Published online 15 December 2014 Nucleic Acids Research, 2015, Vol. 43, Database issue D707–D713doi: 10.1093/nar/gku1117

VectorBase: an updated bioinformatics resource forinvertebrate vectors and other organisms related withhuman diseasesGloria I. Giraldo-Calderon1,†, Scott J. Emrich2,3,†,*, Robert M. MacCallum4, Gareth Maslen5,Emmanuel Dialynas6, Pantelis Topalis6, Nicholas Ho4, Sandra Gesing7, theVectorBase Consortium, Gregory Madey2,3, Frank H. Collins1,3 and Daniel Lawson5,*

1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA, 2Department ofComputer Science and Engineering, University of Notre Dame, Notre Dame, IN 46556, USA, 3ECK Institute for GlobalHealth, University of Notre Dame, Notre Dame, IN 46556, USA, 4Department of Life Sciences, Imperial CollegeLondon, South Kensington Campus, London SW7 2AZ, UK, 5European Molecular Biology Laboratory, EuropeanBioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK, 6Instituteof Molecular Biology and Biotechnology (IMBB), FORTH, Vassilika Vouton,Nikolaou Plastira 100, 70013 Heraklion,Crete, Greece and 7Center for Research Computing, University of Notre Dame, Notre Dame, IN 46556, USA

Received September 23, 2014; Accepted October 16, 2014

ABSTRACT

VectorBase is a National Institute of Allergy andInfectious Diseases supported Bioinformatics Re-source Center (BRC) for invertebrate vectors of hu-man pathogens. Now in its 11th year, VectorBasecurrently hosts the genomes of 35 organisms includ-ing a number of non-vectors for comparative anal-ysis. Hosted data range from genome assemblieswith annotated gene features, transcript and pro-tein expression data to population genetics includ-ing variation and insecticide-resistance phenotypes.Here we describe improvements to our resource andthe set of tools available for interrogating and ac-cessing BRC data including the integration of WebApollo to facilitate community annotation and provid-ing Galaxy to support user-based workflows. Vector-Base also actively supports our community throughhands-on workshops and online tutorials. All infor-mation and data are freely available from our websiteat https://www.vectorbase.org/.

INTRODUCTION

VectorBase is a National Institute of Allergy and InfectiousDiseases (NIAID) and National Institutes of Health (NIH)funded Bioinformatics Resource Center (BRC) (1). Ourmission is to support the invertebrate vector research com-munity by providing access to genome assemblies, genome

annotations and high-throughput genomics data. For ex-ample, VectorBase is often involved in the first-pass annota-tion of de novo genome assemblies and subsequent captureof community annotations. More recently, genome varia-tion, gene expression and proteomics were integrated withrespect to reference genomes, as well as non-genic datasuch as field-associated samples from surveillance studies,insecticide-resistance phenotypes and pathogen transmis-sion data. Controlled vocabularies and ontologies are usedto organize and annotate experimental and sample-relatedmetadata where appropriate.

VectorBase now hosts the genomes from 35 organisms:22 mosquitoes (Aedes aegypti, Culex quinquefasciatus and20 Anopheles spp. including major, minor and non-vectors),tick (Ixodes scapularis), body louse (Pediculus humanus),kissing bug (Rhodnius prolixus), 5 tsetse flies (Glossina spp.),house fly (Musca domestica), 2 sandflies (Lutzomyia longi-palpis and Phlebotomus papatasi) and the intermediate snailhost of Schistosoma mansoni, Biomphalaria glabrata. Inthe future, we anticipate hosting other important vectorgenome clusters such as the blackflies (Simulium spp). Cur-rent details about genomes hosted by the BRC can be foundat https://www.vectorbase.org/genomes.

After the 2002 sequencing of the Anopheles gambiaegenome, NIAID/NIH requested development of a BRCthat would host data on that Anopheles genome and allnewly sequenced genomes of invertebrate vectors that trans-mit human pathogens. The VectorBase BRC was proposedin response to that request and was first funded in June 2004

*To whom correspondence should be addressed. Tel: +1 574 631 0353; Fax: +1 574 631 3996; Email: semrich@nd.eduCorrespondence may also be addressed to Daniel Lawson. Tel: +44 1223 494 627; Fax: +44 223 494 468; Email: lawson@ebi.ac.uk†The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

C© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), whichpermits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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under a broader initiative entitled ‘BRCs for Biodefenseand Emerging/Re-emerging Infectious Diseases’. That ini-tiative had special focus on organisms in the NIAID Cat-egory A–C priority pathogens, i.e. those causing emergingand re-emerging diseases, and for VectorBase, the vectorstransmitting such diseases. All VectorBase source code ismade publically available and can be obtained either fromonline repositories or by contacting the BRC. With Vector-Base now entering its second decade, usage by the scientificcommunity has grown significantly (per Google Analytics)and its user community (per Google Scholar) has cited oracknowledged VectorBase in over 1230 publications.

