BicOverlapper: a tool for bicluster visualization

Summary: BicOverlapper is a tool to visualize biclusters fromgene-expression matrices in a way that helps to compare biclusteringmethods, to unravel trends and to highlight relevant genes andconditions. A visual approach can complement biological andstatistical analysis and reduce the time spent by specialistsinterpreting the results of biclustering algorithms. The techniqueis based on a force-directed graph where biclusters are representedas flexible overlapped groups of genes and conditions. Availability: The BicOverlapper software and supplementary materialare available at http://vis.usal.es/bicoverlapper Contact: rodri{at}usal.es Associate Editor: John Quackenbush The first two authors should be reported as joint first authors.     

MMG: a probabilistic tool to identify submodules of metabolic pathways

Motivation: A fundamental task in systems biology is the identificationof groups of genes that are involved in the cellular responseto particular signals. At its simplest level, this often reducesto identifying biological quantities (mRNA abundance, enzymeconcentrations, etc.) which are differentially expressed intwo different conditions. Popular approaches involve using t-teststatistics, based on modelling the data as arising from a mixturedistribution. A common assumption of these approaches is thatthe data are independent and identically distributed; however,biological quantities are usually related through a complex(weighted) network of interactions, and often the more pertinentquestion is which subnetworks are differentially expressed,rather than which genes. Furthermore, in many interesting cases(such as high-throughput proteomics and metabolomics), onlyvery partial observations are available, resulting in the needfor efficient imputation techniques. Results: We introduce Mixture Model on Graphs (MMG), a novelprobabilistic model to identify differentially expressed submodulesof biological networks and pathways. The method can easily incorporateinformation about weights in the network, is robust againstmissing data and can be easily generalized to directed networks.We propose an efficient sampling strategy to infer posteriorprobabilities of differential expression, as well as posteriorprobabilities over the model parameters. We assess our methodon artificial data demonstrating significant improvements overstandard mixture model clustering. Analysis of our model resultson quantitative high-throughput proteomic data leads to theidentification of biologically significant subnetworks, as wellas the prediction of the expression level of a number of enzymes,some of which are then verified experimentally. Availability: MATLAB code is available from http://www.dcs.shef.ac.uk/~guido/software.html Contact: guido{at}dcs.shef.ac.uk Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Jonathan Wren     

DeconMSn: a software tool for accurate parent ion monoisotopic mass determination for tandem mass spectra

Summary: DeconMSn accurately determines the monoisotopic massand charge state of parent ions from high-resolution tandemmass spectrometry data, offering significant improvement forLTQ_FT and LTQ_Orbitrap instruments over the commercially deliveredThermo Fisher Scientific's extract_msn tool. Optimal parention mass tolerance values can be determined using accurate massinformation, thus improving peptide identifications for high-massmeasurement accuracy experiments. For low-resolution data fromLCQ and LTQ instruments, DeconMSn incorporates a support-vector-machine-basedcharge detection algorithm that identifies the most likely chargeof a parent species through peak characteristics of its fragmentationpattern. Availability: http://ncrr.pnl.gov/software/ or http://www.proteomicsresource.org/ Contact: rds{at}pnl.gov Supplementary information: PowerPoint presentation/Poster onhttp://ncrr.pnl.gov/software/. Associate Editor: Alfonso Valencia     

CRONOS: the cross-reference navigation server

Summary: Cross-mapping of gene and protein identifiers betweendifferent databases is a tedious and time-consuming task. Toovercome this, we developed CRONOS, a cross-reference serverthat contains entries from five mammalian organisms presentedby major gene and protein information resources. Sequence similarityanalysis of the mapped entries shows that the cross-referencesare highly accurate. In total, up to 18 different identifiertypes can be used for identification of cross-references. Thequality of the mapping could be improved substantially by exclusionof ambiguous gene and protein names which were manually validated.Organism-specific lists of ambiguous terms, which are valuablefor a variety of bioinformatics applications like text miningare available for download. Availability: CRONOS is freely available to non-commercial usersat http://mips.gsf.de/genre/proj/cronos/index.html, web servicesare available at http://mips.gsf.de/CronosWSService/CronosWS?wsdl. Contact: brigitte.waegele{at}helmholtz-muenchen.de Supplementary information: Supplementary data are availableat Bioinformatics online. The online Supplementary Materialcontains all figures and tables referenced by this article. Associate Editor: Martin Bishop     

