Two or three myths about bioinformatics.
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Computational Biology↗
Biomedical subjects
C Ouzounis
Publications and source records attributed to C Ouzounis.
Automatic extraction of protein interactions from scientific abstracts.
This paper motivates the use of Information Extraction (IE) for gathering data on protein interactions, describes the customization of an existing IE system, SRI's Highlight, for this task and presents the results of an experiment on unseen Medline abstracts which show that customization to a new domain can be fast, reliable and cost-effective.
Abstracting and Indexing↗
Dictionary building via unsupervised hierarchical motif discovery in the sequence space of natural proteins.
Using Teiresias, a pattern discovery method that identifies all motifs present in any given set of protein sequences without requiring alignment or explicit enumeration of the solution space, we have explored the GenPept sequence database and built a dictionary of all sequence patterns with two or more instances. The entries of this dictionary, henceforth named seqlets, cover 98.12% of all amino acid positions in the input database and in essence provide a comprehensive finite set of descriptors for protein sequence space. As such, seqlets can be effectively used to describe almost every naturally occurring protein. In fact, seqlets can be thought of as building blocks of protein molecules that are a necessary (but not sufficient) condition for function or family equivalence memberships. Thus, seqlets can either define conserved family signatures or cut across molecular families and previously undetected sequence signals deriving from functional convergence. Moreover, we show that seqlets also can capture structurally conserved motifs. The availability of a dictionary of seqlets that has been derived in such an unsupervised, hierarchical manner is generating new opportunities for addressing problems that range from reliable classification and the correlation of sequence fragments with functional categories to faster and sensitive engines for homology searches, evolutionary studies, and protein structure prediction.
Amino Acid Motifs↗
Universal protein families and the functional content of the last universal common ancestor.
The phylogenetic distribution of Methanococcus jannaschii proteins can provide, for the first time, an estimate of the genome content of the last common ancestor of the three domains of life. Relying on annotation and comparison with reference to the species distribution of sequence similarities results in 324 proteins forming the universal family set. This set is very well characterized and relatively small and nonredundant, containing 301 biochemical functions, of which 246 are unique. This universal function set contains mostly genes coding for energy metabolism or information processing. It appears that the Last Universal Common Ancestor was an organism with metabolic networks and genetic machinery similar to those of extant unicellular organisms.
Archaeal Proteins↗
Functional classes in the three domains of life.
The evolutionary divergence among the three major domains of life can now be addressed through the first set of complete genomes from representative species. These model species from the three domains of life, Haemophilus influenzae for Bacteria, Saccharomyces cerevisiae for Eukarya, and Methanococcus jannaschii for Archaea, provide the basis for a universal functional classification and analysis. We have chosen 13 functional classes and three superclasses (ENERGY, COMMUNICATION and INFORMATION) as global descriptors of protein function. Compositional comparison of the three complete genomes reveals that functional classes are ubiquitous yet diverse in the three domains of life. Proteins related with ENERGY processes are generally represented in all three domains, while those related with COMMUNICATION represent the most distinctive functional feature of each single domain. Finally, functions related with INFORMATION processing (translation, transcription, and replication) show a complex behaviour. In Archaea, proteins in this superclass are related with proteins in either Eukarya or Bacteria, as recognized previously. The distribution of functional classes in the three domains accurately reflects the principal characteristics of cellular life forms.
Archaeal Proteins↗
Orthology: another terminology muddle.
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Bibliometrics↗
Automated genome sequence analysis and annotation.
MOTIVATION: Large-scale genome projects generate a rapidly increasing number of sequences, most of them biochemically uncharacterized. Research in bioinformatics contributes to the development of methods for the computational characterization of these sequences. However, the installation and application of these methods require experience and are time consuming. RESULTS: We present here an automatic system for preliminary functional annotation of protein sequences that has been applied to the analysis of sets of sequences from complete genomes, both to refine overall performance and to make new discoveries comparable to those made by human experts. The GeneQuiz system includes a Web-based browser that allows examination of the evidence leading to an automatic annotation and offers additional information, views of the results, and links to biological databases that complement the automatic analysis. System structure and operating principles concerning the use of multiple sequence databases, underlying sequence analysis tools, lexical analyses of database annotations and decision criteria for functional assignments are detailed. The system makes automatic quality assessments of results based on prior experience with the underlying sequence analysis tools; overall error rates in functional assignment are estimated at 2.5-5% for cases annotated with highest reliability ('clear' cases). Sources of over-interpretation of results are discussed with proposals for improvement. A conservative definition for reporting 'new findings' that takes account of database maturity is presented along with examples of possible kinds of discoveries (new function, family and superfamily) made by the system. System performance in relation to sequence database coverage, database dynamics and database search methods is analysed, demonstrating the inherent advantages of an integrated automatic approach using multiple databases and search methods applied in an objective and repeatable manner. AVAILABILITY: The GeneQuiz system is publicly available for analysis of protein sequences through a Web server at http://www.sander.ebi.ac. uk/gqsrv/submit
Amino Acid Sequence↗
Automatic extraction of biological information from scientific text: protein-protein interactions.
