machine learning, predictive annotation, semantic inference, and comparative analyses.
PMCID: PMC4290088  PMID: 25584184
Image annotation; Semantic web; Plant ontology; Image segmentation; Plant anatomy; Web services; Computer vision; Image curation; Machine learning
11.  Linking Human Diseases to Animal Models Using Ontology-Based Phenotype Annotation 
PLoS Biology  2009;7(11):e1000247.
A novel method for quantifying the similarity between phenotypes by the use of ontologies can be used to search for candidate genes, pathway members, and human disease models on the basis of phenotypes alone.
Scientists and clinicians who study genetic alterations and disease have traditionally described phenotypes in natural language. The considerable variation in these free-text descriptions has posed a hindrance to the important task of identifying candidate genes and models for human diseases and indicates the need for a computationally tractable method to mine data resources for mutant phenotypes. In this study, we tested the hypothesis that ontological annotation of disease phenotypes will facilitate the discovery of new genotype-phenotype relationships within and across species. To describe phenotypes using ontologies, we used an Entity-Quality (EQ) methodology, wherein the affected entity (E) and how it is affected (Q) are recorded using terms from a variety of ontologies. Using this EQ method, we annotated the phenotypes of 11 gene-linked human diseases described in Online Mendelian Inheritance in Man (OMIM). These human annotations were loaded into our Ontology-Based Database (OBD) along with other ontology-based phenotype descriptions of mutants from various model organism databases. Phenotypes recorded with this EQ method can be computationally compared based on the hierarchy of terms in the ontologies and the frequency of annotation. We utilized four similarity metrics to compare phenotypes and developed an ontology of homologous and analogous anatomical structures to compare phenotypes between species. Using these tools, we demonstrate that we can identify, through the similarity of the recorded phenotypes, other alleles of the same gene, other members of a signaling pathway, and orthologous genes and pathway members across species. We conclude that EQ-based annotation of phenotypes, in conjunction with a cross-species ontology, and a variety of similarity metrics can identify biologically meaningful similarities between genes by comparing phenotypes alone. This annotation and search method provides a novel and efficient means to identify gene candidates and animal models of human disease, which may shorten the lengthy path to identification and understanding of the genetic basis of human disease.
Author Summary
Model organisms such as fruit flies, mice, and zebrafish are useful for investigating gene function because they are easy to grow, dissect, and genetically manipulate in the laboratory. By examining mutations in these organisms, one can identify candidate genes that cause disease in humans, and develop models to better understand human disease and gene function. A fundamental roadblock for analysis is, however, the lack of a computational method for describing and comparing phenotypes of mutant animals and of human diseases when the genetic basis is unknown. We describe here a novel method using ontologies to record and quantify the similarity between phenotypes. We tested our method by using the annotated mutant phenotype of one member of the Hedgehog signaling pathway in zebrafish to identify other pathway members with similar recorded phenotypes. We also compared human disease phenotypes to those produced by mutation in model organisms, and show that orthologous and biologically relevant genes can be identified by this method. Given that the genetic basis of human disease is often unknown, this method provides a means for identifying candidate genes, pathway members, and disease models by computationally identifying similar phenotypes within and across species.
PMCID: PMC2774506  PMID: 19956802
12.  AVID: An integrative framework for discovering functional relationships among proteins 
BMC Bioinformatics  2005;6:136.
Determining the functions of uncharacterized proteins is one of the most pressing problems in the post-genomic era. Large scale protein-protein interaction assays, global mRNA expression analyses and systematic protein localization studies provide experimental information that can be used for this purpose. The data from such experiments contain many false positives and false negatives, but can be processed using computational methods to provide reliable information about protein-protein relationships and protein function. An outstanding and important goal is to predict detailed functional annotation for all uncharacterized proteins that is reliable enough to effectively guide experiments.
We present AVID, a computational method that uses a multi-stage learning framework to integrate experimental results with sequence information, generating networks reflecting functional similarities among proteins. We illustrate use of the networks by making predictions of detailed Gene Ontology (GO) annotations in three categories: molecular function, biological process, and cellular component. Applied to the yeast Saccharomyces cerevisiae, AVID provides 37,451 pair-wise functional linkages between 4,191 proteins. These relationships are ~65–78% accurate, as assessed by cross-validation testing. Assignments of highly detailed functional descriptors to proteins, based on the networks, are estimated to be ~67% accurate for GO categories describing molecular function and cellular component and ~52% accurate for terms describing biological process. The predictions cover 1,490 proteins with no previous annotation in GO and also assign more detailed functions to many proteins annotated only with less descriptive terms. Predictions made by AVID are largely distinct from those made by other methods. Out of 37,451 predicted pair-wise relationships, the greatest number shared in common with another method is 3,413.
