Open Access

Remodeling Cildb, a popular database for cilia and links for ciliopathies

  • Olivier Arnaiz1,
  • Jean Cohen1,
  • Anne-Marie Tassin1 and
  • France Koll1Email author
Cilia20143:9

https://doi.org/10.1186/2046-2530-3-9

Received: 29 September 2014

Accepted: 30 October 2014

Published: 17 November 2014

Abstract

Background

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.

Methods

Othology between recent versions of the whole proteomes was computed usingInparanoid and ciliary high throughput studies were remapped on these recentversions.

Results

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.

Conclusions

This already popular database is designed now for easier use and is up to date inregard to high throughput ciliary studies.

Background

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/) [1]. Cildb progressively became a reference cilium database, with anumber of users reaching now 700 per month. Since its creation and publication[1], 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. [1], 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 [2], and centrioles [3],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.

Methods

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 [4], and on the other side thedetection of each protein in a set of ciliary studies [1]. 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[5]. 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.
Figure 1

The species whose whole proteome has been included into Cildb V3.0 aregathered by taxonomy groups, with indication whether they are centric or notand of the number of high throughput studies, ciliary or not, performed inthe species. The choice of species to include into Cildb was 1) speciesin which high throughput ciliary studies have been performed, 2) speciesroutinely used as models in ciliary studies in general, and 3) centric andacentric species, because the presence/absence of certain proteins may berelevant for the conservation of ciliary proteins through evolution. The caseof the Bug22/GTL3/C16orf80 protein, composed of a domain called DUF667,essential for ciliary motility [6], wascarefully examined for the choice of fungi to add in Cildb for comparativegenomics. Bug22 is a protein highly conserved in all centric species, be theymetazoans, protozoa, plants or fungi and curiously also highly conserved in theacentric land plants, but absent from the genomes of higher fungi alreadysequenced at the time of the publication, i.e. acentric ascomycetes[6]. Owing to constant new genomesequencing, novel fungal whole proteomes appeared and the occurrence of Bug22was different from what was thought earlier. It is still undetectable inascomycetes, but is found conserved in the acentric Mortierellaverticillata (accession MVEG_01915), and a more divergent Bug22 withrecognizable DUF667 domain is found in several basidiomycetes represented inCildb by Laccaria bicolor (accession 598201). This property was one ofthe reasons to include those two fungi proteomes into Cildb V3.0. This alsoemphasizes that constant arrival of new knowledge as new genomes are sequencedcan put into questions former assumptions such as the absence of particularproteins in some species, here Bug22 in fungi.

Table 1

High throughput studies compiled in Cildb V3.0

Reference for the study

Method

Species

Ciliary analysis

Andersen et al., 2003 [3]

Centriole proteome

Homo sapiens

yes

Arnaiz et al., 2009 [1]

Cilium proteome

Paramecium tetraurelia

yes

Arnaiz et al., 2010 [7]

Expression during ciliogenesis

Paramecium tetraurelia

yes

Avidor-Reiss et al., 2004 [8]

Comparative genomics

Drosophila melanogaster

yes

Baker et al., 2008a [9]

Spermatozoa proteome

Mus musculus

no

Baker et al., 2008b [10]

Spermatozoa proteome

Rattus norvegicus

no

Bechstedt et al., 2010 [11]

Expression in tissues containing sensory cilia

Drosophila melanogaster

yes

Blacque et al., 2005 [12]

Differential expression between ciliated and non ciliated cells

Caenorhabditis elegans

yes

Blacque et al., 2005 [12]

Genomic screening for X-boxes in promoters

Caenorhabditis elegans

yes

Boesger et al., 2009 [13]

Flagellum phosphoproteome

Chlamydomonas reinhardtii

yes

Broadhead et al., 2006 [14]

Flagellum proteome

Trypanosoma brucei

yes

Cachero et al., 2011 [15]

Expression in early development of future neural cells

Drosophila melanogaster

no

Cao et al., 2006 [16]