We describe the basic design of a system for automatic detection of protein-protein interactions extracted from scientific abstracts. By restricting the problem domain and imposing a number of strong assumptions which include pre-specified protein names and a limited set of verbs that represent actions, we show that it is possible to perform accurate information extraction. The performance of the system is evaluated with different cases of real-world interaction networks, including the Drosophila cell cycle control. The results obtained computationally are in good agreement with current biological knowledge and demonstrate the feasibility of developing a fully automated system able to describe networks of protein interactions with sufficient accuracy.
Algorithms↗
RGD sequences in several receptor proteins: novel cell adhesion function of receptors?
In the process of homology modelling of the 3-dimensional structure of alleles of the human histocompatibility protein HLA-DQ, we discovered that its RGD tripeptide (beta 167-169) forms part of a loop. A search through protein sequence data bases, revealed this cell adhesion motif in 67 integral plasma membrane proteins (in 48 extracellularly, and in the remaining 19 intracellularly), which are bona fide receptors, and none of them has thus far been considered as a cell adhesion protein. The 3-dimensional structure of one of these, the rat neonatal Fc receptor, is known and its extracellular RGD sequence is in an adhesion-like loop, a fact that went unnoticed in the original papers. In a few other cases, e.g. rat and mouse growth hormone receptor, and mouse CD40 ligand, homology modelling by ourselves and others reveals that the said sequences are part of a loop, in similarity to all RGD sequences found in proteins with established adhesion function and known 3-dimensional structure. Likewise, inspection of all known protein 3-dimensional structures containing an RGD sequence, and not having a documented cell adhesion function (total of 65 separate entries) shows that such sequence is mostly (52/65 or 80% of cases) part of a loop. We therefore call attention to these surprising findings, discuss the possible cell adhesion role of these receptor proteins, and draw an analogy from the two well characterised examples, that of soluble IGF binding protein 1 and the transcriptional activator protein Tat of HIV, where their RGD sequences have been shown by site-directed mutagenesis to participate in cell-adhesion interactions, without prior knowledge of the location of the tripeptide, or the 3-dimensional structure of the respective protein.
Animals↗
EUCLID: automatic classification of proteins in functional classes by their database annotations.
UNLABELLED: A tool is described for the automatic classification of sequences in functional classes using their database annotations. The Euclid system is based on a simple learning procedure from examples provided by human experts. AVAILABILITY: Euclid is freely available for academics at http://www.gredos.cnb.uam.es/EUCLID, with the corresponding dictionaries for the generation of three, eight and 14 functional classes. CONTACT: E-mail: valencia@cnb.uam.es SUPPLEMENTARY INFORMATION: The results of the EUCLID classification of different genomes are available at http://www.sander.ebi.ac. uk/genequiz/. A detailed description of the different applications mentioned in the text is available at http://www.gredos.cnb.uam. es/EUCLID/Full_Paper
Computational Biology↗
Are binding residues conserved?
We present our attempt to quantify the evolutionary dynamics of functional residues in a representative set of protein structures and their homologous sequences. Using the log-odds formalism, the preference for all twenty amino acids to be conserved or participate in binding (or active) sites is examined. It appears that while there is a tendency for functional residues to be conserved, the two preference scales do not coincide. Remarkable differences between amino acid types emerge from this comparative study. The current approach is expected to lead towards a better understanding of functional site architecture in proteins.
Amino Acid Sequence↗
Conserved clusters of functionally related genes in two bacterial genomes.
An approach for genome comparison, combining function classification of gene products and sequence comparison, is presented. The genomes of Haemophilus influenzae and Escherichia coli are analyzed, and all genes are classified into nine major functional classes, corresponding to important cellular processes. To study gene order relationships and genome organization in the two bacteria, we performed statistics on neighboring pairs of genes. To estimate the significance of the observations, a statistical model based on binomial distributions has been developed. Significant patterns of gene order are observed within, as well as between, the two bacterial genomes: Functionally related genes tend to be neighbors more often than do unrelated genes. Some of these groups represent well-known operons, but additional gene clusters are identified. These clusters correspond to genomic elements that have been conserved during bacterial evolution. In addition to nearest-neighbor relationships, the method is also useful to study the relative direction of transcription in genomes, which is also highly conserved between homologous gene pairs. This new approach combines the high-level description of molecular function with pair statistics that express genome organization. It is expected to complement traditional methods of sequence analysis in the study of genomic structure, function, and evolution.