AVID provides three networks reflecting functional associations among proteins. We use these networks to generate new, highly detailed functional predictions for roughly half of the yeast proteome that are reliable enough to drive targeted experimental investigations. The predictions suggest many specific, testable hypotheses. All of the data are available as downloadable files as well as through an interactive website at . Thus, AVID will be a valuable resource for experimental biologists.
PMCID: PMC1177925  PMID: 15929793
13.  The Gene Ontology's Reference Genome Project: A Unified Framework for Functional Annotation across Species 
PLoS Computational Biology  2009;5(7):e1000431.
The Gene Ontology (GO) is a collaborative effort that provides structured vocabularies for annotating the molecular function, biological role, and cellular location of gene products in a highly systematic way and in a species-neutral manner with the aim of unifying the representation of gene function across different organisms. Each contributing member of the GO Consortium independently associates GO terms to gene products from the organism(s) they are annotating. Here we introduce the Reference Genome project, which brings together those independent efforts into a unified framework based on the evolutionary relationships between genes in these different organisms. The Reference Genome project has two primary goals: to increase the depth and breadth of annotations for genes in each of the organisms in the project, and to create data sets and tools that enable other genome annotation efforts to infer GO annotations for homologous genes in their organisms. In addition, the project has several important incidental benefits, such as increasing annotation consistency across genome databases, and providing important improvements to the GO's logical structure and biological content.
Author Summary
Biological research is increasingly dependent on the availability of well-structured representations of biological data with detailed, accurate descriptions provided by the curators of the data repositories. The Reference Genome project's goal is to provide comprehensive functional annotation for the genomes of human as well as eleven organisms that are important models in biomedical research. To achieve this, we have developed an approach that superposes experimentally-based annotations onto the leaves of phylogenetic trees and then we manually annotate the function of the common ancestors, predicated on the assumption that the ancestors possessed the experimentally determined functions that are held in common at these leaves, and that these functions are likely to be conserved in all other descendents of each family.
PMCID: PMC2699109  PMID: 19578431
14.  FastAnnotator- an efficient transcript annotation web tool 
BMC Genomics  2012;13(Suppl 7):S9.
Recent developments in high-throughput sequencing (HTS) technologies have made it feasible to sequence the complete transcriptomes of non-model organisms or metatranscriptomes from environmental samples. The challenge after generating hundreds of millions of sequences is to annotate these transcripts and classify the transcripts based on their putative functions. Because many biological scientists lack the knowledge to install Linux-based software packages or maintain databases used for transcript annotation, we developed an automatic annotation tool with an easy-to-use interface.
To elucidate the potential functions of gene transcripts, we integrated well-established annotation tools: Blast2GO, PRIAM and RPS BLAST in a web-based service, FastAnnotator, which can assign Gene Ontology (GO) terms, Enzyme Commission numbers (EC numbers) and functional domains to query sequences.
Using six transcriptome sequence datasets as examples, we demonstrated the ability of FastAnnotator to assign functional annotations. FastAnnotator annotated 88.1% and 81.3% of the transcripts from the well-studied organisms Caenorhabditis elegans and Streptococcus parasanguinis, respectively. Furthermore, FastAnnotator annotated 62.9%, 20.4%, 53.1% and 42.0% of the sequences from the transcriptomes of sweet potato, clam, amoeba, and Trichomonas vaginalis, respectively, which lack reference genomes. We demonstrated that FastAnnotator can complete the annotation process in a reasonable amount of time and is suitable for the annotation of transcriptomes from model organisms or organisms for which annotated reference genomes are not avaiable.