Sperm flagellar axonemes proteome

Mus musculus

yes

Chen et al., 2006 [17]

Expression in daf-19 mutant

Caenorhabditis elegans

yes

Datta et al., 2011 [18]

Gene expression with HIPPI expression modulation

Homo sapiens

no

Dorus et al., 2006 [19]

Spermatozoa proteome

Drosophila melanogaster

no

Efimenko et al., 2005 [20]

Genomic screening for X-boxes in promoters

Caenorhabditis elegans

yes

Fritz-Laylin and Cande, 2010 [21]

Flagellum proteome

Naegleria gruberi

yes

Geremek et al., 2011 [22]

Expression in primary ciliary dyskinesia patients

Homo sapiens

yes

Geremek et al., 2014 [23]

Expression in primary ciliary dyskinesia patients

Homo sapiens

yes

Guo et al., 2010 [24]

Proteomics associated with spermiogenesis

Mus musculus

no

Hodges et al., 2011 [25]

Comparative genomics

Chlamydomonas reinhardtii

yes

Hoh et al., 2012 [26]

Expression in multiciliated cells from trachea

Mus musculus

yes

Huang et al., 2008 [27]

Proteomics associated with spermiogenesis

Mus musculus

no

Hughes et al., 2008 [28]

Proteome of Microtubule-Associated Proteins

Drosophila melanogaster

no

Ishikawa et al., 2012 [29]

Primary cilium proteome

Mus musculus

yes

Ivliev et al., 2012 [30]

Expression profile in different tissues

Homo sapiens

yes

Jakobsen et al., 2011 [31]

Centrosome proteomics

Homo sapiens

yes

Keller et al., 2005 [32]

Expression during ciliogenesis

Chlamydomonas reinhardtii

yes

Keller et al., 2005 [32]

Basal body proteome

Chlamydomonas reinhardtii

yes

Kilburn et al., 2007 [33]

Basal body proteome

Tetrahymena thermophila

yes

Kim et al., 2010 [34]

Ciliogenesis modulation

Homo sapiens

yes

Kubo et al., 2008 [35]

Expression in ciliated tissues

Homo sapiens

yes

Laurençon et al., 2007 [36]

Genomic screening for X-boxes in promoters

Drosophila melanogaster

yes

Lauwaet et al., 2011 [37]

Homology search for basal body proteins

Giardia lamblia

yes

Lauwaet et al., 2011 [37]

Basal body proteome

Giardia lamblia

yes

Li et al., 2004 [38]

Comparative genomics

Chlamydomonas reinhardtii

yes

Liu et al., 2007 [39]

Cilium proteome

Mus musculus

yes

Martínez-Heredia et al., 2006 [40]

Spermatozoa proteome

Homo sapiens

no

Mayer et al., 2008 [41]

Cilium proteome

Rattus norvegicus

yes

Mayer et al., 2009 [42]

Cilium proteome

Rattus norvegicus

yes

McClintock et al., 2008 [43]

Expression in ciliated tissues

Mus musculus

yes

Merchant et al., 2007 [44]

Comparative genomics

Chlamydomonas reinhardtii

yes

Müller et al., 2010 [45]

Centrosome proteome

Drosophila melanogaster

yes

Nakachi et al., 2011 [46]

Sperm tail proteome

Ciona intestinalis

yes

Nogales-Cadenas et al., 2009 [47]

Centrosome human curation

Homo sapiens

yes

Ostrowski et al., 2002 [2]

Cilium proteome

Homo sapiens

yes

Pazour et al., 2005 [5]

Expression during ciliogenesis

Chlamydomonas reinhardtii

yes

Pazour et al., 2005 [5]

Flagellum proteome

Chlamydomonas reinhardtii

yes

Phirke et al., 2011 [48]

Down and upregulated genes in daf-19 mutant

Caenorhabditis elegans

yes

Reinders et al., 2006 [49]

Nuclear-associated body proteome

Dictyostelium discoideum

no

Ross et al., 2007 [50]

Expression during ciliogenesis

Homo sapiens

yes

Sakamoto et al., 2008 [51]