Binomial Distribution↗
Evolution of immunoglobulin-like modules in chitinases: their structural flexibility and functional implications.
BACKGROUND: Chitinase A from Serratia marcescens is a glycosyl hydrolase consisting of three distinct domains. The N-terminal domain (ChiN domain, amino acids 24-137) has an immunoglobulin-like fold. This ChiN domain is structurally similar to fibronectin type III domains (FnIII domains), which exist in other chitinases, but does not share any sequence similarity with them. RESULT: Structure comparisons of the ChiN domain and FnIII domains confirm the similar fold, but fail to establish any sequence similarity. Sequence searches and comparisons between ChiN and FnIII domain sequences show a remarkable difference between the two domains in chitinases from an evolutionary point of view. A low temperature structure of chitinase A shows that the ChiN module is flexible with respect to the catalytic body of the protein. CONCLUSIONS: We postulate that the ChiN and FnIII domains evolved independently in chitinases which share otherwise homologous catalytic domains. The flexibility of the ChiN domain, together with biochemical knowledge of the function of similar domains, leads us to propose that immunoglobulin-like folds in chitinases are involved in interactions with the chitin chain during catalysis.
Bacterial Proteins↗
Sequence analysis of the Methanococcus jannaschii genome and the prediction of protein function.
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Bacterial Proteins↗
The emergence of major cellular processes in evolution.
The phylogenetic distribution of divergently related protein families into the three domains of life (archaea, bacteria and eukaryotes) can signify the presence or absence of entire cellular processes in these domains and their ancestors. We can thus study the emergence of the major transitions during cellular evolution, and resolve some of the controversies surrounding the evolutionary status of archaea and the origins of the eukaryotic cell. In view of the ongoing projects that sequence the complete genomes of several Archaea, this work forms a testable prediction when the genome sequences become available. Using the presence of the protein families as taxonomic traits, and linking them to biochemical pathways, we are able to reason about the presence of the corresponding cellular processes in the last universal ancestor of contemporary cells. The analysis shows that metabolism was already a complex network of reactions which included amino acid, nucleotide, fatty acid, sugar and coenzyme metabolism. In addition, genetic processes such as translation are conserved and close to the original form. However, other processes such as DNA replication and repair or transcription are exceptional and seem to be associated with the structural changes that drove eukaryotes and bacteria away from their common ancestor. There are two major hypotheses in the present work: first, that archaea are probably closer to the last universal ancestor than any other extant life form, and second, that the major cellular processes were in place before the major splitting. The last universal ancestor had metabolism and translation very similar to the contemporary ones, while having an operonic genome organization and archaean-like transcription. Evidently, all cells today contain remnants of the primordial genome of the last universal ancestor.
Archaea↗
Genomes with distinct function composition.
The functional composition of organisms can be analysed for the first time with the appearance of complete or sizeable parts of various genomes. We have reduced the problem of protein function classification to a simple scheme with three classes of protein function: energy-, information- and communication-associated proteins. Finer classification schemes can be easily mapped to the above three classes. To deal with the vast amount of information, a system for automatic function classification using database annotations has been developed. The system is able to classify correctly about 80% of the query sequences with annotations. Using this system, we can analyse samples from the genomes of the most represented species in sequence databases and compare their genomic composition. The similarities and differences for different taxonomic groups are strikingly intuitive. Viruses have the highest proportion of proteins involved in the control and expression of genetic information. Bacteria have the highest proportion of their genes dedicated to the production of proteins associated with small molecule transformations and transport. Animals have a very large proportion of proteins associated with intra- and intercellular communication and other regulatory processes. In general, the proportion of communication-related proteins increases during evolution, indicating trends that led to the emergence of the eukaryotic cell and later the transition from unicellular to multicellular organisms.
Animals↗
Computational comparisons of model genomes.
Complete genomes from model organisms provide new challenges for computational molecular biology. Novel questions emerge from the genome data obtained from the functional prediction of thousands of gene products. In this review, we present some approaches to the computational comparison of genomes, based on sequence and text analysis, and comparisons of genome composition and gene order.
Biotechnology↗
Novelties from the complete genome of Mycoplasma genitalium.
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DNA, Bacterial↗