A new algorithm for cluster analysis of genomic methylation: the Helicobacter pylori case

Motivation: The genomic methylation analysis is useful to typebacteria that have a high number of expressed type II methyltransferases.Methyltransferases are usually committed to Restriction andModification (R-M) systems, in which the restriction endonucleaseimposes high pressure on the expression of the cognate methyltransferasethat hinder R-M system loss. Conventional cluster methods donot reflect this tendency. An algorithm was developed for dendrogramconstruction reflecting the propensity for conservation of R-MType II systems. Results: The new algorithm was applied to 52 Helicobacter pyloristrains from different geographical regions and compared withconventional clustering methods. The algorithm works by firstgrouping strains that share a common minimum set of R-M systemsand gradually adds strains according to the number of the R-Msystems acquired. Dendrograms revealed a cluster of Africanstrains, which suggest that R-M systems are present in H.pylorigenome since its human host migrates from Africa. Availability: The software files are available at http://www.ff.ul.pt/paginas/jvitor/Bioinformatics/MCRM_algorithm.zip Contact: filipavale{at}fe.ucp.pt Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Martin Bishop     

GlycoBase and autoGU: tools for HPLC-based glycan analysis

Summary: The development of robust high-performance liquid chromatography(HPLC) technologies continues to improve the detailed analysisand sequencing of glycan structures released from glycoproteins.Here, we present a database (GlycoBase) and analytical tool(autoGU) to assist the interpretation and assignment of HPLC-glycanprofiles. GlycoBase is a relational database which containsthe HPLC elution positions for over 350 2-AB labelled N-glycanstructures together with predicted products of exoglycosidasedigestions. AutoGU assigns provisional structures to each integratedHPLC peak and, when used in combination with exoglycosidasedigestions, progressively assigns each structure automaticallybased on the footprint data. These tools are potentially verypromising and facilitate basic research as well as the quantitativehigh-throughput analysis of low concentrations of glycans releasedfrom glycoproteins. Availability: http://glycobase.ucd.ie Contact: matthew.campbell{at}nibrt.ie Associate Editor: Limsoon Wong Present address: Dublin-Oxford Glycobiology Laboratory, NationalInstitute for Bioprocessing Research and Training, Conway Institute,University College Dublin, Dublin, Ireland. Present address: Ludger Ltd, Culham Science Centre, Abingdon,Oxfordshire OX14 3EB., UK.     

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

Motivation: Staining the human metaphase chromosomes revealscharacteristic banding patterns known as cytogenetic bands orcytobands. Using technologies based on metaphase chromosomes,researchers have accumulated much knowledge about the correlationsbetween human diseases and specific cytoband aberrations, indicatingthe presence of disease-associated genes in those bands. Withthe progress of human genome project and techniques such asfluorescent in situ hybridization, many genes have been assignedto the cytobands and annotated in public databases, making itpossible to find all genes in the disease-related cytobandsthrough database queries. However, finding genes in cytobandsremains an imprecise process, partly due to the insufficiencyof current methods for cytoband queries, especially for thosebased on cytogenetic annotations. Results: By transforming the cytoband annotations into numericalsegments, a new query method is developed that is able to accuratelydefine any cytogenetic ranges in human chromosomes. A querysystem (designated cytoband query sys CQS) is implemented usingcytogenetic annotations in the public domain. Judged by a performancetest, CQS executed as accurately as expected using cytogeneticannotations from NCBI Map Viewer. The new method is scalableand can be applied to genomes from other species. Availability: The CQS is freely accessible over the Internetat http://moris.csie.ncku.edu.tw/cqs/ Contact: clh9{at}mail.ncku.edu.tw Supplementary information: http://moris.csie.ncku.edu.tw/cqs/     

