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PubMed2007

Ontology annotation: mapping genomic regions to biological function.

With numerous whole genomes now in hand, and experimental data about genes and biological pathways on the increase, a systems approach to biological research is becoming essential. Ontologies provide a formal representation of knowledge that is amenable to computational as well as human analysis, an obvious underpinning of systems biology. Mapping function to gene products in the genome consists of two, somewhat intertwined enterprises: ontology building and ontology annotation. Ontology building is the formal representation of a domain of knowledge; ontology annotation is association of specific genomic regions (which we refer to simply as 'genes', including genes and their regulatory elements and products such as proteins and functional RNAs) to parts of the ontology. We consider two complementary representations of gene function: the Gene Ontology (GO) and pathway ontologies. GO represents function from the gene's eye view, in relation to a large and growing context of biological knowledge at all levels. Pathway ontologies represent function from the point of view of biochemical reactions and interactions, which are ordered into networks and causal cascades. The more mature GO provides an example of ontology annotation: how conclusions from the scientific literature and from evolutionary relationships are converted into formal statements about gene function. Annotations are made using a variety of different types of evidence, which can be used to estimate the relative reliability of different annotations.

Animals↗

PubMed2005

Developing a corpus of clinical notes manually annotated for part-of-speech.

PURPOSE: This paper presents a project whose main goal is to construct a corpus of clinical text manually annotated for part-of-speech (POS) information. We describe and discuss the process of training three domain experts to perform linguistic annotation. METHODS: Three domain experts were trained to perform manual annotation of a corpus of clinical notes. A part of this corpus was combined with the Penn Treebank corpus of general purpose English text and another part was set aside for testing. The corpora were then used for training and testing statistical part-of-speech taggers. We list some of the challenges as well as encouraging results pertaining to inter-rater agreement and consistency of annotation. RESULTS: We used the Trigrams'n'Tags (TnT) [T. Brants, TnT-a statistical part-of-speech tagger, In: Proceedings of NAACL/ANLP-2000 Symposium, 2000] tagger trained on general English data to achieve 89.79% correctness. The same tagger trained on a portion of the medical data annotated for this project improved the performance to 94.69%. Furthermore, we find that discriminating between different types of discourse represented by different sections of clinical text may be very beneficial to improve correctness of POS tagging. CONCLUSION: Our preliminary experimental results indicate the necessity for adapting state-of-the-art POS taggers to the sublanguage domain of clinical text.

Abstracting and Indexing↗

PubMed2004

Quantifying structure-function uncertainty: a graph theoretical exploration into the origins and limitations of protein annotation.

Since the advent of investigations into structural genomics, research has focused on correctly identifying domain boundaries, as well as domain similarities and differences in the context of their evolutionary relationships. As the science of structural genomics ramps up adding more and more information into the databanks, questions about the accuracy and completeness of our classification and annotation systems appear on the forefront of this research. A central question of paramount importance is how structural similarity relates to functional similarity. Here, we begin to rigorously and quantitatively answer these questions by first exploring the consensus between the most common protein domain structure annotation databases CATH, SCOP and FSSP. Each of these databases explores the evolutionary relationships between protein domains using a combination of automatic and manual, structural and functional, continuous and discrete similarity measures. In order to examine the issue of consensus thoroughly, we build a generalized graph out of each of these databases and hierarchically cluster these graphs at interval thresholds. We then employ a distance measure to find regions of greatest overlap. Using this procedure we were able not only to enumerate the level of consensus between the different annotation systems, but also to define the graph-theoretical origins behind the annotation schema of class, family and superfamily by observing that the same thresholds that define the best consensus regions between FSSP, SCOP and CATH correspond to distinct, non-random phase-transitions in the structure comparison graph itself. To investigate the correspondence in divergence between structure and function further, we introduce a measure of functional entropy that calculates divergence in function space. First, we use this measure to calculate the general correlation between structural homology and functional proximity. We extend this analysis further by quantitatively calculating the average amount of functional information gained from our understanding of structural distance and the corollary inherent uncertainty that represents the theoretical limit of our ability to infer function from structural similarity. Finally we show how our measure of functional "entropy" translates into a more intuitive concept of functional annotation into similarity EC classes.