The sequencing process no longer represents the bottleneck in the study of genomics, and automatic annotation tools have become invaluable as the annotation procedure has become the limiting step. We present FastAnnotator, which was an automated annotation web tool designed to efficiently annotate sequences with their gene functions, enzyme functions or domains. FastAnnotator is useful in transcriptome studies and especially for those focusing on non-model organisms or metatranscriptomes. FastAnnotator does not require local installation and is freely available at
PMCID: PMC3521244  PMID: 23281853
15.  Ontorat: automatic generation of new ontology terms, annotations, and axioms based on ontology design patterns 
It is time-consuming to build an ontology with many terms and axioms. Thus it is desired to automate the process of ontology development. Ontology Design Patterns (ODPs) provide a reusable solution to solve a recurrent modeling problem in the context of ontology engineering. Because ontology terms often follow specific ODPs, the Ontology for Biomedical Investigations (OBI) developers proposed a Quick Term Templates (QTTs) process targeted at generating new ontology classes following the same pattern, using term templates in a spreadsheet format.
Inspired by the ODPs and QTTs, the Ontorat web application is developed to automatically generate new ontology terms, annotations of terms, and logical axioms based on a specific ODP(s). The inputs of an Ontorat execution include axiom expression settings, an input data file, ID generation settings, and a target ontology (optional). The axiom expression settings can be saved as a predesigned Ontorat setting format text file for reuse. The input data file is generated based on a template file created by a specific ODP (text or Excel format). Ontorat is an efficient tool for ontology expansion. Different use cases are described. For example, Ontorat was applied to automatically generate over 1,000 Japan RIKEN cell line cell terms with both logical axioms and rich annotation axioms in the Cell Line Ontology (CLO). Approximately 800 licensed animal vaccines were represented and annotated in the Vaccine Ontology (VO) by Ontorat. The OBI team used Ontorat to add assay and device terms required by ENCODE project. Ontorat was also used to add missing annotations to all existing Biobank specific terms in the Biobank Ontology. A collection of ODPs and templates with examples are provided on the Ontorat website and can be reused to facilitate ontology development.
With ever increasing ontology development and applications, Ontorat provides a timely platform for generating and annotating a large number of ontology terms by following design patterns.
PMCID: PMC4362828  PMID: 25785185
Ontorat; Ontology design pattern; ODP; Quick term templates; QTT; Ontology development
16.  Assessing the impact of human genome annotation choice on RNA-seq expression estimates 
BMC Bioinformatics  2013;14(Suppl 11):S8.
Genome annotation is a crucial component of RNA-seq data analysis. Much effort has been devoted to producing an accurate and rational annotation of the human genome. An annotated genome provides a comprehensive catalogue of genomic functional elements. Currently, at least six human genome annotations are publicly available, including AceView Genes, Ensembl Genes, H-InvDB Genes, RefSeq Genes, UCSC Known Genes, and Vega Genes. Characteristics of these annotations differ because of variations in annotation strategies and information sources. When performing RNA-seq data analysis, researchers need to choose a genome annotation. However, the effect of genome annotation choice on downstream RNA-seq expression estimates is still unclear. This study (1) investigates the effect of different genome annotations on RNA-seq quantification and (2) provides guidelines for choosing a genome annotation based on research focus.
We define the complexity of human genome annotations in terms of the number of genes, isoforms, and exons. This definition facilitates an investigation of potential relationships between complexity and variations in RNA-seq quantification. We apply several evaluation metrics to demonstrate the impact of genome annotation choice on RNA-seq expression estimates. In the mapping stage, the least complex genome annotation, RefSeq Genes, appears to have the highest percentage of uniquely mapped short sequence reads. In the quantification stage, RefSeq Genes results in the most stable expression estimates in terms of the average coefficient of variation over all genes. Stable expression estimates in the quantification stage translate to accurate statistics for detecting differentially expressed genes. We observe that RefSeq Genes produces the most accurate fold-change measures with respect to a ground truth of RT-qPCR gene expression estimates.
Based on the observed variations in the mapping, quantification, and differential expression calling stages, we demonstrate that the selection of human genome annotation results in different gene expression estimates. When conducting research that emphasizes reproducible and robust gene expression estimates, a less complex genome annotation may be preferred. However, simpler genome annotations may limit opportunities for identifying or characterizing novel transcriptional or regulatory mechanisms. When conducting research that aims to be more exploratory, a more complex genome annotation may be preferred.
PMCID: PMC3816316  PMID: 24564364
17.  CGKB: an annotation knowledge base for cowpea (Vigna unguiculata L.) methylation filtered genomic genespace sequences 
BMC Bioinformatics  2007;8:129.