Proteome of Microtubule-Associated Proteins

Rattus norvegicus

no

Sauer et al., 2005 [52]

Mitotic spindle proteome

Homo sapiens

no

Smith et al., 2005 [53]

Cilium proteome

Tetrahymena thermophila

yes

Stolc et al., 2005 [54]

Expression during ciliogenesis

Chlamydomonas reinhardtii

yes

Stubbs et al., 2008 [55]

Expression Under FoxJ1 silencing

Xenopus laevis

yes

Wigge et al., 1998 [56]

Spindle pole body proteome

Saccharomyces cerevisiae

no

Yano et al., 2013 [57]

Ciliary membrane proteome

Paramecium tetraurelia

yes

The high throughput studies present in Cildb V3.0 are summarized in thetable with indication in the second column whether it is a proteomic, geneexpression, or genomic study. The species in which the studies have beenperformed are specified in the third column. In the fourth column is thefact whether a given study is ciliary (concerns cilia, flagella, basalbodies, centrioles, centrosomes or spindle pole bodies) or not. The table isordered alphabetically by first author of publication of the studies presentin Cildb V3.0.

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 [1], 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 [58] (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.
Figure 2

An advanced search on Cildb V3.0 is started by clicking on the‘Search’ button on the top row on the right. Then, it isnecessary to choose the species in which the proteome has to be searched for.The filter window then appears to adjust the filters in the left panel (nofilter means that the full proteome will be retrieved). Similarly, the outputwindow allows displaying particular properties (attributes) in columns for eachfiltered protein. A summary on the right reminds the user of all the filtersand attributes currently used. This also allows direct modification of theorders of the columns in the output by moving the attributes up and down in thelist. The last operation of the process is to show the results. The results aregiven by pages of 20 items with a maximum of 1000 items. To see all results,they have to be downloaded as a file. At any time, if the result output seemsincomplete or inappropriate, the filters and attributes can be modified byusing the ‘Back’ button (edit results) to refine the search andshow the results again. The quick search allows a rapid search by keywords. Theresult can be processed the same way as the one described above, with thepossibility to add attributes by ‘Edit results’ and to download thefile. Note the direct access to BLAST, Human genome Gbrowse, Motif search, Helpand access to older Versions of Cildb on the top row buttons to the right.

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 [4].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.
Table 2

Evolutionary conservation of centrosomal proteins viewed through CildbV3.0

 

Protein ID

Synonyms

Mus

Rattus

Danio

Apis

Drosophila

Class

1

ENSP00000380378

PAFAH1B1,LIS1,LIS2,MDCR

yes

yes

yes

yes

yes

1 (yyyyy)

2

ENSP00000364691

CROCC,ROLT,ROLT,rootletin

yes

yes

yes

yes

yes

1 (yyyyy)

3

ENSP00000309591

PRKACA,PKACA,PKACa

yes

yes

yes

yes

yes

1 (yyyyy)

4

ENSP00000263710

CLASP1,MAST1

yes

yes

yes

yes

yes

1 (yyyyy)

5

ENSP00000263811

DYNC1I2,DNCI2,IC2

yes

yes

yes

yes

yes

1 (yyyyy)

6

ENSP00000216911

AURKA,AIK,ARK1,AURA,AURORA2

yes

yes

yes

yes

yes

1 (yyyyy)

7

ENSP00000364721

MAPRE1,EB1,EB1

yes

yes

yes

yes

yes

1 (yyyyy)

8

ENSP00000265563

PRKAR2A,PKR2,PRKAR2

yes

yes

yes

yes

yes

1 (yyyyy)

9

ENSP00000355966

NEK2,HsPK21,NEK2A,NLK1

yes

yes

yes

yes

yes

1 (yyyyy)

10

ENSP00000261965

TUBGCP3,GCP3,SPBC98

yes

yes

yes

yes

yes

1 (yyyyy)

11

ENSP00000252936

TUBGCP2,GCP2,Grip103,h103p

yes

yes

yes

yes

yes

1 (yyyyy)