Unequal group variances in microarray data analyses

Motivation: In searching for differentially expressed (DE) genesin microarray data, we often observe a fraction of the genesto have unequal variability between groups. This is not an issuein large samples, where a valid test exists that uses individualvariances separately. The problem arises in the small-samplesetting, where the approximately valid Welch test lacks sensitivity,while the more sensitive moderated t-test assumes equal variance. Methods: We introduce a moderated Welch test (MWT) that allowsunequal variance between groups. It is based on (i) weightingof pooled and unpooled standard errors and (ii) improved estimationof the gene-level variance that exploits the information fromacross the genes. Results: When a non-trivial proportion of genes has unequalvariability, false discovery rate (FDR) estimates based on thestandard t and moderated t-tests are often too optimistic, whilethe standard Welch test has low sensitivity. The MWT is shownto (i) perform better than the standard t, the standard Welchand the moderated t-tests when the variances are unequal betweengroups and (ii) perform similarly to the moderated t, and betterthan the standard t and Welch tests when the group variancesare equal. These results mean that MWT is more reliable thanother existing tests over wider range of data conditions. Availability: R package to perform MWT is available at http://www.meb.ki.se/~yudpaw Contact: yudi.pawitan{at}ki.se Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Martin Bishop     

Align human interactome with phenome to identify causative genes and networks underlying disease families

Motivation: Understanding the complexity in gene–phenotyperelationship is vital for revealing the genetic basis of commondiseases. Recent studies on the basis of human interactome andphenome not only uncovers prevalent phenotypic overlap and geneticoverlap between diseases, but also reveals a modular organizationof the genetic landscape of human diseases, providing new opportunitiesto reduce the complexity in dissecting the gene–phenotypeassociation. Results: We provide systematic and quantitative evidence thatphenotypic overlap implies genetic overlap. With these results,we perform the first heterogeneous alignment of human interactomeand phenome via a network alignment technique and identify 39disease families with corresponding causative gene networks.Finally, we propose AlignPI, an alignment-based framework topredict disease genes, and identify plausible candidates for70 diseases. Our method scales well to the whole genome, asdemonstrated by prioritizing 6154 genes across 37 chromosomeregions for Crohn's disease (CD). Results are consistent witha recent meta-analysis of genome-wide association studies forCD. Availability: Bi-modules and disease gene predictions are freelyavailable at the URL http://bioinfo.au.tsinghua.edu.cn/alignpi/ Contact: ruijiang{at}tsinghua.edu.cn Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Trey Ideker     

AIMIE: a web-based environment for detection and interpretation of significant sequence motifs in prokaryotic genomes

Motivation: Genomes contain biologically significant informationthat extends beyond that encoded in genes. Some of this informationrelates to various short dispersed repeats distributed throughoutthe genome. The goal of this work was to combine tools for detectionof statistically significant dispersed repeats in DNA sequenceswith tools to aid development of hypotheses regarding theirpossible physiological functions in an easy-to-use web-basedenvironment. Results: Ab Initio Motif Identification Environment (AIMIE)was designed to facilitate investigations of dispersed sequencemotifs in prokaryotic genomes. We used AIMIE to analyze theEscherichia coli and Haemophilus influenzae genomes in orderto demonstrate the utility of the new environment. AIMIE detectedrepeated extragenic palindrome (REP) elements, CRISPR repeats,uptake signal sequences, intergenic dyad sequences and severalother over-represented sequence motifs. Distributional patternsof these motifs were analyzed using the tools included in AIMIE. Availability: AIMIE and the related software can be accessedat our web site http://www.cmbl.uga.edu/software.html. Contact: mrazek{at}uga.edu Associate Editor: Alex Bateman     

e-LiSe--an online tool for finding needles in the '(Medline) haystack'

Summary: Using literature databases one can find not only knownand true relations between processes but also less studied,non-obvious associations. The main problem with discoveringsuch type of relevant biological information is ‘selection’.The ability to distinguish between a true correlation (e.g.between different types of biological processes) and randomchance that this correlation is statistically significant iscrucial for any bio-medical research, literature mining beingno exception. This problem is especially visible when searchingfor information which has not been studied and described inmany publications. Therefore, a novel bio-linguistic statisticalmethod is required, capable of ‘selecting’ truecorrelations, even when they are low-frequency associations.In this article, we present such statistical approach basedon Z-score and implemented in a web-based application ‘e-LiSe’. Availability: The software is available at http://miron.ibb.waw.pl/elise/ Contact: piotr{at}ibb.waw.pl Supplementary information: Supplementary materials are availableat http://miron.ibb.waw.pl/elise/supplementary/ Associate Editor: Alfonso Valencia     