NEW FEATURES

Website

As the project has expanded, the site’s navigation focus hasshifted to data types rather than a small set of referencegenomes. Hence, the BRC now contains prominent linksto genomes, transcriptomes, proteomes, mitochondrial se-quences and population biology data. Other aspects of thesite have been re-organized to improve navigation. For ex-ample, organism pages are now dynamically generated de-pending on the available data and tools for each organ-ism. Many of these changes were achieved by adopting thepopular Drupal content management system, which facili-tates the rapid inclusion of new features while maintaininginternal consistency of tables, summaries and pages. Dru-pal also provides users with personal accounts for enhanc-ing their use of the BRC, and past analyses like Basic Lo-cal Alignment Search Tool (BLAST) jobs can now be se-curely retrieved, along with user-specific tool parameteriza-tion. The site continues to use cookies to store data relatingto the genome browser such that users can configure evi-dence tracks that are on/off by default.

Accessing data: search

Accompanying the website’s shift to data types, Vector-Base reimplemented a data-centric search system poweredby Apache Solr (Lucene Solr, http://lucene.apache.org/solr/#intro). All VectorBase release data are now organized intodomains (e.g. Genome, Gene expression, PopBio) and sub-domains (e.g. Genes, Samples, Assays), which allows effi-cient filtering of diverse results via a new faceted searchfeature. Simple keyword searches are available from ev-ery page on the website (Figure 1), while more complexand/or large-scale queries to search and retrieve data canbe conducted using the BioMart system (2). The search sys-tem is under active development in two main areas. First,we are expanding the availability of ‘ontology enhanced’search from the currently available PopBio domain to alldomains. Ontology-enhanced search enables users to queryfor broad-scale concepts such as ‘insecticide’ and retrievesresults for items annotated with fine-scale-related con-cepts such as ‘permethrin’ and ‘DDT’ (dichlorodiphenyl-trichloroethane). This is achieved through the annotationsof items in our databases with ontology terms developedwithin and outside VectorBase. Second, advanced search,which facilitates complex field-based queries, is being fur-ther developed to facilitate specific-use cases obtained from

our Scientific User Group to improve overall effectivenessof search for our users.

Gene manual annotations and metadata

VectorBase generates gene sets for each organism based onaggregating both ab initio and evidence-based gene predic-tions using the MAKER system (3). Although gene pre-diction is influenced greatly by available transcript evidenceand tandemly arrayed gene clusters in the genome, our BRCis further affected by our diverse taxonomic breadth wheresome genomes have many informative comparators (e.g.mosquitoes) while others such as a tick or gastropod haverelatively little data available. To address these issues, Vec-torBase has adopted the Web Apollo tool (4) where userscan immediately view and modify annotations for inclusioninto subsequence releases of the canonical gene set. For thesubmission of gene metadata, PubMed citations, repeats orRNA-seq experiments, we provide a separate submission in-terface based on forms.

Galaxy

Galaxy is an open web-based science gateway that facili-tates access to a wide range of computational tools (5). It iswidely used for bioinformatics analysis with an extensive de-veloper and outreach support network, and the web-basedinterface allows providing common tools in a transparentand reproducible framework. As tools can be connected inan intuitive way in so-called workflows, users can also easilymanage their data, share analysis pipelines, and edit and re-run jobs/workflows without locally installing software. Vec-torBase has also made available the latest relevant canonicaldata in this Galaxy instance. Examples of workflow analy-ses include alignment of Next Generation Sequence (NGS)data sets, calculation of expression values, or predicting sin-gle nucleotide polymorphisms (SNPs). Registered users canstore their raw data, intermediate files and final analysis re-sults for download or direct sharing via the BRC, whichgreatly improves the ability to collaborate with colleaguesand VectorBase developers.