12

ENSP00000251413

TUBG1,CDCBM4,GCP-1

yes

yes

yes

yes

yes

1 (yyyyy)

13

ENSP00000456648

TUBGCP4,76P,GCP-4,GCP4

yes

yes

yes

yes

yes

1 (yyyyy)

14

ENSP00000323302

POC1B,PIX1,TUWD12,WDR51B

yes

yes

yes

yes

yes

1 (yyyyy)

15

ENSP00000324464

CSNK1D,ASPS,CKIdelta,FASPS2,HCKID

yes

yes

yes

yes

yes

1 (yyyyy)

16

ENSP00000270861

PLK4,SAK,STK18,Sak

yes

yes

yes

yes

yes

1 (yyyyy)

17

ENSP00000356785

NME7,MN23H7,NDK7

yes

yes

yes

yes

yes

1 (yyyyy)

18

ENSP00000273130

DYNC1LI1,DNCLI1,LIC1

yes

yes

yes

yes

yes

1 (yyyyy)

19

ENSP00000359300

CETN2,CALT,CEN2

yes

yes

yes

yes

yes

1 (yyyyy)

20

ENSP00000287380

TBC1D31,Gm85,WDR67

yes

yes

yes

yes

yes

1 (yyyyy)

21

ENSP00000287482

SASS6,SAS-6,SAS6

yes

yes

yes

yes

yes

1 (yyyyy)

22

ENSP00000300093

PLK1,PLK,STPK13

yes

yes

yes

yes

yes

1 (yyyyy)

23

ENSP00000257287

CEP135,CEP4,MCPH8

yes

yes

yes

yes

yes

1 (yyyyy)

24

ENSP00000439376

DCTN2,DCTN50,DYNAMITIN,RBP50

yes

yes

yes

yes

yes

1 (yyyyy)

25

ENSP00000395302

CKAP5,ch-TOG,CHTOG,MSPS

yes

yes

yes

yes

yes

1 (yyyyy)

26

ENSP00000342510

CEP97,LRRIQ2

yes

yes

yes

yes

yes

1 (yyyyy)

27

ENSP00000348965

DYNC1H1,DHC1,DHC1a

yes

yes

yes

yes

yes

1 (yyyyy)

28

ENSP00000469720

CETN2,CALT,CEN2

yes

yes

yes

yes

yes

1 (yyyyy)

29

ENSP00000317156

CEP192,PPP1R62

yes

yes

yes

yes

no

2 (yyyyn)

30

ENSP00000270708

WRAP73,WDR8

yes

yes

yes

yes

no

2 (yyyyn)

31

ENSP00000248846

TUBGCP6,GCP-6,GCP6,MCCRP,MCPHCR

yes

yes

yes

yes

no

2 (yyyyn)

32

ENSP00000393583

AZI1,AZ1,Cep131,ZA1

yes

yes

yes

yes

no

2 (yyyyn)

33

ENSP00000283645

TUBGCP5,GCP5

yes

yes

yes

yes

no

2 (yyyyn)

34

ENSP00000303058

CEP120,CCDC100

yes

yes

yes

yes

no

2 (yyyyn)

35

ENSP00000313752

SSNA1,N14,NA-14

yes

yes

yes

yes

no

2 (yyyyn)

36

ENSP00000355812

FGFR1OP,FOP

yes

yes

yes

yes

no

2 (yyyyn)

37

ENSP00000343818

CDK5RAP2,C48,Cep215,MCPH3

yes

yes

yes

no

yes

3 (yyyny)

38

ENSP00000344314

OFD1,CXorf5,JBTS10,RP23

yes

yes

yes

no

no

4 (yyynn)

39

ENSP00000317144

PIBF1,C13orf24,CEP90

yes

yes

yes

no

no

4 (yyynn)

40

ENSP00000204726

GOLGA3,GCP170,MEA-2,golgin-160

yes

yes

yes

no

no

4 (yyynn)