Cowpea [Vigna unguiculata (L.) Walp.] is one of the most important food and forage legumes in the semi-arid tropics because of its ability to tolerate drought and grow on poor soils. It is cultivated mostly by poor farmers in developing countries, with 80% of production taking place in the dry savannah of tropical West and Central Africa. Cowpea is largely an underexploited crop with relatively little genomic information available for use in applied plant breeding. The goal of the Cowpea Genomics Initiative (CGI), funded by the Kirkhouse Trust, a UK-based charitable organization, is to leverage modern molecular genetic tools for gene discovery and cowpea improvement. One aspect of the initiative is the sequencing of the gene-rich region of the cowpea genome (termed the genespace) recovered using methylation filtration technology and providing annotation and analysis of the sequence data.
CGKB, Cowpea Genespace/Genomics Knowledge Base, is an annotation knowledge base developed under the CGI. The database is based on information derived from 298,848 cowpea genespace sequences (GSS) isolated by methylation filtering of genomic DNA. The CGKB consists of three knowledge bases: GSS annotation and comparative genomics knowledge base, GSS enzyme and metabolic pathway knowledge base, and GSS simple sequence repeats (SSRs) knowledge base for molecular marker discovery. A homology-based approach was applied for annotations of the GSS, mainly using BLASTX against four public FASTA formatted protein databases (NCBI GenBank Proteins, UniProtKB-Swiss-Prot, UniprotKB-PIR (Protein Information Resource), and UniProtKB-TrEMBL). Comparative genome analysis was done by BLASTX searches of the cowpea GSS against four plant proteomes from Arabidopsis thaliana, Oryza sativa, Medicago truncatula, and Populus trichocarpa. The possible exons and introns on each cowpea GSS were predicted using the HMM-based Genscan gene predication program and the potential domains on annotated GSS were analyzed using the HMMER package against the Pfam database. The annotated GSS were also assigned with Gene Ontology annotation terms and integrated with 228 curated plant metabolic pathways from the Arabidopsis Information Resource (TAIR) knowledge base. The UniProtKB-Swiss-Prot ENZYME database was used to assign putative enzymatic function to each GSS. Each GSS was also analyzed with the Tandem Repeat Finder (TRF) program in order to identify potential SSRs for molecular marker discovery. The raw sequence data, processed annotation, and SSR results were stored in relational tables designed in key-value pair fashion using a PostgreSQL relational database management system. The biological knowledge derived from the sequence data and processed results are represented as views or materialized views in the relational database management system. All materialized views are indexed for quick data access and retrieval. Data processing and analysis pipelines were implemented using the Perl programming language. The web interface was implemented in JavaScript and Perl CGI running on an Apache web server. The CPU intensive data processing and analysis pipelines were run on a computer cluster of more than 30 dual-processor Apple XServes. A job management system called Vela was created as a robust way to submit large numbers of jobs to the Portable Batch System (PBS).
CGKB is an integrated and annotated resource for cowpea GSS with features of homology-based and HMM-based annotations, enzyme and pathway annotations, GO term annotation, toolkits, and a large number of other facilities to perform complex queries. The cowpea GSS, chloroplast sequences, mitochondrial sequences, retroelements, and SSR sequences are available as FASTA formatted files and downloadable at CGKB. This database and web interface are publicly accessible at .
PMCID: PMC1868039  PMID: 17445272
18.  An evaluation of GO annotation retrieval for BioCreAtIvE and GOA 
BMC Bioinformatics  2005;6(Suppl 1):S17.
The Gene Ontology Annotation (GOA) database aims to provide high-quality supplementary GO annotation to proteins in the UniProt Knowledgebase. Like many other biological databases, GOA gathers much of its content from the careful manual curation of literature. However, as both the volume of literature and of proteins requiring characterization increases, the manual processing capability can become overloaded.
Consequently, semi-automated aids are often employed to expedite the curation process. Traditionally, electronic techniques in GOA depend largely on exploiting the knowledge in existing resources such as InterPro. However, in recent years, text mining has been hailed as a potentially useful tool to aid the curation process.
To encourage the development of such tools, the GOA team at EBI agreed to take part in the functional annotation task of the BioCreAtIvE (Critical Assessment of Information Extraction systems in Biology) challenge.