Expression map

The expression resource has grown over the years to con-tain a wide variety of quantitative expression data, particu-larly for the main mosquito vectors A. gambiae and A. ae-gypti. Gene expression report pages provide an overview ofa gene’s expression in many experiments, but the transcrip-tional regulatory context of that gene in relation to all oth-ers was lacking. The expression map (6) was developed tovisualize the clustering of all genes of an organism basedon their combined expression profiles from a large numberof experiments (excluding a few with excess missing data ornoise). The clustering is performed using a self-organizingmap algorithm using a grid of 25 × 20 clusters. The webinterface allows the user to explore and infer the functionof genes in a particular cluster or neighborhood, to findgenes with particular expression characteristics, and to givea functional overview of large gene families (7). It is inte-grated with BioMart for advanced data retrieval and furtherquery refinement.

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Figure 1. A search workflow to find VectorBase data. (A) The search box is located in the top right-hand side of all VectorBase pages. Keywords for thequeries can be typed in the box or the user can select to go to ‘Advanced Search’. (B) The word ‘pyrethroid’ could retrieve a results page like this one(Because VectorBase data is updated every 2 months, you may obtain different results). In the left-hand side is the ‘Filter Results’ box, the results can befiltered down when clicking on the domains, subdomains or species links. The filters can also be reset. In the center of the page are the results, linking tothe page where they are displayed. (C) Alternatively, advanced search can be used to start with a more specific query, making use of the different menusand boxes.

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Figure 2. A search workflow to find genes involved in metabolic pathways. (A) To find a gene of interest, either search or BLAST can be used. With search,the keywords can be the gene ID (e.g. AGAP004786), the gene name (e.g. pyruvate dehydrogenase) or the gene symbol (not available for this example).If using BLAST, click on the best transcript or protein hit and follow the ‘Browse Genome’ icon to the genome browser. (B) In the genome browsergene tab, there will be a link called ‘Pathways’. Click on this link to load the pathways table. Follow the link in the top hit, ‘aga00010’. (C) This is theglycolysis/gluconeogenesis cycle in the KEGG pathways. The notation and color coding of the pathways are described in the ‘Help’ link located in the topright-hand side.

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Ontology browser

We have developed a new lightweight ontology browserwith extended web browser compatibility (Chrome, Inter-net Explorer, Firefox, Opera and Safari). This is, to ourknowledge, the only web browser-based ontology browserthat is capable of efficiently handling very large ontolo-gies (e.g. Gazetteer ∼530 000 terms) with fast responsetimes. The root terms of the selected ontology are dis-played in a tree fashion and the user can expand or col-lapse branches/nodes. The ontology browser has a power-ful search capability for terms, including their synonyms, aswell as partial and misspelled ones. Moreover, in the caseof ontologies in which images are linked to terms (e.g. theanatomy ontologies in VectorBase), the browser is also ableto display those. The latest functionality added to the on-tology browser is the integration of VectorBase’s search en-gine. Upon clicking on a term on the ‘tree-output’ of theontology-browser, a search request is posted to the serverand the returned results are displayed in a panel next to theontology tree. These are the same results that would havebeen shown if one had directly searched VectorBase usingthe term’s name or its ID as a query.

NEW DATA

Population biology/insecticide resistance

As detailed in our previous update (8), a population bi-ology (PopBio) browser prototype was introduced in 2011in anticipation of receiving increased amounts of genome-scale data from field, population and insecticide-resistancestudies. The PopBio browser provides structured meta-data for samples, assays, genotypes and phenotypes andthe projects/publications to which they belong, supple-mented by more detailed genetic variation data displayedin the genome browser where appropriate. Advanced visu-alization and meta-analysis tools are still under develop-ment but the PopBio browser already provides basic sum-mary visualizations for nearly all projects, including plotsof numeric data, and for categorical data, histograms andzoomable/scrollable maps with automatically adjusting pie-charts are shown.

A major overhaul of the PopBio infrastructure was un-dertaken in 2012–13 and a few of the more user-visiblechanges are described here. URL robustness and data main-tainability were improved by the allocation of stable IDs forprojects, samples and assays. The submission procedure wasstreamlined to a single ISA-Tab (9) spreadsheet submission.When using Google Spreadsheets, the user has direct accessto an ontology term lookup tool called OntoMaton (10)and the ability to fill in data collaboratively with colleaguesor seek assistance from VectorBase curators. The PopBioand genome browsers are now integrated via mutual linksfor samples with high-throughput genotype assays.