41

ENSP00000206474

HAUS4,C14orf94

yes

yes

yes

no

no

4 (yyynn)

42

ENSP00000281129

CEP128,C14orf145,C14orf61,LEDP/132

yes

yes

yes

no

no

4 (yyynn)

43

ENSP00000262127

CEP76,C18orf9,HsT1705

yes

yes

yes

no

no

4 (yyynn)

44

ENSP00000370803

CCP110,Cep110,CP110

yes

yes

yes

no

no

4 (yyynn)

45

ENSP00000263284

CCDC61

yes

yes

yes

no

no

4 (yyynn)

46

ENSP00000223208

CEP41,JBTS15,TSGA14

yes

yes

yes

no

no

4 (yyynn)

47

ENSP00000303769

AKNA

yes

yes

yes

no

no

4 (yyynn)

48

ENSP00000302537

MDM1

yes

yes

yes

no

no

4 (yyynn)

49

ENSP00000264935

CEP72,FLJ10565

yes

yes

yes

no

no

4 (yyynn)

50

ENSP00000419231

CEP70,BITE

yes

yes

yes

no

no

4 (yyynn)

51

ENSP00000306105

CEP89,CCDC123

yes

yes

yes

no

no

4 (yyynn)

52

ENSP00000380661

CEP250,C-NAP1,CEP2,CNAP1

yes

yes

yes

no

no

4 (yyynn)

53

ENSP00000356579

CEP350,CAP350,GM133

yes

yes

yes

no

no

4 (yyynn)

54

ENSP00000260372

HAUS2,C15orf25,CEP27,HsT17025

yes

yes

yes

no

no

4 (yyynn)

55

ENSP00000360540

CEP55,C10orf3,CT111,URCC6

yes

yes

yes

no

no

4 (yyynn)

56

ENSP00000355500

CEP170,FAM68A,KAB

yes

yes

yes

no

no

4 (yyynn)

57

ENSP00000369871

HAUS6,Dgt6,FAM29A

yes

yes

yes

no

no

4 (yyynn)

58

ENSP00000371308

CENPJ,BM032,CENP-J,CPAP,LAP,LIP1,MCPH6,Sas-4

yes

yes

yes

no

no

4 (yyynn)

59

ENSP00000282058

HAUS1,CCDC5,HEI-C,HEIC

yes

yes

yes

no

no

4 (yyynn)

60

ENSP00000283122

CETN3,CDC31,CEN3

yes

yes

yes

no

no

4 (yyynn)

61

ENSP00000352572

PCNT,KEN,MOPD2,PCN,PCNT2,PCNTB

yes

yes

yes

no

no

4 (yyynn)

62

ENSP00000295872

SPICE1,CCDC52,SPICE

yes

yes

yes

no

no

4 (yyynn)

63

ENSP00000317902

CEP57,MVA2,PIG8,TSP57

yes

yes

yes

no

no

4 (yyynn)

64

ENSP00000426129

CEP63

yes

yes

yes

no

no

4 (yyynn)

65

ENSP00000308021

CEP290,BBS14,JBTS5,LCA10,MKS4,NPHP6,POC3,rd16,SLSN6

yes

yes

yes

no

no

4 (yyynn)

66

ENSP00000439056

HAUS5,dgt5

yes

yes

yes

no

no

4 (yyynn)

67

ENSP00000462740

CEP41,JBTS15,TSGA14

yes

yes

yes

no

no

4 (yyynn)

68

ENSP00000265717

PRKAR2B,PRKAR2,RII-BETA

yes

yes

no

yes

yes

5 (yynyy)

69

ENSP00000345892

NDE1,HOM-TES-87,LIS4,NDE,NUDE

yes

yes

no

yes

yes

5 (yynyy)

70

ENSP00000358921

ACTR1A,ARP1,CTRN1

yes

yes

no

yes

yes

5 (yynyy)

71

ENSP00000447907

DYNLL1,DLC1,DLC8,DNCL1,DNCLC1,hdlc1,LC8

yes

yes

no

no

no

6 (yynnn)