BioCreAtIvE task 2 was an experiment to test if automatically derived classification using information retrieval and extraction could assist expert biologists in the annotation of the GO vocabulary to the proteins in the UniProt Knowledgebase.
GOA provided the training corpus of over 9000 manual GO annotations extracted from the literature. For the test set, we provided a corpus of 200 new Journal of Biological Chemistry articles used to annotate 286 human proteins with GO terms. A team of experts manually evaluated the results of 9 participating groups, each of which provided highlighted sentences to support their GO and protein annotation predictions. Here, we give a biological perspective on the evaluation, explain how we annotate GO using literature and offer some suggestions to improve the precision of future text-retrieval and extraction techniques. Finally, we provide the results of the first inter-annotator agreement study for manual GO curation, as well as an assessment of our current electronic GO annotation strategies.
The GOA database currently extracts GO annotation from the literature with 91 to 100% precision, and at least 72% recall. This creates a particularly high threshold for text mining systems which in BioCreAtIvE task 2 (GO annotation extraction and retrieval) initial results precisely predicted GO terms only 10 to 20% of the time.
Improvements in the performance and accuracy of text mining for GO terms should be expected in the next BioCreAtIvE challenge. In the meantime the manual and electronic GO annotation strategies already employed by GOA will provide high quality annotations.
PMCID: PMC1869009  PMID: 15960829
19.  Overview and Utilization of the NCI Thesaurus 
The NCI Thesaurus is a reference terminology covering areas of basic and clinical science, built with the goal of facilitating translational research in cancer. It contains nearly 110 000 terms in approximately 36000 concepts, partitioned in 20 subdomains, which include diseases, drugs, anatomy, genes, gene products, techniques, and biological processes, among others, all with a cancer-centric focus in content, and originally designed to support coding activities across the National Cancer Institute. Each concept represents a unit of meaning and contains a number of annotations, such as synonyms and preferred name, as well as annotations such as textual definitions and optional references to external authorities. In addition, concepts are modelled with description logic (DL) and defined by their relationships to other concepts; there are currently approximately 90 types of named relations declared in the terminology. The NCI Thesaurus is produced by the Enterprise Vocabulary Services project, a collaborative effort between the NCI Center for Bioinformatics and the NCI Office of Communications, and is part of the caCORE infrastructure stack ( It can be accessed programmatically through the open caBIO API and browsed via the web ( A history of editing changes is also accessible through the API. In addition, the Thesaurus is available for download in various file formats, including OWL, the web ontology language, to facilitate its utilization by others.
PMCID: PMC2447470  PMID: 18629178
20.  The Mammalian Phenotype Ontology as a unifying standard for experimental and high-throughput phenotyping data 
Mammalian Genome  2012;23(9-10):653-668.
The Mammalian Phenotype Ontology (MP) is a structured vocabulary for describing mammalian phenotypes and serves as a critical tool for efficient annotation and comprehensive retrieval of phenotype data. Importantly, the ontology contains broad and specific terms, facilitating annotation of data from initial observations or screens and detailed data from subsequent experimental research. Using the ontology structure, data are retrieved inclusively, i.e., data annotated to chosen terms and to terms subordinate in the hierarchy. Thus, searching for “abnormal craniofacial morphology” also returns annotations to “megacephaly” and “microcephaly,” more specific terms in the hierarchy path. The development and refinement of the MP is ongoing, with new terms and modifications to its organization undergoing continuous assessment as users and expert reviewers propose expansions and revisions. A wealth of phenotype data on mouse mutations and variants annotated to the MP already exists in the Mouse Genome Informatics database. These data, along with data curated to the MP by many mouse mutagenesis programs and mouse repositories, provide a platform for comparative analyses and correlative discoveries. The MP provides a standard underpinning to mouse phenotype descriptions for existing and future experimental and large-scale phenotyping projects. In this review we describe the MP as it presently exists, its application to phenotype annotations, the relationship of the MP to other ontologies, and the integration of the MP within large-scale phenotyping projects. Finally we discuss future application of the MP in providing standard descriptors of the phenotype pipeline test results from the International Mouse Phenotype Consortium projects.
PMCID: PMC3463787  PMID: 22961259
21.  IntelliGO: a new vector-based semantic similarity measure including annotation origin 
BMC Bioinformatics  2010;11:588.