As of the August 2014 release, the PopBio resourcecontains 57,312 samples from 99 projects, of which 81are insecticide-resistance studies imported from IRBase(8). A full list is available in the PopBio browser un-der the Tools menu, and only a few notable additionsare described here. To supplement the large multi-countryUCLA/UC Davis (University of California, Los Angeles

/ University of California, Davis) data set of A. gambiaespecies complex chromosomal inversion karyotypes thatwas present in the prototype, two similar data sets for Burk-ina Faso and Cameroon from other research groups havebeen added (11,12). This has expanded coverage of thisrapidly evolving malaria vector both spatially and tempo-rally. More recently, we developed a ‘meta project’ (PopBioproject VBP0000012) that stores 8496 samples collected inCameroon by three different research teams over a periodof four years. Several thousand field-isolate species identifi-cations used in the Malaria Atlas Project (13) covering fourcontinents are also now available in the BRC. A large-scaleinsecticide-resistance phenotyping and genotyping study(14) has also been incorporated (VBP0000004) with genomevariation browser integration. After October 2014, Pop-Bio will become the NIH NIAID-supported insecticide-resistance repository for the vector community and willbe open for new data submissions. Advanced search has aspecialized ontology-enhanced subdomain for insecticide-resistance data.

Genomic variation

We significantly expanded variation data sets for both newand previously described species since our last update. Vec-torBase currently contains genetic variation data for 11 dis-ease vector species (nine Anopheles, one Aedes and Ixodes),with most species having in the range of 1–10 million SNPand indel variants. The functional effects of DNA variantson transcripts are calculated for all species each release, andthe availability of the Ensembl Variation Effect Predictor(15) allows users to evaluate their own novel SNP and indelvariant effects and display the results in their genomic con-text within the browser. Where possible, variants are linkedback to their originating studies and phenotypes, and sup-port for basic population genetic data such as allele frequen-cies and linkage disequilibrium calculations is provided.

Linkage of genomic, phenotypic (e.g. insecticide resis-tance) and population genetic data is also being developedthrough the PopBio browser system that provides searchtools and geolocation displays of sample data, along withcross-linkage back to the underlying molecular variants.We also intend to integrate large-scale population samplingdata published by the community to provide a consolidatedresource for researchers to compare studies using the BRC.

Ontologies

VectorBase continues to develop and maintain ontologiesrelating to control of disease vectors (16). Specifically, wehost anatomy ontologies (TGMA -Taxonomist Guide ofMosquito Anatomy for mosquitoes and TADS – TickAnatomy Daniel Sonenshine- for ticks (17)) and an ontol-ogy of insecticide resistance (MIRO - Mosquito InsecticideResistance Ontology (18)). Our most recent additions are(i) a new ontology describing dengue fever (IDODEN – In-fectious Disease Ontology DENgue) (Mitraka et al., sub-mitted), (ii) and update of the malaria ontology (IDOMAL- Infectious Disease Ontology MALaria) (19,20) and (iii)an ontology describing the domain of microRNAs (MiR-NAO – MicroRNA Ontology). All VectorBase ontologies

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follow the rules established by the OBO (Open BiomedicalOntologies) Foundry (21), and can be browsed either at Vec-torBase (https://www.vectorbase.org/ontology-browser) orthe NCBO (National Center for Biomedical Ontology) Bio-portal (http://bioportal.bioontology.org).

Transcriptomes (RNA-seq) and gene expression data

Advances in the rapid generation of transcriptome data us-ing inexpensive NGS sequencing approaches (RNA-seq)have led to a proliferation of data available for inverte-brate vectors. VectorBase currently presents summaries thatare annotated using relevant ontologies for developmen-tal stages, anatomy and other aspects of the experimentaldesign (https://www.vectorbase.org/rna-seq-data-sets). Wealso align relevant data extracted from the Sequence ReadArchive using standard alignment workflows to presentcoverage plots (bigWig format) via the genome browser.Customization of these displays allows for aggregation ofrelated data into logical groups in the browser, i.e. timecourses or body atlas-style studies.

More recently, we have started to quantify transcript ex-pression values (FPKM) from these RNA-seq data basedon the canonical gene set as reference. The association ofmapped reads to transcripts is dynamic because of potentialgene structure updates. To update and maintain mappingsacross assembly or gene set updates, Galaxy workflows areused.

Previously, the Expression Browser housed only datafrom microarray experiments. We have since upgraded theExpression Browser to facilitate the analysis of both mi-croarray and RNA-seq experiments. These expression datacontinue to be managed through a third-party open sourcedata management system called BASE (22), with the up-grade to BASE version 3.3 adding the capability to han-dle RNA-seq data. This necessitated upgrading our JavaAPI (GESOL) layer that operates on top of the BASE APIand simplified its data model. Our webcode has also beenupdated to reflect the new data classes (e.g. referring to‘probes’ for microarray data and ‘reference transcripts’ forRNA-seq studies). As of the August 2014 release, users haveaccess to 65 microarray experiments for A. gambiae, A. ae-gypti, C. quinquefasciatus and Anopheles funestus, and oneRNA-seq experiment for A. aegypti (23) within the Expres-sion Browser. As before, there is a requirement for data tocome from replicated experiments in order to be compat-ible with our statistical treatment. The mix of microarrayand RNA-seq data has been carried downstream into theExpression Maps, BioMart, data file downloads and sitesearch.

