PedMine--a simulated annealing algorithm to identify maximally unrelated individuals in population isolates

Summary: In family-based genetic studies, it is often usefulto identify a subset of unrelated individuals. When such studiesare conducted in population isolates, however, most if not allindividuals are often detectably related to each other. To identifya set of maximally unrelated (or equivalently, minimally related)individuals, we have implemented simulated annealing, a general-purposealgorithm for solving difficult combinatorial optimization problems.We illustrate our method on data from a genetic study in theOld Order Amish of Lancaster County, Pennsylvania, a populationisolate derived from a modest number of founders. Given oneor more pedigrees, our program automatically and rapidly extractsa fixed number of maximally unrelated individuals. Availability: http://www.hg.med.umich.edu/labs/douglaslab/software.html(version 1.0.0) Contact: jddoug{at}umich.edu Associate Editor: Martin Bishop     

GenomeVx: simple web-based creation of editable circular chromosome maps

We describe GenomeVx, a web-based tool for making editable,publication-quality, maps of mitochondrial and chloroplast genomesand of large plasmids. These maps show the location of genesand chromosomal features as well as a position scale. The programtakes as input either raw feature positions or GenBank records.In the latter case, features are automatically extracted andcolored, an example of which is given. Output is in the AdobePortable Document Format (PDF) and can be edited by programssuch as Adobe Illustrator. Availability: GenomeVx is available at http://wolfe.gen.tcd.ie/GenomeVx Contact: conantg{at}tcd.ie Associate Editor: Martin Bishop     

A multivariate test of association

Summary: Although genetic association studies often test multiple,related phenotypes, few formal multivariate tests of associationare available. We describe a test of association that can beefficiently applied to large population-based designs. Availability: A C++ implementation can be obtained from theauthors. Contact: manuel.ferreira{at}qimr.edu.au Supplementary information: Supplementary figures are availableat Bioinformatics online. Associate Editor: Alex Bateman     

PQuad--a visual analysis platform for proteomic data exploration of microbial organisms

Summary: The visual Platform for Proteomics Peptide and Proteindata exploration (PQuad) is a multi-resolution environment thatvisually integrates genomic and proteomic data for prokaryoticsystems, overlays categorical annotation and compares differentialexpression experiments. PQuad requires Java 1.5 and has beentested to run across different operating systems. Availability: http://ncrr.pnl.gov/software Contact: bobbie-jo.webb-robertson{at}pnl.gov Associate Editor: Thomas Lengauer     

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     

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     

Tree-guided Bayesian inference of population structures

Motivation: Inferring population structures using genetic datasampled from a group of individuals is a challenging task. Manymethods either consider a fixed population number or ignorethe correlation between populations. As a result, they can losesensitivity and specificity in detecting subtle stratifications.In addition, when a large number of genetic markers are used,many existing algorithms perform rather inefficiently. Result: We propose a new Bayesian method to infer populationstructures using multiple unlinked single nucleotide polymorphisms(SNPs). Our approach explicitly considers the population correlationthrough a tree hierarchy, and treat the population number asa random variable. Using both simulated and real datasets ofworldwide samples, we demonstrate that an incorporated treecan consistently improve the power in detecting subtle populationstratifications. A tree-based model often involves a large numberof unknown parameters, and the corresponding estimation procedurecan be highly inefficient. We further implement a partitionmethod to analytically integrate out all nuisance parametersin the tree. As a result, our method can analyze large SNP datasetswith significantly improved convergence rate. Availability: http://www.stat.psu.edu/~yuzhang/tips.tar Contact: yuzhang{at}stat.psu.edu Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Keith Crandall     

Slider--maximum use of probability information for alignment of short sequence reads and SNP detection

Motivation: A plethora of alignment tools have been createdthat are designed to best fit different types of alignment conditions.While some of these are made for aligning Illumina SequenceAnalyzer reads, none of these are fully utilizing its probability(prb) output. In this article, we will introduce a new alignmentapproach (Slider) that reduces the alignment problem space byutilizing each read base's probabilities given in the prb files. Results: Compared with other aligners, Slider has higher alignmentaccuracy and efficiency. In addition, given that Slider matchesbases with probabilities other than the most probable, it significantlyreduces the percentage of base mismatches. The result is thatits SNP predictions are more accurate than other SNP predictionapproaches used today that start from the most probable sequence,including those using base quality. Contact: nmalhis{at}bcgsc.ca Supplementary information and availability: http://www.bcgsc.ca/platform/bioinfo/software/slider Associate Editor: Dmitrij Frishman     

Model-based deconvolution of genome-wide DNA binding

Motivation: Chromatin immunoprecipitation followed by hybridizationto a genomic tiling microarray (ChIP-chip) is a routinely usedprotocol for localizing the genomic targets of DNA-binding proteins.The resolution to which binding sites in this assay can be identifiedis commonly considered to be limited by two factors: (1) theresolution at which the genomic targets are tiled in the microarrayand (2) the large and variable lengths of the immunoprecipitatedDNA fragments. Results: We have developed a generative model of binding sitesin ChIP-chip data and an approach, MeDiChI, for efficientlyand robustly learning that model from diverse data sets. Wehave evaluated MeDiChI's performance using simulated data, aswell as on several diverse ChIP-chip data sets collected onwidely different tiling array platforms for two different organisms(Saccharomyces cerevisiae and Halobacterium salinarium NRC-1).We find that MeDiChI accurately predicts binding locations toa resolution greater than that of the probe spacing, even foroverlapping peaks, and can increase the effective resolutionof tiling array data by a factor of 5x or better. Moreover,the method's performance on simulated data provides insightsinto effectively optimizing the experimental design for increasedbinding site localization accuracy and efficacy. Availability: MeDiChI is available as an open-source R package,including all data, from http://baliga.systemsbiology.net/medichi. Contact: dreiss{at}systemsbiology.org Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Martin Bishop     

BLISS 2.0: a web-based tool for predicting conserved regulatory modules in distantly-related orthologous sequences

Summary: BLISS 2.0 is a web-based application for identifyingconserved regulatory modules in distantly related orthologoussequences. Unlike existing approaches, it performs the cross-genomecomparison at the binding site level. Experimental results onsimulated and real world data indicate that BLISS 2.0 can identifyconserved regulatory modules from sequences with little overallsimilarity at the DNA sequence level. Availability: http://www.blisstool.org/ Contact: leizhou{at}ufl.edu Associate Editor: Olga Troyanskaya     

Genetic association analysis with FAMHAP: a major program update

Summary: FAMHAP is an established software for haplotype associationanalysis of nuclear families. We have released a major updatethat comprises various new features for case-control data. Furthermore,weprovide an additional program runFamhap that allows usersto start the same method repeatedly for varying sets of geneticmarkers. In addition, a platform-independent graphical userinterface (GUI) was developed to simplify the usage of bothFAMHAP and runFamhap. The runFamhap program greatly facilitatesthe application of FAMHAP to genome-wide association studies(GWAS) and supports flexible genome-wide haplotype analysis.As an example, we describe application to HapMap data. Availability: The software is available at http://famhap.meb.uni-bonn.de Contact: herold{at}imbie.meb.uni-bonn.de; becker{at}imbie.meb.uni-bonn.de Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Alex Bateman     

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     

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     

Using flowViz to visualize flow cytometry data

Summary: Automated analysis of flow cytometry (FCM) data isessential for it to become successful as a high throughput technology.We believe that the principles of Trellis graphics can be adaptedto provide useful visualizations that can aid such automation.In this article, we describe the R/Bioconductor package flowVizthat implements such visualizations. Availability: flowViz is available as an R package from theBioconductor project: http://bioconductor.org Contact: dsarkar{at}fhcrc.org Associate Editor: Olga Troyanskaya     

Combining multiple positive training sets to generate confidence scores for protein-protein interactions

Motivation: High-throughput experimental and computational methodsare generating a wealth of protein–protein interactiondata for a variety of organisms. However, data produced by currentstate-of-the-art methods include many false positives, whichcan hinder the analyses needed to derive biological insights.One way to address this problem is to assign confidence scoresthat reflect the reliability and biological significance ofeach interaction. Most previously described scoring methodsuse a set of likely true positives to train a model to scoreall interactions in a dataset. A single positive training set,however, may be biased and not representative of true interactionspace. Results: We demonstrate a method to score protein interactionsby utilizing multiple independent sets of training positivesto reduce the potential bias inherent in using a single trainingset. We used a set of benchmark yeast protein interactions toshow that our approach outperforms other scoring methods. Ourapproach can also score interactions across data types, whichmakes it more widely applicable than many previously proposedmethods. We applied the method to protein interaction data fromboth Drosophila melanogaster and Homo sapiens. Independent evaluationsshow that the resulting confidence scores accurately reflectthe biological significance of the interactions. Contact: rfinley{at}wayne.edu Supplementary information: Supplementary data are availableat Bioinformatics Online. Associate Editor: Burkhard Rost     

Celestial3D: a novel method for 3D visualization of familial data

Summary: Traditional two-dimensional (2D) software programsfor drawing pedigrees are limited when dealing with extendedpedigrees. In successive generations, the number of individualsgrows exponentially, leading to an unworkable amount of spacerequired in the horizontal direction for 2D displays. In addition,it is not always possible to place closely related individualsnear each other due to the lack of space in 2Ds. To addressthese issues we have developed three-dimensional (3D) pedigreedrawing techniques to enable clearer visualization of extendedpedigrees. Currently no other methods are available for displayingextended pedigrees in 3Ds. We have made freely available a softwaretool—‘Celestial3D’—that implements thesenovel techniques. Availability: Freely available to non-commercial users Contact: celestial3d{at}genepi.org.au Supplementary information: www.genepi.org.au/celestial3d Associate Editor: Martin Bishop ¹A more extensive list of software tools appears in the SupplementaryMaterial.     

TaxonGap: a visualization tool for intra- and inter-species variation among individual biomarkers

Summary: Selection of optimal biomarkers for the identificationof different operational taxonomic units (OTUs) may be a hardand tedious task, especially when phylogenetic trees for multiplegenes need to be compared. With TaxonGap we present a noveland easy-to-handle software tool that allows visual comparisonof the discriminative power of multiple biomarkers for a setof OTUs. The compact graphical output allows for easy comparisonand selection of individual biomarkers. Availability: Graphical User Interface; Executable JAVA archivefile, source code, supplementary information and sample filescan be downloaded from the website: http://www.kermit.ugent.be/taxongap Contact: Bram.Slabbinck{at}UGent.be Associate Editor: John Quackenbush