Biochemical Phenomena↗

PubMed2004

Expression profiling of the Leishmania life cycle: cDNA arrays identify developmentally regulated genes present but not annotated in the genome.

As genomic sequencing of Leishmania nears completion, functional analyses that provide a global genetic perspective on biological processes are important. Despite polycistronic transcription, RNA transcript abundance can be measured using microarrays. To provide a resource to evaluate cDNA arrays, we undertook 5' expressed sequence tag analysis of 2183 full-length randomly selected cDNAs from Leishmania major promastigote (days 3, 7, 10 of culture in vitro), and lesion-derived amastigote libraries. PCR-amplified inserts from 1830 of these cDNA representing 1001 unique genes were spotted onto microarrays, and compared internally with PCR-amplified open reading frames (ORFs) from 904 genes representing 842 unique genes annotated in the L. major genome. Microarrays were screened with RNA from procyclic, metacyclic and amastigote populations of L. major. Redundant clones on the array gave highly reproducible results, providing confidence in identification of stage-specific gene expression. Four hundred and thirty unique (i.e. non-redundant) stage-specific genes were identified. A higher percentage of stage-specific gene expression was observed in amastigotes ( approximately 35%) compared to metacyclics ( approximately 12%) for both cDNAs and ORFs, but cDNAs provided a richer source of regulated genes than currently annotated ORFs from the Leishmania genome. In mapping cDNAs onto the Leishmania genome, we noted that approximately 42% aligned to regions not recognised as genes using current predictive annotation tools. These genes are highly represented in our stage-specific genes, and therefore represent important drug targets and vaccine candidates. Careful annotation of cDNAs onto the Leishmania genome will be important before producing the next generation of oligonucleotide arrays based on annotated genes of the genomic sequencing project.

Animals↗

PubMed2005

Annotating nonspecific SAGE tags with microarray data.

SAGE (serial analysis of gene expression) detects transcripts by extracting short tags from the transcripts. Because of the limited length, many SAGE tags are shared by transcripts from different genes. Relying on sequence information in the general gene expression database has limited power to solve this problem due to the highly heterogeneous nature of the deposited sequences. Considering that the complexity of gene expression at a single tissue level should be much simpler than that in the general expression database, we reasoned that by restricting gene expression to tissue level, the accuracy of gene annotation for the nonspecific SAGE tags should be significantly improved. To test the idea, we developed a tissue-specific SAGE annotation database based on microarray data (). This database contains microarray expression information represented as UniGene clusters for 73 normal human tissues and 18 cancer tissues and cell lines. The nonspecific SAGE tag is first matched to the database by the same tissue type used by both SAGE and microarray analysis; then the multiple UniGene clusters assigned to the nonspecific SAGE tag are searched in the database under the matched tissue type. The UniGene cluster presented solely or at higher expression levels in the database is annotated to represent the specific gene for the nonspecific SAGE tags. The accuracy of gene annotation by this database was largely confirmed by experimental data. Our study shows that microarray data provide a useful source for annotating the nonspecific SAGE tags.

Cell Line↗

PubMed2002

Software-annotated, digitally photographed, and printed MR images: suitability for publication.

RATIONALE AND OBJECTIVES: The authors performed this study to evaluate whether digitally photographed, computer-annotated MR images produced by clinical radiologists and printed with an inexpensive photo printer are suitable for publication. MATERIALS AND METHODS: Laser prints of 20 magnetic resonance images of the brain were photographed with a 3-megapixel digital camera and annotated with arrows, arrowheads, and asterisks by using graphics software that incorporates vector support. Then, 5 x 7-inch glossy prints with white borders were made by using an inexpensive photo printer. These prints were compared with those produced of the same 20 images by members of the medical center's graphics department with professional scanning and printing equipment and annotated with conventional rub-on symbols. Eight radiologists evaluated image and annotation quality and overall suitability for publication. RESULTS: In all three categories, the images produced by radiologists outscored those produced by the graphics department. CONCLUSION: Digitally photographed, software-annotated MR images printed with an inexpensive photo printer are suitable for publication.

