- Open Access
Remodeling Cildb, a popular database for cilia and links for ciliopathies
Ciliavolume 3, Article number: 9 (2014)
New generation technologies in cell and molecular biology generate large amountsof data hard to exploit for individual proteins. This is particularly true forciliary and centrosomal research. Cildb is a multi–species knowledgebasegathering high throughput studies, which allows advanced searches to identifyproteins involved in centrosome, basal body or cilia biogenesis, composition andfunction. Combined to localization of genetic diseases on human chromosomes givenby OMIM links, candidate ciliopathy proteins can be compiled through Cildbsearches.
Othology between recent versions of the whole proteomes was computed usingInparanoid and ciliary high throughput studies were remapped on these recentversions.
Due to constant evolution of the ciliary and centrosomal field, Cildb has beenrecently upgraded twice, with new species whole proteomes and new ciliary studies,and the latter version displays a novel BioMart interface, much more intuitivethan the previous ones.
This already popular database is designed now for easier use and is up to date inregard to high throughput ciliary studies.
Whatever the field studied in biology, due to the prevalence of new generationtechnologies, retrieving relevant information from high throughput studies represents amost important challenge. In this view, five years ago, we developed Cildb, aknowledgebase that allowed data mining concerning cilia and ciliopathies(http://cildb.cgm.cnrs-gif.fr/) . Cildb progressively became a reference cilium database, with anumber of users reaching now 700 per month. Since its creation and publication, Cildb underwent several modificationsand improvements, yielding an evolution to Version 2.1 in 2010 and now to Version 3.0 in2014. Although data in Cildb are raw data treated automatically, so that false positivesand false negatives may occur, results are fully informative and make easier searches onciliary genes.
The purpose of this note is fourfold, reminding the reader of the main uses of thisdatabase already described in more detail by Arnaiz et al. , providing explanation of the updates, describing the newinterface and evaluating the orthology relationships as calculated in Cildb.
Cildb, a database for ciliary studies… and more
In the early 2000’s, high throughput studies started to appear concerningcilia, a re-emerging organelle at that time , and centrioles ,precursors of basal bodies of cilia in metazoans. Such studies generated largeamounts of data on cilia, basal body, centriole, and centrosome proteomes, ontranscriptome analyses realized under various conditions (ciliogenesis etc.), and oncomputation issued from comparative genomics between centric (i.e. withcilia/flagella or at least centrioles at some stage of their life cycle) and acentricorganisms. Developing a way to browse these data became essential, not only from thestatistician’s point of view, but also for experimental biologists who want toseek information on individual proteins from the bulk of the results.
The originality of Cildb was in its backbone that related on the one side a network oforthology between the whole proteomes, complete sets of protein sequences, of all thespecies taken pair-wise, calculated with the algorithm of Inparanoid version 4.1 withdefault parameters , and on the other side thedetection of each protein in a set of ciliary studies . Therefore, the database allows searches for possible ciliaryproperties on the whole proteome of one species, e.g. Homo sapiens, based onciliary properties established by studies conducted in another species, e.g. flagellumproteomics in Chlamydomonas. Inaddition, the whole human proteome has been linked to the OMIM database(http://www.ncbi.nlm.nih.gov/omim/) that gathers all known human geneticdisorders with the corresponding genes. This allows searches of proteins involved indiseases and to display the OMIM description as attribute in the output of a search.Conversely, searches in the whole proteome of any non-human species can tell if theresultant proteins are orthologous to human proteins linked to human diseases.
In addition to the ciliary properties of proteins, Cildb contains other information suchas synonyms, descriptions, molecular weight, isoelectric point, probability of presenceof a signal peptide, of transmembrane helices, as well as the FASTA sequence. This extrainformation can be searched for and displayed as properties using Cildb.
Cildb has been imagined and worked out to manipulate outputs of high throughput studies.All data coming from studies dedicated to the function of only a specific or of severalproteins are not included in Cildb so that some ciliary proteins may escape from Cildbsearches if they are not revealed by high throughput studies.
Results and discussion
What is new in Cildb V3.0?