The Gene Ontology (GO) is a well known controlled vocabulary describing the biological process, molecular function and cellular component aspects of gene annotation. It has become a widely used knowledge source in bioinformatics for annotating genes and measuring their semantic similarity. These measures generally involve the GO graph structure, the information content of GO aspects, or a combination of both. However, only a few of the semantic similarity measures described so far can handle GO annotations differently according to their origin (i.e. their evidence codes).
We present here a new semantic similarity measure called IntelliGO which integrates several complementary properties in a novel vector space model. The coefficients associated with each GO term that annotates a given gene or protein include its information content as well as a customized value for each type of GO evidence code. The generalized cosine similarity measure, used for calculating the dot product between two vectors, has been rigorously adapted to the context of the GO graph. The IntelliGO similarity measure is tested on two benchmark datasets consisting of KEGG pathways and Pfam domains grouped as clans, considering the GO biological process and molecular function terms, respectively, for a total of 683 yeast and human genes and involving more than 67,900 pair-wise comparisons. The ability of the IntelliGO similarity measure to express the biological cohesion of sets of genes compares favourably to four existing similarity measures. For inter-set comparison, it consistently discriminates between distinct sets of genes. Furthermore, the IntelliGO similarity measure allows the influence of weights assigned to evidence codes to be checked. Finally, the results obtained with a complementary reference technique give intermediate but correct correlation values with the sequence similarity, Pfam, and Enzyme classifications when compared to previously published measures.
The IntelliGO similarity measure provides a customizable and comprehensive method for quantifying gene similarity based on GO annotations. It also displays a robust set-discriminating power which suggests it will be useful for functional clustering.
An on-line version of the IntelliGO similarity measure is available at:
PMCID: PMC3098105  PMID: 21122125
22.  Inferring Function Using Patterns of Native Disorder in Proteins 
PLoS Computational Biology  2007;3(8):e162.
Natively unstructured regions are a common feature of eukaryotic proteomes. Between 30% and 60% of proteins are predicted to contain long stretches of disordered residues, and not only have many of these regions been confirmed experimentally, but they have also been found to be essential for protein function. In this study, we directly address the potential contribution of protein disorder in predicting protein function using standard Gene Ontology (GO) categories. Initially we analyse the occurrence of protein disorder in the human proteome and report ontology categories that are enriched in disordered proteins. Pattern analysis of the distributions of disordered regions in human sequences demonstrated that the functions of intrinsically disordered proteins are both length- and position-dependent. These dependencies were then encoded in feature vectors to quantify the contribution of disorder in human protein function prediction using Support Vector Machine classifiers. The prediction accuracies of 26 GO categories relating to signalling and molecular recognition are improved using the disorder features. The most significant improvements were observed for kinase, phosphorylation, growth factor, and helicase categories. Furthermore, we provide predicted GO term assignments using these classifiers for a set of unannotated and orphan human proteins. In this study, the importance of capturing protein disorder information and its value in function prediction is demonstrated. The GO category classifiers generated can be used to provide more reliable predictions and further insights into the behaviour of orphan and unannotated proteins.
Author Summary
As a result of high throughput sequencing technologies, there is a growing need to provide fast and accurate computational tools to predict the function of proteins from amino acid sequence. Most methods that attempt to do this rely on transferring function annotations between closely related proteins; however, a large proportion of unannotated proteins are orphans and do not share sufficient similarity to other proteins to be annotated in this way. Methods that target the annotation of these difficult proteins are feature-based methods and utilise relationships between the physical characteristics of proteins and function to make predictions. One important characteristic of proteins that remains unexploited in these feature-based methods is native structural disorder. Disordered regions of proteins are thought to adopt little or no regular structure and have been experimentally linked with the correct functioning of many proteins. Additionally, disordered regions of proteins can be successfully predicted from amino acid sequence. To address the requirement for protein function prediction methods that target the annotation of orphan proteins and explore the use of information describing protein disorder, a machine learning method for predicting protein function from sequence has been implemented. The inclusion of disorder features significantly improves prediction accuracies for many function categories relating to molecular recognition. The practical utility of the method is also demonstrated by providing annotations for a set of orphan and unannotated human proteins.