Brain↗

PubMed2004

Only one of the two annotated Lactococcus lactis fabG genes encodes a functional beta-ketoacyl-acyl carrier protein reductase.

The small genome of the Gram-positive bacterium Lactococcus lactis ssp. lactis IL1403 contains two genes that encode proteins annotated as homologues of Escherichia coli beta-hydroxyacyl-acyl carrier protein (ACP) reductase. E. coli fabG encodes beta-ketoacyl-acyl carrier protein (ACP) reductase, the enzyme responsible for the first reductive step of the fatty acid synthetic cycle. Both of the L. lactis genes are adjacent to (and predicted to be cotranscribed with) other genes that encode proteins having homology to known fatty acid synthetic enzymes. Such relationships have often been used to strengthen annotations based on sequence alignments. Annotation in the case of beta-ketoacyl-ACP reductase is particularly problematic because the protein is a member of a vast protein family, the short-chain alcohol dehydrogenase/reductase (SDR) family. The recent isolation of an E. coli fabG mutant strain encoding a conditionally active beta-ketoacyl-ACP reductase allowed physiological and biochemical testing of the putative L. lactishomologues. We report that expression of only one of the two L. lactis proteins (that annotated as FabG1) allows growth of the E. coli fabG strain under nonpermissive conditions and restores in vitro fatty acid synthetic ability to extracts of the mutant strain. Therefore, like E. coli, L. lactis has a single beta-ketoacyl-ACP reductase active with substrates of all fatty acid chain lengths. The second protein (annotated as FabG2), although inactive in fatty acid synthesis both in vivo and in vitro, was highly active in reduction of the model substrate, beta-ketobutyryl-CoA. As expected from work on the E. coli enzyme, the FabG1 beta-ketobutyryl-CoA reductase activity was inhibited by ACP (which blocks access to the active site) whereas the activity of FabG2 was unaffected by the presence of ACP. These results seem to be an example of a gene duplication event followed by divergence of one copy of the gene to encode a protein having a new function.

Alcohol Oxidoreductases↗

PubMed2001

Homology-based annotation yields 1,042 new candidate genes in the Drosophila melanogaster genome.

The approach to annotating a genome critically affects the number and accuracy of genes identified in the genome sequence. Genome annotation based on stringent gene identification is prone to underestimate the complement of genes encoded in a genome. In contrast, over-prediction of putative genes followed by exhaustive computational sequence, motif and structural homology search will find rarely expressed, possibly unique, new genes at the risk of including non-functional genes. We developed a two-stage approach that combines the merits of stringent genome annotation with the benefits of over-prediction. First we identify plausible genes regardless of matches with EST, cDNA or protein sequences from the organism (stage 1). In the second stage, proteins predicted from the plausible genes are compared at the protein level with EST, cDNA and protein sequences, and protein structures from other organisms (stage 2). Remote but biologically meaningful protein sequence or structure homologies provide supporting evidence for genuine genes. The method, applied to the Drosophila melanogaster genome, validated 1,042 novel candidate genes after filtering 19,410 plausible genes, of which 12,124 matched the original 13,601 annotated genes. This annotation strategy is applicable to genomes of all organisms, including human.

Animals↗

PubMed2002

Continuous Holter telemetry of atrial electrograms and marker annotations using a common Holter recording system: impact on Holter electrocardiogram interpretation in patients with dual chamber pacemakers.