72

ENSP00000278935

CEP164,NPHP15

yes

yes

no

no

no

6 (yynnn)

73

ENSP00000264448

ALMS1,ALSS

yes

yes

no

no

no

6 (yynnn)

74

ENSP00000316681

KIAA1731

yes

yes

no

no

no

6 (yynnn)

75

ENSP00000456335

CNTROB,LIP8,PP1221

yes

yes

no

no

no

6 (yynnn)

76

ENSP00000348573

AKAP9,AKAP350,AKAP450,CG-NAP,HYPERION,LQT11

yes

no

no

no

no

7 (ynnnn)

77

ENSP00000384844

DCTN1,DAP-150,P135

no

no

yes

yes

yes

8 (nnyyy)

This table presents the list of 77 human proteins obtained from a BioMartsearch described in the text. The output gives a total of 133 proteinsencoded by 77 genes, due to the presence of splice variants. For clarity,only one protein ID per gene has been presented in the table, afterverification that all the splice variants of each gene displays the sameorthology relationships with the species presented here. This tableillustrates evolutionary conservation where a “yes” indicatesthat the human protein has an Inparalog in Cildb and a “no” thatno Inparanoid orthology was found. The column ‘class’ serves toorder the output genes in the table (from 5× ‘yes’ at thetop to much fewer ‘yes’ at the bottom, along criteria of certainspecies being closer to each other than others, whereby the order from leftto right goes human-mouse-rat (mammals), then fish (vertebrate), then beeand fly (insects). All instances of lacking orthology (“no”)were individually verified by BLAST searches using the Cildb BLAST. TheBLAST results were consistent with the absence of orthologs in the species,and only three exceptions contradict the Inparanoid results, highlighted asbold characters in the table.

1- Human Azi1 (ENSP00000393583) has no inparalog in Drosophilaalthough an ortholog called dilatory exists. BLAST search on theDrosophila genome indeed light up dilatory, with ascore very close to the one found for the Apis inparalogs by BLAST.The difference between these different outputs may result from the value ofdefault thresholds taken by the Inparanoid program and the different lengthsof the proteins.

2- Human cdk5rap2 (ENSP00000343818) has no Inparalog in Apis,although homologs are found by BLAST. Inparanoid relationships of the topthree Apis proteins in the list (XP_006563202.1, XP_006563201.1,XP_392107.3) appear to be Inparalogs of Drosophila centrosomin(cnn, cdk5rap2) for which 8 of 12 splice variant proteins display humanInparalogs. However, no direct Inparanoid relationships exist between theApis proteins and any human protein.

3- Human dynactin/dctn1 (ENSP00000384844) has surprisingly no Inparalogs inmouse and rat whereas some are found in fish, bee and fly. However, mouseand rat homologs are easily found by BLAST search. After carefulexamination, it appears that the only ENSP00000384844 dynactin protein foundcommon to the three human centrosomal studies, is one of the splice variantsexcluded from Inparalog groups. Indeed, the 16 splice variants for the humandynactin gene ENSG00000204843 and the seven splice variants for itsmouse counterpart ENSMUSG00000031865 are related by Inparanoidorthology through three groups, hsap_mmus.17187 (one human and onemouse gene), hsap_mmus.1073 (four human and one mouse gene) andhsap_mmus.977 (one human and two mouse genes). The remaining tenhuman protein variants (among which is ENSP00000384844) and three mouseprotein variants encoded by these genes are not included in the orthologygroups, probably because their exon composition was too different from theother protein variants.

These three examples represent the limits of Inparanoid orthologyprediction, highlighting the fact that reciprocal BLAST searches cannot beavoided, and thus represent an important complementary approach, for theanalysis of individual proteins.

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 ‘Hsapiens’ and select ‘yes’ for the centrosomal studies [3, 31] and [47]

  • 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.

Conclusion

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.

Declarations

Acknowledgements

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”.

Authors’ Affiliations

(1)
Centre de Génétique Moléculaire, CNRS

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