Pathways

To aid in downstream analysis, pathway information fromthe Kyoto Encyclopedia of Genes and Genomes (KEGG)database was added for mosquitoes (A. gambiae, A. aegyptiand C. quinquefasciatus), tick (I. scapularis) and lice (P. hu-manus). As shown in Figure 2, these new data are accessiblefrom the VectorBase genome browser.

OUTREACH

VectorBase also assists the community with a helpdesk sys-tem at info@vectorbase.org or via our ‘Contact Us’ link(https://www.vectorbase.org/contact). Helpdesk inquiriescan be of any type, and we supplement our availability withonline documentation such as FAQs, a Glossary of rele-vant terms and data policies. Constantly updated Vector-Base tutorials provide training material for both novice andadvanced users, and include practice exercises and samplefiles. Tutorials are updated several times per year. Addi-tional outreach activities are posted on the main BRC page,and we hold ad hoc virtual workshops on request.

FUTURE DEVELOPMENTS

In this update we described improvements to the existingfeatures and integration of new data sets in terms of data in-tegration, through search and new tools such as Web Apolloand Galaxy, along with multiple enhancements to previ-ously reported VectorBase features. The most significantgoals for the next five years are to continue to integrate ref-erence genetic data with variation and insecticide-resistancephenotypes provided by our vector community. By becom-ing the NIAID-supported insecticide-resistance database,we expect to start helping our users connect genotypes tophenotypes with these and other surveillance data. UsingGalaxy as a resource facilitates common and transparentanalysis of these data, and VectorBase is currently develop-ing RNA-seq and variant discovery pipelines for our users.We anticipate a mature cross-BRC workspace environmentwill be also developed, allowing more direct connections be-tween the vector host and the pathogens they transmit.

ACKNOWLEDGEMENTS

We would like to acknowledge the many scientists that haveprovided data to VectorBase including gene manual an-notations, microarrays, SNPs, insecticide assays, RNAseqand proteomics data. We also want to give special thanksto the feedback provided by our scientific working group(https://www.vectorbase.org/swg), our user group (https://www.vectorbase.org/sug) and to all our users.As well as the authors listed above, the VectorBase Consor-tium is composed of:European Bioinformatics Institute, UK: Paul Kersey, JamesAllen, Mikkel Christensen, Daniel Hughes, Gautier Ko-scielny, Nick Langridge, Daniel Lawson, Ernesto LowyGallego, Gareth Maslen, Karine Megy, Derek Wilson. Har-vard University, USA: Bill Gelbart, Dave Emmert, SusanRusso, Pinglei Zhou. Imperial College London, UK: GeorgeChristophides, Andrew Brockman, Nicholas Ho, IoannisKirmitzoglou, Bob MacCallum, Timo Tiirikka. Institute ofMolecular Biology and Biotechnology (IMBB), Greece: Kit-sos Louis, Emmanuel Dialynas, Vicky Dritsou, Elvira Mi-traka, Pantelis Topalis. University of New Mexico, USA:Maggie Werner-Washburn, Phil Baker, Harriet Platero.University of Notre Dame, USA: Frank Collins, AntelmoAguilar, Steve Bogol, Dave Campbell, Rory Carmichael,David Cieslak, Greg Davis, Scott Emrich, Sandra Gesing,Gloria I. Giraldo-Calderon, Nathan Konopinski, Greg

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Madey, Jarek Nabrzyski, Caleb Reinking, Andrew Shee-han, Scott Szakonyi, Robert Wieck.

FUNDING

National Institutes of Health/National Institute for Al-lergy and Infectious Diseases [HHSN266200400039C,HHSN272200900039C]. Evimalar network of excellence[242095]; INFRAVEC from the FP7 program of the Eu-ropean Commission [228421]; Transmalariabloc from theFP7 program of the European Commission [HEALTH-F3–2008–223736]. Funding for open access charge: NationalInstitutes of Health/National Institute for Allergy and In-fectious Diseases [HHSN272201400029C].Conflict of interest statement. None declared.

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