The impact of continuous telemetry of atrial electrogram and marker annotations on Holter ECG interpretation was assessed in 98 patients with bipolar dual chamber pacemakers (VDD pacemakers n = 29, DDD(R) systems n = 69). Atrial electrogram and marker annotations were continuously sampled by a telemetry coil that was externally positioned on the pacemaker pocket, amplified, and transduced to a three-channel Holter ECG recorder in addition to an ECG recording. Holter tapes were analyzed by two experienced investigators for quality of P wave recognition and episodes suspicious of pacemaker dysfunction. Initially, only the ECG channel was analyzed. Thereafter, results were compared to those achieved on the basis of the complete recording including atrial electrogram and marker annotations. Recognition of atrial rhythm was markedly improved by Holter telemetry. During 99.3% of recording time telemetry showed a satisfying quality, whereas ECG alone allowed a reliable P wave recognition only during 84.4% of recording time (P < 0.001). One hundred twenty-nine episodes suspicious of pacemaker malfunction occurred in 17 of 98 patients. By analysis of ECG, only 78.3% of episodes were concordantly classified by the investigators. However, 98.4% of all episodes were properly identified when atrial electrogram and marker annotations were added to the analysis (P < 0.001). In particular, discrimination between atrial undersensing, sinus bradycardia, and atrial sensed events within the refractory periods was facilitated. Holter telemetry of atrial electrogram and marker annotations facilitates the analysis of Holter ECGs in pacemaker recipients and improves the detection of pacemaker dysfunctions.

Aged↗

PubMed2002

Applications of InterPro in protein annotation and genome analysis.

The applications of InterPro span a range of biologically important areas that includes automatic annotation of protein sequences and genome analysis. In automatic annotation of protein sequences InterPro has been utilised to provide reliable characterisation of sequences, identifying them as candidates for functional annotation. Rules based on the InterPro characterisation are stored and operated through a database called RuleBase. RuleBase is used as the main tool in the sequence database group at the EBI to apply automatic annotation to unknown sequences. The annotated sequences are stored and distributed in the TrEMBL protein sequence database. InterPro also provides a means to carry out statistical and comparative analyses of whole genomes. In the Proteome Analysis Database, InterPro analyses have been combined with other analyses based on CluSTr, the Gene Ontology (GO) and structural information on the proteins.

Amino Acid Sequence↗

PubMed2002

Modeling the percolation of annotation errors in a database of protein sequences.

Public sequence databases contain information on the sequence, structure and function of proteins. Genome sequencing projects have led to a rapid increase in protein sequence information, but reliable, experimentally verified, information on protein function lags a long way behind. To address this deficit, functional annotation in protein databases is often inferred by sequence similarity to homologous, annotated proteins, with the attendant possibility of error. Now, the functional annotation in these homologous proteins may itself have been acquired through sequence similarity to yet other proteins, and it is generally not possible to determine how the functional annotation of any given protein has been acquired. Thus the possibility of chains of misannotation arises, a process we term 'error percolation'. With some simple assumptions, we develop a dynamical probabilistic model for these misannotation chains. By exploring the consequences of the model for annotation quality it is evident that this iterative approach leads to a systematic deterioration of database quality.

Animals↗

PubMed2002

Microarray data warehouse allowing for inclusion of experiment annotations in statistical analysis.

MOTIVATION: Microarray technology provides access to expression levels of thousands of genes at once, producing large amounts of data. These datasets are valuable only if they are annotated by sufficiently detailed experiment descriptions. However, in many databases a substantial number of these annotations is in free-text format and not readily accessible to computer-aided analysis. RESULTS: The Multi-Conditional Hybridization Intensity Processing System (M-CHIPS), a data warehousing concept, focuses on providing both structure and algorithms suitable for statistical analysis of a microarray database's entire contents including the experiment annotations. It addresses the rapid growth of the amount of hybridization data, more detailed experimental descriptions, and new kinds of experiments in the future. We have developed a storage concept, a particular instance of which is an organism-specific database. Although these databases may contain different ontologies of experiment annotations, they share the same structure and therefore can be accessed by the very same statistical algorithms. Experiment ontologies have not yet reached their final shape, and standards are reduced to minimal conventions that do not yet warrant extensive description. An ontology-independent structure enables updates of annotation hierarchies during normal database operation without altering the structure. AVAILABILITY AND SUPPLEMENTARY INFORMATION: http://www.dkfz.de/tbi/services/mchips

Algorithms↗

PubMed2004

CAAT-Box, Contigs-Assembly and Annotation Tool-Box for genome sequencing projects.