Since the last version of Cildb, new high throughput ciliary studies have appearedand more model organisms have been used for ciliary studies. Thus, we remodeled Cildbto include the proteomes of altogether 44 species, among which are 41 eukaryotes and3 bacteria (http://cildb.cgm.cnrs-gif.fr/v3/cgi/genome_versions;Figure 1) and 66 studies, among which 55 directlyconcern cilia, and 11 other, related studies(http://cildb.cgm.cnrs-gif.fr/v3/cgi/ciliary_studies; Table 1). BLAST server and human GBrowse facilities are maintained inthe new version. In addition, a Motif Search tool has been implemented in order tosearch proteomes with a sequence motif using the patmatdb program from the EMBOSSpackage (http://bioweb2.pasteur.fr/docs/EMBOSS/patmatdb.html), based onthe format of pattern used in the PROSITE database(http://prosite.expasy.org/prosuser.html). For example, an amino acidmotif such as MKK[KP]K, in which either K or P can stand at the fourth position, canbe queried in the proteome of any species of Cildb.
Species implemented in Cildb V3.0
Cildb V3.0 contains now whole proteomes of 41 eukaryotes among which 32 arecentric species. Fifteen of these species were used for the 66 high throughputstudies of Cildb. The 17 other species are good models for ciliary experimentsalthough no high throughput study has been published as of yet. Nine eukaryoticacentric species which lack cilia and centrioles were also taken because theyrepresent ‘negative controls’ in comparative genomics experiments: twospecies for which two analyses on spindle pole proteomes are available and sevenspecies without high throughput relevant studies.
Since orthology relationships are a major tool in Cildb, we corrected aninconsistency in the proteome composition in various species. Indeed, speciespresent in Cildb are not homogeneous in their whole proteome, some of themincluding organelle proteomes (mitochondria, chloroplasts), others not. Organelleproteomes represent a minor part of all the proteins, but since some organellarproteins can be encoded either by nuclear genes or by the organelle, according tothe species, this may influence the orthology calculation in some cases. Thisissue has been fixed in Cildb V3.0. In addition, to study the origin of organellarproteins, we added the whole proteomes of three bacteria because they are closestto those of mitochondria (Rickettsia prowazekii) and chloroplasts(Synechocystis sp PCC6803, Chlamydia pneumoniae).
Since the original publication of Cildb , the whole proteomes of 26 novel eukaryotic species have beenintroduced into Cildb. A notable proportion of fungi, eight fungal wholeproteomes, are incorporated in Cildb mainly because fungi represent a phylum at ahinge position in the evolution of centric and acentric species.
Studies in Cildb V3.0
The 66 studies incorporated in Cildb V3.0 mainly consist in high throughputproteomics, differential expression, and comparative genomics studies. 53 of thesestudies approach ciliary and centriolar/basal body components, structure, functionor biogenesis. We also integrated 13 studies concerning related topics, such asmicrotubule-associated proteins, spindle proteins, spindle pole bodies,nuclear-associated bodies, whole sperm proteome, and others. Compared to CildbV1.0, 45 novel studies have been introduced in Cildb.
High throughput studies concerning cilia appear monthly in the literature, butcomputation in Cildb needs full recalculation of the database, so that it cannotbe updated each time. However, if the output of a study not present in Cildb hasto be compared to a study already present, this can be performed using the keywordbox in the general properties filter by querying a list of gene or protein IDsbordered by ‘%’, one per line. The limitation is that the query isslow, since this is not the main task designed for BioMart queries.
Simplified interface and structure for Cildb V3.0
For users trained with previous versions of Cildb, the most prominent change is thenew interface. Indeed, it takes advantage of the novel environment provided byBioMart Version 9  (Figure 2). In consequence, making an advanced search becomes much moreintuitive than earlier, even for non-trained users, who can easily enter thefunctionalities of the database.