PMCID: PMC1950950  PMID: 17722973
23.  GARNET – gene set analysis with exploration of annotation relations 
BMC Bioinformatics  2011;12(Suppl 1):S25.
Gene set analysis is a powerful method of deducing biological meaning for an a priori defined set of genes. Numerous tools have been developed to test statistical enrichment or depletion in specific pathways or gene ontology (GO) terms. Major difficulties towards biological interpretation are integrating diverse types of annotation categories and exploring the relationships between annotation terms of similar information.
GARNET (Gene Annotation Relationship NEtwork Tools) is an integrative platform for gene set analysis with many novel features. It includes tools for retrieval of genes from annotation database, statistical analysis & visualization of annotation relationships, and managing gene sets. In an effort to allow access to a full spectrum of amassed biological knowledge, we have integrated a variety of annotation data that include the GO, domain, disease, drug, chromosomal location, and custom-defined annotations. Diverse types of molecular networks (pathways, transcription and microRNA regulations, protein-protein interaction) are also included. The pair-wise relationship between annotation gene sets was calculated using kappa statistics. GARNET consists of three modules - gene set manager, gene set analysis and gene set retrieval, which are tightly integrated to provide virtually automatic analysis for gene sets. A dedicated viewer for annotation network has been developed to facilitate exploration of the related annotations.
GARNET (gene annotation relationship network tools) is an integrative platform for diverse types of gene set analysis, where complex relationships among gene annotations can be easily explored with an intuitive network visualization tool ( or
PMCID: PMC3044280  PMID: 21342555
24.  Improving the Sequence Ontology terminology for genomic variant annotation 
The Genome Variant Format (GVF) uses the Sequence Ontology (SO) to enable detailed annotation of sequence variation. The annotation includes SO terms for the type of sequence alteration, the genomic features that are changed and the effect of the alteration. The SO maintains and updates the specification and provides the underlying ontologicial structure.
A requirements analysis was undertaken to gather terms missing in the SO release at the time, but needed to adequately describe the effects of sequence alteration on a set of variant genomic annotations. We have extended and remodeled the SO to include and define all terms that describe the effect of variation upon reference genomic features in the Ensembl variation databases.
The new terminology was used to annotate the human reference genome with a set of variants from both COSMIC and dbSNP. A GVF file containing 170,853 sequence alterations was generated using the SO terminology to annotate the kinds of alteration, the effect of the alteration and the reference feature changed. There are four kinds of alteration and 24 kinds of effect seen in this dataset. (Ensembl Variation annotates 34 different SO consequence terms:
We explain the updates to the Sequence Ontology to describe the effect of variation on existing reference features. We have provided a set of annotations using this terminology, and the well defined GVF specification. We have also provided a provisional exploration of this large annotation dataset.
PMCID: PMC4520272
25.  CvManGO, a method for leveraging computational predictions to improve literature-based Gene Ontology annotations 
The set of annotations at the Saccharomyces Genome Database (SGD) that classifies the cellular function of S. cerevisiae gene products using Gene Ontology (GO) terms has become an important resource for facilitating experimental analysis. In addition to capturing and summarizing experimental results, the structured nature of GO annotations allows for functional comparison across organisms as well as propagation of functional predictions between related gene products. Due to their relevance to many areas of research, ensuring the accuracy and quality of these annotations is a priority at SGD. GO annotations are assigned either manually, by biocurators extracting experimental evidence from the scientific literature, or through automated methods that leverage computational algorithms to predict functional information. Here, we discuss the relationship between literature-based and computationally predicted GO annotations in SGD and extend a strategy whereby comparison of these two types of annotation identifies genes whose annotations need review. Our method, CvManGO (Computational versus Manual GO annotations), pairs literature-based GO annotations with computational GO predictions and evaluates the relationship of the two terms within GO, looking for instances of discrepancy. We found that this method will identify genes that require annotation updates, taking an important step towards finding ways to prioritize literature review. Additionally, we explored factors that may influence the effectiveness of CvManGO in identifying relevant gene targets to find in particular those genes that are missing literature-supported annotations, but our survey found that there are no immediately identifiable criteria by which one could enrich for these under-annotated genes. Finally, we discuss possible ways to improve this strategy, and the applicability of this method to other projects that use the GO for curation.
Database URL:
PMCID: PMC3308158  PMID: 22434836

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