In silico Biochemical Reaction Network Analysis (IBRENA): a package for simulation and analysis of reaction networks

Summary: We present In silico Biochemical Reaction Network Analysis(IBRENA), a software package which facilitates multiple functionsincluding cellular reaction network simulation and sensitivityanalysis (both forward and adjoint methods), coupled with principalcomponent analysis, singular-value decomposition and model reduction.The software features a graphical user interface that aids simulationand plotting of in silico results. While the primary focus isto aid formulation, testing and reduction of theoretical biochemicalreaction networks, the program can also be used for analysisof high-throughput genomic and proteomic data. Availability: The software package, manual and examples areavailable at http://www.eng.buffalo.edu/~neel/ibrena Contact: neel{at}eng.buffalo.edu Associate Editor: Limsoon Wong     

GOTreePlus: an interactive gene ontology browser

Summary: We developed an interactive gene ontology (GO) browsernamed GOTreePlus that superimposes annotation information overGO structures. It can facilitate the identification of importantGO terms through interactive visualization of them in the GOstructure. The interactive pie chart summarizing an annotationdistribution for a selected GO term provides users with a succinctcontext-sensitive overview of their experimental results. Wetested our GOTreePlus using a proteome profiling dataset obtainedon differentiation of retinal pigment epithelial cells where399 proteins were quantified. Availability: http://bioinformatics.cnmcresearch.org/GOTreePlus/ Contact: jseo{at}cnmcresearch.org Associate Editor: John Quackenbush     

Model-based analysis of non-specific binding for background correction of high-density oligonucleotide microarrays

Motivation: High-density DNA microarrays provide us with usefultools for analyzing DNA and RNA comprehensively. However, thebackground signal caused by the non-specific binding (NSB) betweenprobe and target makes it difficult to obtain accurate measurements.To remove the background signal, there is a set of backgroundprobes on Affymetrix Exon arrays to represent the amount ofnon-specific signals, and an accurate estimation of non-specificsignals using these background probes is desirable for improvementof microarray analyses. Results: We developed a thermodynamic model of NSB on shortnucleotide microarrays in which the NSBs are modeled by duplexformation of probes and multiple hypothetical targets. We fittedthe observed signal intensities of the background probes withthose expected by the model to obtain the model parameters.As a result, we found that the presented model can improve theaccuracy of prediction of non-specific signals in comparisonwith previously proposed methods. This result will provide auseful method to correct for the background signal in oligonucleotidemicroarray analysis. Availability: The software is implemented in the R languageand can be downloaded from our website (http://www-shimizu.ist.osaka-u.ac.jp/shimizu_lab/MSNS/). Contact: furusawa{at}ist.osaka-u.ac.jp Supplementary information: Supplementary data are availableat Bioinformatics online. The authors wish it to be known that, in their opinion, thefirst two authors should be regarded as joint First Authors. Associate Editor: Trey Ideker     

GENOME: a rapid coalescent-based whole genome simulator

Summary: GENOME proposes a rapid coalescent-based approach tosimulate whole genome data. In addition to features of standardcoalescent simulators, the program allows for recombinationrates to vary along the genome and for flexible population histories.Within small regions, we have evaluated samples simulated byGENOME to verify that GENOME provides the expected LD patternsand frequency spectra. The program can be used to study thesampling properties of any statistic for a whole genome study. Availability: The program and C++ source code are availableonline at http://www.sph.umich.edu/csg/liang/genome/ Contact: lianglim{at}umich.edu Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Martin Bishop     

Thermodynamic Roles of Solubility in Taste Responses of Amino Acids

Bitter, sour and sweet responses of amino acids were relatedto their solubilities S_w, which are virtually equal to the reciprocalsof activity coefficients at infinite dilution in water _w, andalso related to their excess partial molar entropies of transferTS_t^E. Chem. Senses 21: 405–409, 1996. Present address: 5-32-12 Tamanawa, Kamakura-shi, 247 Japan