The simplification of the interface is accompanied by a simplification of thestructure of the database. First of all, the orthology calculation has beenexclusively centered on Inparanoid .Formerly, users could choose between Inparanoid and Inparanoid plus ‘inhouse’ filtered blast hits. The most recent version of Inparanoid appearsefficient enough to prevent the output of too many false negatives that occurred withthe previous versions, so that the addition of ‘in house’ filtered blasthits was no more necessary, as detailed in the next section and in the legend ofTable 2. We also simplified the way to filter ciliary studiesand removed less useful other searches (operator ‘OR’, customizedsearches). However, the functions removed in the query menu compared to previousCildb versions can be applied by another process that consists of downloading data astables with relevant attributes and sorting these tables thereafter using aspreadsheet software.
The changes brought to Cildb may have unexpected impact and we would be grateful forany feedback by the users. In addition, since genome annotations evolve with time,proteins can be gained or lost in the deduced proteomes from a time to the next. Forall these reasons, we kept the former “data freeze” versions of Cildbavailable through the “Version” menu for comparisons when it isnecessary.
Evolutionary conservation viewed through Cildb, the example of centrosomalproteins
To evaluate the identification of orthologs by Inparanoid, called‘inparalogs’, we studied centrosomal proteins in more detail, since theyare conserved proteins already pretty well known. We wondered whether centrosomalproteins identified in three studies in Homo sapiens would reveal theorthologs, when they exist, in other species. We used the following protocol:
click the ‘Search’ button on the bar on the to right
select ‘Hsapiens’ as organism in the scroll-down menu
click ‘Next’ and open ‘Ciliary Evidences’ on the left menu
click ‘Next’ and display ortholog names, synonyms, etc. for any desired species listed in the left menu. You can select here as an output the stringency for the studies chosen in the queries, if you want to sort the output table thereafter.
click ‘Results’ to visualize the output
modification of the filters and output can be obtained by the back button ‘Edit Results’
when satisfied with the result, click ‘Download data’
We chose to emphasize the orthologs in Mus musculus, Rattusnorvegicus, Danio rerio, Apis mellifera and Drosophilamelanogaster in the output to follow the evolutionary conservation, as viewedwith Inparanoid. Among the 113 human proteins encoded by 77 genes found ascentrosomal by this filter, inparalogs were detected for 76 genes in mouse, 75 inrat, 68 genes in fish, 37 genes in bee and 33 genes in fly (Table 2). A vast majority of these proteins were identified in mammals, as wellas in fish, a vertebrate. More negative examples were found in the insects bee andfly. To check whether homologues were indeed absent when no Inparalogs were found, weperformed BLAST searches on individual species proteomes using the Cildb BLAST.Except for the two cases discussed in the legend of Table 2, all the absence of Inparalogs corresponds to no or weak BLAST hitdetection. In addition, none of the BLAST targets were found in the previous versionof Cildb as filtered best hits, a calculation method that we suppress in the presentversion. Altogether, although reciprocal BLAST searches are always useful to studythe occurrence of individual proteins in various species, the orthology calculationvia Inparanoid is pretty suitable for batch identification of conserved proteinsusing Cildb.
The version V3.0 of Cildb preserves its major original principles of relating orthologyto ciliary studies, but, by improving its structure and its interface, makes thedatabase more suitable for advanced searches. Altogether, Cildb V3.0 is a particularlyuseful tool for unraveling ciliary and ciliopathy networks and will hopefully help inidentification of new orphan diseases.
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Funding from the Centre National de la Recherche Scientifique (CNRS) and theFoetocilpath grant from the Agence Nationale de la Recherche (ANR), are gratefullyacknowledged. We are grateful to the INRA MIGALE bioinformatics platform(http://migale.jouy.inra.fr) for providing computational resources.This work was carried out in the context of the CNRS-supported European ResearchGroup “Paramecium Genome Dynamics and Evolution”.
The authors declare that they have no competing interests.
OA made bioinformatics calculations and developed, designed the database, JC and FKbrought the biological knowledge on ciliary high throughput studies and species relevantto be included in the database, AMT validated the present version of the databaseconcerning orthology of ciliary and centrosomal conserved proteins viewed by Inparanoid,JC, FK and AMT wrote the manuscript. All authors read and approved the finalmanuscript.