Call for an enzyme genomics initiative

I propose an Enzyme Genomics Initiative, the goal of which is to obtain at least one protein sequence for each enzyme that has previously been characterized biochemically. There are 1,437 enzyme activities for which Enzyme Commission (EC) numbers have been assigned but no sequence can be found in public protein-sequence databases

Many Genbank Entries for Complete Microbial Genomes Violate the Genbank Standard

A survey of Genbank entries for complete microbial genomes reveals that the majority do not conform to the Genbank standard. Typical deviations from the Genbank standard include records with information in incorrect fields, addition of extraneous and confusing information within a field, and omission of useful fields. This situation results from two principal causes: genome centres do not submit Genbank records in the proper form and the Genbank, EMBL and DDBJ staffs do not enforce the database standards that they have defined

Web-based metabolic network visualization with a zooming user interface

<p>Abstract</p> <p>Background</p> <p>Displaying complex metabolic-map diagrams, for Web browsers, and allowing users to interact with them for querying and overlaying expression data over them is challenging.</p> <p>Description</p> <p>We present a Web-based metabolic-map diagram, which can be interactively explored by the user, called the <it>Cellular Overview</it>. The main characteristic of this application is the zooming user interface enabling the user to focus on appropriate granularities of the network at will. Various searching commands are available to visually highlight sets of reactions, pathways, enzymes, metabolites, and so on. Expression data from single or multiple experiments can be overlaid on the diagram, which we call the Omics Viewer capability. The application provides Web services to highlight the diagram and to invoke the <it>Omics Viewer</it>. This application is entirely written in JavaScript for the client browsers and connect to a Pathway Tools Web server to retrieve data and diagrams. It uses the OpenLayers library to display tiled diagrams.</p> <p>Conclusions</p> <p>This new online tool is capable of displaying large and complex metabolic-map diagrams in a very interactive manner. This application is available as part of the Pathway Tools software that powers multiple metabolic databases including <monospace>Biocyc.org</monospace>: The Cellular Overview is accessible under the <monospace>Tools</monospace> menu.</p

The Pathway Tools cellular overview diagram and Omics Viewer

The Pathway Tools cellular overview diagram is a visual representation of the biochemical network of an organism. The overview is automatically created from a Pathway/Genome Database describing that organism. The cellular overview includes metabolic, transport and signaling pathways, and other membrane and periplasmic proteins. Pathway Tools supports interrogation and exploration of cellular biochemical networks through the overview diagram. Furthermore, a software component called the Omics Viewer provides visual analysis of whole-organism datasets using the overview diagram as an organizing framework. For example, gene expression and metabolomics measurements, alone or in combination, can be painted onto the overview, as can computed whole-organism datasets, such as predicted reaction-flux values. The cellular overview and Omics Viewer provide a mechanism whereby biologists can apply the pattern-recognition capabilities of the human visual system to analyze large-scale datasets in a biologically meaningful context. SRI's BioCyc.org website provides overview diagrams for more than 200 organisms. This article describes enhancements to the overview made since a 1999 publication, including the automatic layout capability, expansion of the cellular machinery that it includes, new semantic zooming and poster-generating capabilities, and extension of the Omics Viewer to support painting of metabolites, animations and zooming to individual pathway diagrams

Machine learning methods for metabolic pathway prediction

<p>Abstract</p> <p>Background</p> <p>A key challenge in systems biology is the reconstruction of an organism's metabolic network from its genome sequence. One strategy for addressing this problem is to predict which metabolic pathways, from a reference database of known pathways, are present in the organism, based on the annotated genome of the organism.</p> <p>Results</p> <p>To quantitatively validate methods for pathway prediction, we developed a large "gold standard" dataset of 5,610 pathway instances known to be present or absent in curated metabolic pathway databases for six organisms. We defined a collection of 123 pathway features, whose information content we evaluated with respect to the gold standard. Feature data were used as input to an extensive collection of machine learning (ML) methods, including naïve Bayes, decision trees, and logistic regression, together with feature selection and ensemble methods. We compared the ML methods to the previous PathoLogic algorithm for pathway prediction using the gold standard dataset. We found that ML-based prediction methods can match the performance of the PathoLogic algorithm. PathoLogic achieved an accuracy of 91% and an F-measure of 0.786. The ML-based prediction methods achieved accuracy as high as 91.2% and F-measure as high as 0.787. The ML-based methods output a probability for each predicted pathway, whereas PathoLogic does not, which provides more information to the user and facilitates filtering of predicted pathways.</p> <p>Conclusions</p> <p>ML methods for pathway prediction perform as well as existing methods, and have qualitative advantages in terms of extensibility, tunability, and explainability. More advanced prediction methods and/or more sophisticated input features may improve the performance of ML methods. However, pathway prediction performance appears to be limited largely by the ability to correctly match enzymes to the reactions they catalyze based on genome annotations.</p

A systematic study of genome context methods: calibration, normalization and combination

<p>Abstract</p> <p>Background</p> <p>Genome context methods have been introduced in the last decade as automatic methods to predict functional relatedness between genes in a target genome using the patterns of existence and relative locations of the homologs of those genes in a set of reference genomes. Much work has been done in the application of these methods to different bioinformatics tasks, but few papers present a systematic study of the methods and their combination necessary for their optimal use.</p> <p>Results</p> <p>We present a thorough study of the four main families of genome context methods found in the literature: phylogenetic profile, gene fusion, gene cluster, and gene neighbor. We find that for most organisms the gene neighbor method outperforms the phylogenetic profile method by as much as 40% in sensitivity, being competitive with the gene cluster method at low sensitivities. Gene fusion is generally the worst performing of the four methods. A thorough exploration of the parameter space for each method is performed and results across different target organisms are presented.</p> <p>We propose the use of normalization procedures as those used on microarray data for the genome context scores. We show that substantial gains can be achieved from the use of a simple normalization technique. In particular, the sensitivity of the phylogenetic profile method is improved by around 25% after normalization, resulting, to our knowledge, on the best-performing phylogenetic profile system in the literature.</p> <p>Finally, we show results from combining the various genome context methods into a single score. When using a cross-validation procedure to train the combiners, with both original and normalized scores as input, a decision tree combiner results in gains of up to 20% with respect to the gene neighbor method. Overall, this represents a gain of around 15% over what can be considered the state of the art in this area: the four original genome context methods combined using a procedure like that used in the STRING database. Unfortunately, we find that these gains disappear when the combiner is trained only with organisms that are phylogenetically distant from the target organism.</p> <p>Conclusions</p> <p>Our experiments indicate that gene neighbor is the best individual genome context method and that gains from the combination of individual methods are very sensitive to the training data used to obtain the combiner's parameters. If adequate training data is not available, using the gene neighbor score by itself instead of a combined score might be the best choice.</p

Genes and (Common) Pathways Underlying Drug Addiction

Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn), the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction