GOLD--graphical overview of linkage disequilibrium

SUMMARY: We describe a software package that provides a graphical summary of linkage disequilibrium in human genetic data. It allows for the analysis of family data and is well suited to the analysis of dense genetic maps. AVAILABILITY: http://www.well.ox.ac.uk/asthma/GOLD CONTACT: goncalo@well.ox.ac.uk     

Bounds on the minimum number of recombination events in a sample history

Recombination is an important evolutionary factor in many organisms, including humans, and understanding its effects is an important task facing geneticists. Detecting past recombination events is thus important; this article introduces statistics that give a lower bound on the number of recombination events in the history of a sample, on the basis of the patterns of variation in the sample DNA. Such lower bounds are appropriate, since many recombination events in the history are typically undetectable, so the true number of historical recombinations is unobtainable. The statistics can be calculated quickly by computer and improve upon the earlier bound of Hudson and Kaplan 1985. A method is developed to combine bounds on local regions in the data to produce more powerful improved bounds. The method is flexible to different models of recombination occurrence. The approach gives recombination event bounds between all pairs of sites, to help identify regions with more detectable recombinations, and these bounds can be viewed graphically. Under coalescent simulations, there is a substantial improvement over the earlier method (of up to a factor of 2) in the expected number of recombination events detected by one of the new minima, across a wide range of parameter values. The method is applied to data from a region within the lipoprotein lipase gene and the amount of detected recombination is substantially increased. Further, there is strong clustering of detected recombination events in an area near the center of the region. A program implementing these statistics, which was used for this article, is available from http://www.stats.ox.ac.uk/mathgen/programs.html.     

Sequence type analysis and recombinational tests (START).

The 32-bit Windows application START is implemented using Visual Basic and C(++) and performs analyses to aid in the investigation of bacterial population structure using multilocus sequence data. These analyses include data summary, lineage assignment, and tests for recombination and selection. AVAILABILITY: START is available at http://outbreak.ceid.ox.ac.uk/software.htm. CONTACT: keith.jolley@ceid.ox.ac.uk     

ABodyBuilder: Automated antibody structure prediction with data–driven accuracy estimation

Computational modeling of antibody structures plays a critical role in therapeutic antibody design. Several antibody modeling pipelines exist, but no freely available methods currently model nanobodies, provide estimates of expected model accuracy, or highlight potential issues with the antibody's experimental development. Here, we describe our automated antibody modeling pipeline, ABodyBuilder, designed to overcome these issues. The algorithm itself follows the standard 4 steps of template selection, orientation prediction, complementarity-determining region (CDR) loop modeling, and side chain prediction. ABodyBuilder then annotates the ‘confidence’ of the model as a probability that a component of the antibody (e.g., CDRL3 loop) will be modeled within a root–mean square deviation threshold. It also flags structural motifs on the model that are known to cause issues during in vitro development. ABodyBuilder was tested on 4 separate datasets, including the 11 antibodies from the Antibody Modeling Assessment–II competition. ABodyBuilder builds models that are of similar quality to other methodologies, with sub–Angstrom predictions for the ‘canonical’ CDR loops. Its ability to model nanobodies, and rapidly generate models (～30 seconds per model) widens its potential usage. ABodyBuilder can also help users in decision–making for the development of novel antibodies because it provides model confidence and potential sequence liabilities. ABodyBuilder is freely available at http://opig.stats.ox.ac.uk/webapps/abodybuilder.     

Inference of population structure using multilocus genotype data

We describe a model-based clustering method for using multilocus genotype data to infer population structure and assign individuals to populations. We assume a model in which there are K populations (where K may be unknown), each of which is characterized by a set of allele frequencies at each locus. Individuals in the sample are assigned (probabilistically) to populations, or jointly to two or more populations if their genotypes indicate that they are admixed. Our model does not assume a particular mutation process, and it can be applied to most of the commonly used genetic markers, provided that they are not closely linked. Applications of our method include demonstrating the presence of population structure, assigning individuals to populations, studying hybrid zones, and identifying migrants and admixed individuals. We show that the method can produce highly accurate assignments using modest numbers of loci-e.g. , seven microsatellite loci in an example using genotype data from an endangered bird species. The software used for this article is available from http://www.stats.ox.ac.uk/ approximately pritch/home. html.     

Building a Better Fragment Library for De Novo Protein Structure Prediction

Fragment-based approaches are the current standard for de novo protein structure prediction. These approaches rely on accurate and reliable fragment libraries to generate good structural models. In this work, we describe a novel method for structure fragment library generation and its application in fragment-based de novo protein structure prediction. The importance of correct testing procedures in assessing the quality of fragment libraries is demonstrated. In particular, the exclusion of homologs to the target from the libraries to correctly simulate a de novo protein structure prediction scenario, something which surprisingly is not always done. We demonstrate that fragments presenting different predominant predicted secondary structures should be treated differently during the fragment library generation step and that exhaustive and random search strategies should both be used. This information was used to develop a novel method, Flib. On a validation set of 41 structurally diverse proteins, Flib libraries presents both a higher precision and coverage than two of the state-of-the-art methods, NNMake and HHFrag. Flib also achieves better precision and coverage on the set of 275 protein domains used in the two previous experiments of the the Critical Assessment of Structure Prediction (CASP9 and CASP10). We compared Flib libraries against NNMake libraries in a structure prediction context. Of the 13 cases in which a correct answer was generated, Flib models were more accurate than NNMake models for 10. “Flib is available for download at: http://www.stats.ox.ac.uk/research/proteins/resources”.     

Efficient selective screening of haplotype tag SNPs

Haplotypes defined by common single nucleotide polymorphisms (SNPs) have important implications for mapping of disease genes and human traits. Often only a small subset of the SNPs is sufficient to capture the full haplotype information. Such subsets of markers are called haplotype tagging SNPs (htSNPs). Although htSNPs can be identified by eye, efficient computer algorithms and flexible interactive software tools are required for large datasets such as the human genome haplotype map. We describe a java-based program, SNPtagger, which screens for minimal sets of SNP markers to represent given haplotypes according to various user requirements. The program offers several options for inclusion/exclusion of specific markers and presents alternative panels for final selection. AVAILABILITY: The www-based program is available at http://www.well.ox.ac.uk/~xiayi/haplotype/index.html.     

Genomes OnLine Database (GOLD 1.0): a monitor of complete and ongoing genome projects world-wide.

SUMMARY: GOLD (Genomes On Line Database) is a World Wide Web resource for comprehensive access to information regarding complete and ongoing genome projects around the world. AVAILABILITY: GOLD is based at the University of Illinois at Urbana-Champaign and is available at http://geta.life.uiuc.edu/ approximately nikos/genomes. html. It is also mirrored at the European Bioinformatics Institute at http://www.ebi.ac.uk/research/cgg/genomes.html. CONTACT: genomes@ebi.ac.uk     

2LD, GENECOUNTING and HAP: Computer programs for linkage disequilibrium analysis

Computer programs are introduced which calculate pair-wise linkage disequilibrium statistics and conduct haplotype frequency estimation, including X chromosome data, and using a heuristic algorithm to handle multiple genetic markers and missing data. AVAILABILITY: Programs 2LD, GENECOUNTING and HAP are available on Internet from http://www.hgmp.mrc.ac.uk/~jzhao and http://www.iop.kcl.ac.uk/IoP/Departments/PsychMed/GEpiBSt/software.shtml     

EMBL-Align: a new public nucleotide and amino acid multiple sequence alignment database

The submission of multiple sequence alignment data to EMBL has grown 30-fold in the past 10 years, creating a problem of archiving them. The EBI has developed a new public database of multiple sequence alignments called EMBL-Align. It has a dedicated web-based submission tool, Webin-Align. Together they represent a comprehensive data management solution for alignment data. Webin-Align accepts all the common alignment formats and can display data in CLUSTALW format as well as a new standard EMBL-Align flat file format. The alignments are stored in the EMBL-Align database and can be queried from the EBI SRS (Sequence Retrieval System) server. AVAILABILITY: Webin-Align: http://www.ebi.ac.uk/embl/Submission/align_top.html, EMBL-Align: ftp://ftp.ebi.ac.uk/pub/databases/embl/align, http://srs.ebi.ac.uk/     

Straightforward and complete deposition of NMR data to the PDBe

We present a suite of software for the complete and easy deposition of NMR data to the PDB and BMRB. This suite uses the CCPN framework and introduces a freely downloadable, graphical desktop application called CcpNmr Entry Completion Interface (ECI) for the secure editing of experimental information and associated datasets through the lifetime of an NMR project. CCPN projects can be created within the CcpNmr Analysis software or by importing existing NMR data files using the CcpNmr FormatConverter. After further data entry and checking with the ECI, the project can then be rapidly deposited to the PDBe using AutoDep, or exported as a complete deposition NMR-STAR file. In full CCPN projects created with ECI, it is straightforward to select chemical shift lists, restraint data sets, structural ensembles and all relevant associated experimental collection details, which all are or will become mandatory when depositing to the PDB. Instructions and download information for the ECI are available from the PDBe web site at http://www.ebi.ac.uk/pdbe/nmr/deposition/eci.html.     

GenoSNP: a variational Bayes within-sample SNP genotyping algorithm that does not require a reference population

Current genotyping algorithms typically call genotypes by clustering allele-specific intensity data on a single nucleotide polymorphism (SNP) by SNP basis. This approach assumes the availability of a large number of control samples that have been sampled on the same array and platform. We have developed a SNP genotyping algorithm for the Illumina Infinium SNP genotyping assay that is entirely within-sample and does not require the need for a population of control samples nor parameters derived from such a population. Our algorithm exhibits high concordance with current methods and >99% call accuracy on HapMap samples. The ability to call genotypes using only within-sample information makes the method computationally light and practical for studies involving small sample sizes and provides a valuable independent quality control metric for other population-based approaches. AVAILABILITY: http://www.stats.ox.ac.uk/~giannoul/GenoSNP/.     

XEMBL: distributing EMBL data in XML format

Data in the EMBL Nucleotide Sequence Database is traditionally available in a flat file format that has a number of known shortcomings. With XML rapidly emerging as a standard data exchange format that can address some problems of flat file formats by defining data structure and syntax, there is now a demand to distribute EMBL data in an XML format. XEMBL is a service tool that employs CORBA servers to access EMBL data, and distributes the data in XML format via a number of mechanisms. AVAILABILITY: Use of the XEMBL service is free of charge at http://www.ebi.ac.uk/xembl/, and can be accessed via web forms, CGI, and a SOAP-enabled service. SUPPLEMENTARY INFORMATION: Information on the EMBL Nucleotide Sequence Database is available at http://www.ebi.ac.uk/embl/. The EMBL Object Model is available at http://corba.ebi.ac.uk/models/. Information on the EMBL CORBA servers is at http://corba.ebi.ac.uk/     

Statistical adjustment of signal censoring in gene expression experiments

MOTIVATION: Numerical output of spotted microarrays displays censoring of pixel intensities at some software dependent threshold. This reduces the quality of gene expression data, because it seriously violates the linearity of expression with respect to signal intensity. Statistical methods based on typically available spot summaries together with some parametric assumptions can suggest ways to correct for this defect. RESULTS: A maximum likelihood approach is suggested together with a sensible approximation to the joint density of the mean, median and variance-which are typically available to the biological end-user. The method 'corrects' the gene expression values for pixel censoring. A by-product of our approach is a comparison between several two-parameter models for pixel intensity values. It suggests that pixels separated by one or two other pixels can be considered independent draws from a Lognormal or a Gamma distribution. AVAILABILITY: The R/S-Plus code is available at http://www.stats.gla.ac.uk/~microarray/software.     

PartiGene--constructing partial genomes

Expressed sequence tags (ESTs) offer a low-cost approach to gene discovery and are being used by an increasing number of laboratories to obtain sequence information for a wide variety of organisms. The challenge lies in processing and organizing this data within a genomic context to facilitate large scale analyses. Here we present PartiGene, an integrated sequence analysis suite that uses freely available public domain software to (1) process raw trace chromatograms into sequence objects suitable for submission to dbEST; (2) place these sequences within a genomic context; (3) perform customizable first-pass annotation of the data; and (4) present the data as HTML tables and an SQL database resource. PartiGene has been used to create a number of non-model organism database resources including NEMBASE (http://www.nematodes.org) and LumbriBase (http://www.earthworms.org/). The packages are readily portable, freely available and can be run on simple Linux-based workstations. AVAILABILITY: PartiGene is available from http://www.nematodes.org/PartiGene and also forms part of the EST analysis software, associated with the Natural Environmental Research Council (UK) Bio-Linux project (http://envgen.nox.ac.uk/biolinux.html).     

Genotype transposer: automated genotype manipulation for linkage disequilibrium analysis

SUMMARY: The purpose of this work is to provide the modern molecular geneticist with tools to perform more efficient and more accurate analysis of the genotype data they produce. By using Microsoft Excel macros written in Visual Basic, we can translate genotype data into a form readable by the versatile software 'Arlequin', read the Arlequin output, calculate statistics of linkage disequilibrium, and put the results in a format for viewing with the software 'GOLD'. AVAILABILITY: The software is available by FTP at: ftp://xcsg.iarc.fr/cox/Genotype_Transposer/. SUPPLEMENTARY INFORMATION: Detailed instruction and examples are available at: ftp://xcsg.iarc.fr/cox/Genotype&_Transposer/. Arlequin is available at: http://lgb.unige.ch/arlequin/. GOLD is available at: http://www.well.ox.ac.uk/asthma/GOLD/.     

Drawing phylogenetic trees in LATEX and Microsoft Word

SUMMARY: newicktree is a PSTricks-based LATEX package which enables phylogenetic trees described in the Newick format to be drawn directly into LATEX documents. mswordtree is a macro for producing phylogenetic trees using the drawing elements available in Microsoft Word. AVAILABILITY: Both programs are available free from the John Innes Centre's Bioinformatics Research Group website at http://jic-bioinfo.bbsrc.ac.uk/bioinformatics-research/software/index.html. SUPPLEMENTARY INFORMATION: A full user-guide for newicktree and installation and usage instructions for mswordtree and available at http://jic-bioinfo.bbsrc.ac.uk/bioinformatics-research/software/index.html     

InterProScan--an integration platform for the signature-recognition methods in InterPro

InterProScan is a tool that scans given protein sequences against the protein signatures of the InterPro member databases, currently--PROSITE, PRINTS, Pfam, ProDom and SMART. The number of signature databases and their associated scanning tools as well as the further refinement procedures make the problem complex. InterProScan is designed to be a scalable and extensible system with a robust internal architecture. AVAILABILITY: The Perl-based InterProScan implementation is available from the EBI ftp server (ftp://ftp.ebi.ac.uk/pub/software/unix/iprscan/) and the SRS-basedInterProScan is available upon request. We provide the public web interface (http://www.ebi.ac.uk/interpro/scan.html) as well as email submission server (interproscan@ebi.ac.uk).     

LVB: parsimony and simulated annealing in the search for phylogenetic trees

The program LVB seeks parsimonious phylogenies from nucleotide alignments, using the simulated annealing heuristic. LVB runs fast and gives high quality results. AVAILABILITY: The software is available at http://www.rubic.reading.ac.uk/lvb/ Supplementary information: Supplementary information may be downloaded from http://www.rubic.reading.ac.uk/~daniel/     

The Bioinformatics Template Library--generic components for biocomputing

MOTIVATION: The efficiency of bioinformatics programmers can be greatly increased through the provision of ready-made software components that can be rapidly combined, with additional bespoke components where necessary, to create finished programs. The new standard for C++ includes an efficient and easy to use library of generic algorithms and data-structures, designed to facilitate low-level component programming. The extension of this library to include functionality that is specifically useful in compute-intensive tasks in bioinformatics and molecular modelling could provide an effective standard for the design of reusable software components within the biocomputing community. RESULTS: A novel application of generic programming techniques in the form of a library of C++ components called the Bioinformatics Template Library (BTL) is presented. This library will facilitate the rapid development of efficient programs by providing efficient code for many algorithms and data-structures that are commonly used in biocomputing, in a generic form that allows them to be flexibly combined with application specific object-oriented class libraries. AVAILABILITY: The BTL is available free of charge from our web site http://www.cryst.bbk.ac.uk/~classlib/ and the EMBL file server http://www.embl-ebi.ac.uk/FTP/index.html