MOTIVATION: Contigs-Assembly and Annotation Tool-Box (CAAT-Box) is a software package developed for the computational part of a genome project where the sequence is obtained by a shotgun strategy. CAAT-Box contains new tools to predict links between contigs by using similarity searches with other whole genome sequences. Most importantly, it allows annotation of a genome to commence during the finishing phase using a gene-oriented strategy. For this purpose, CAAT-Box creates an Individual Protein file (IPF) for each ORF of an assembly. The nucleotide sequence reported in an IPF corresponds to the sequence of the ORF with 500 additional bases before the ORF and 200 bases after. For annotation, additional information like Blast results can be added or linked to the IPFs as well as automatic and/or manual annotations. When a new assembly is performed, CAAT-Box creates new IPFs according to the old IPF panel. CAAT-Box recognizes the modified IPFs which are the only ones used for a new automatic analysis after each assembly. Using this strategy, the user works with a group of IPFs independently of the closure phase progression. The IPFs are accessible by a web server and can therefore be modified and commented by different groups. RESULT: CAAT-Box was used to obtain and to annotate several complete genomes like Listeria monocytogenes or Streptococcus agalactiae. AVAILABILITY: The program may be obtained from the authors and is freely available to non-profit organisations.

Algorithms↗

PubMed2004

Transposable element annotation of the rice genome.

MOTIVATION: The high content of repetitive sequences in the genomes of many higher eukaryotes renders the task of annotating them computationally intensive. Presently, the only widely accepted method of searching and annotating transposable elements (TEs) in large genomic sequences is the use of the RepeatMasker program, which identifies new copies of TEs by pairwise sequence comparisons with a library of known TEs. Profile hidden Markov models (HMMs) have been used successfully in discovering distant homologs of known proteins in large protein databases, but this approach has only rarely been applied to known model TE families in genomic DNA. RESULTS: We used a combination of computational approaches to annotate the TEs in the finished genome of Oryza sativa ssp. japonica. In this paper, we discuss the strengths and the weaknesses of the annotation methods used. These approaches included: the default configuration of RepeatMasker using cross_match, an implementation of the Smith-Waterman-Gotoh algorithm; RepeatMasker using WU-BLAST for similarity searching; and the HMMER package, used to search for TEs with profile HMMs. All the results were converted into GFF format and post-processed using a set of Perl scripts. RepeatMasker was used in the case of most TE families. The WU-BLAST implementation of RepeatMasker was found to be manifold faster than cross_match with only a slight loss in sensitivity and was thus used to obtain the final set of data. HMMER was used in the annotation of the Mutator-like element (MULE) superfamily and the miniature inverted-repeat transposable element (MITE) polyphyletic group of families, for which large libraries of elements were available and which could be divided into well-defined families. The HMMER search algorithm was extremely slow for models over 1000 bp in length, so MULE families with members over 1000 bp long were processed with RepeatMasker instead. The main disadvantage of HMMER in this application is that, since it was developed with protein sequences in mind, it does not search the negative DNA strand. With the exception of TE families with essentially palindromic sequences, reverse complement models had to be created and run to compensate for this shortcoming. We conclude that a modification of RepeatMasker to incorporate libraries of profile HMMs in searches could improve the ability to detect degenerated copies of TEs. AVAILABILITY: The Perl scripts and TE sequences used in construction of the RepeatMasker library and the profile HMMs are available upon request.

Algorithms↗

PubMed2004

Filtering erroneous protein annotation.

MOTIVATION: Automatically generated annotation on protein data of UniProt (Universal Protein Resource) is planned to be publicly available on the UniProt web pages in April 2004. It is expected that the data content of over 500,000 protein entries in the TrEMBL section will be enhanced by the output of an automated annotation pipeline. However, a part of the automatically added data will be erroneous, as are parts of the information coming from other sources. We present a post-processing system called Xanthippe that is based on a simple exclusion mechanism and a decision tree approach using the C4.5 data-mining algorithm. RESULTS: It is shown that Xanthippe detects and flags a large part of the annotation errors and considerably increases the reliability of both automatically generated data and annotation from other sources. As a cross-validation to Swiss-Prot shows, errors in protein descriptions, comments and keywords are successfully filtered out. Xanthippe is a contradictive application that can be combined seamlessly with predictive systems. It can be used either to improve the precision of automated annotation at a constant level of recall or increase the recall at a constant level of precision. AVAILABILITY: The application of the Xanthippe rules can be browsed at http://www.ebi.uniprot.org/

Algorithms↗

PubMed2005

MIPS bacterial genomes functional annotation benchmark dataset.

MOTIVATION: Any development of new methods for automatic functional annotation of proteins according to their sequences requires high-quality data (as benchmark) as well as tedious preparatory work to generate sequence parameters required as input data for the machine learning methods. Different program settings and incompatible protocols make a comparison of the analyzed methods difficult. RESULTS: The MIPS Bacterial Functional Annotation Benchmark dataset (MIPS-BFAB) is a new, high-quality resource comprising four bacterial genomes manually annotated according to the MIPS functional catalogue (FunCat). These resources include precalculated sequence parameters, such as sequence similarity scores, InterPro domain composition and other parameters that could be used to develop and benchmark methods for functional annotation of bacterial protein sequences. These data are provided in XML format and can be used by scientists who are not necessarily experts in genome annotation. AVAILABILITY: BFAB is available at http://mips.gsf.de/proj/bfab

Bacterial Proteins↗

PubMed2005

GandrKB--ontological microarray annotation and visualization.

SUMMARY: The Gandr (gene annotation data representation) knowledgebase is an ontological framework for laboratory-specific gene annotation. Gandr uses Protege 2000 for editing, querying and visualizing microarray data and annotations. Genes can be annotated with provided, newly created or imported ontological concepts. Annotated genes can inherit assigned concept properties and can be related to each other. The resulting knowledgebase can be visualized as interactive network of nodes and edges representing genes and their functional relationships. This allows for immediate and associative gene context exploration. Ontological query techniques allow for powerful data access.

Algorithms↗

PubMed2005

A precise and scalable method for querying genes in chromosomal banding regions based on cytogenetic annotations.

MOTIVATION: Staining the human metaphase chromosomes reveals characteristic banding patterns known as cytogenetic bands or cytobands. Using technologies based on metaphase chromosomes, researchers have accumulated much knowledge about the correlations between human diseases and specific cytoband aberrations, indicating the presence of disease-associated genes in those bands. With the progress of human genome project and techniques such as fluorescent in situ hybridization, many genes have been assigned to the cytobands and annotated in public databases, making it possible to find all genes in the disease-related cytobands through database queries. However, finding genes in cytobands remains an imprecise process, partly due to the insufficiency of current methods for cytoband queries, especially for those based on cytogenetic annotations. RESULTS: By transforming the cytoband annotations into numerical segments, a new query method is developed that is able to accurately define any cytogenetic ranges in human chromosomes. A query system (designated cytoband query sys CQS) is implemented using cytogenetic annotations in the public domain. Judged by a performance test, CQS executed as accurately as expected using cytogenetic annotations from NCBI Map Viewer. The new method is scalable and can be applied to genomes from other species. AVAILABILITY: The CQS is freely accessible over the Internet at http://moris.csie.ncku.edu.tw/cqs/ CONTACT: clh9@mail.ncku.edu.tw SUPPLEMENTARY INFORMATION: http://moris.csie.ncku.edu.tw/cqs/

Algorithms↗