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Letter

Mouse Proteome Analysis

¹EMBL Outstation—European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK ²Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Toyonaka, Osaka 560-8531, Japan ³Institute for Molecular Bioscience and ARC Special Research Centre for Functional and Applied Genomics, University of Queensland, St. Lucia, Queensland 4072, Australia ⁴Genomic Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, USA ⁵Department of Structural Biology, Stanford University, Stanford, California 94305, USA ⁶Knowledge Discovery Team, Bioinformatics Group, RIKEN Genomic Sciences Center, Yokohama 230-0045, Japan ⁷Laboratory for Genome Exploration Research Group, RIKEN Genomic Sciences Center (GSC), RIKEN Yokohama Institute, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan ⁸NTT Software Corporation, Naka-ku, Yokohama, Kanagawa, 231-8554, Japan ⁹Genome Science Laboratory, RIKEN, Hirosawa, Wako, Saitama 351-0198, Japan

	ABSTRACT

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A general overview of the protein sequence set for the mouse transcriptome produced during the FANTOM2 sequencing project is presented here. We applied different algorithms to characterize protein sequences derived from a nonredundant representative protein set (RPS) and a variant protein set (VPS) of the mouse transcriptome. The functional characterization and assignment of Gene Ontology terms was done by analysis of the proteome using InterPro. The Superfamily database analyses gave a detailed structural classification according to SCOP and provide additional evidence for the functional characterization of the proteome data. The MDS database analysis revealed new domains which are not presented in existing protein domain databases. Thus the transcriptome gives us a unique source of data for the detection of new functional groups. The data obtained for the RPS and VPS sets facilitated the comparison of different patterns of protein expression. A comparison of other existing mouse and human protein sequence sets (e.g., the International Protein Index) demonstrates the common patterns in mammalian proteomes. The analysis of the membrane organization within the transcriptome of multiple eukaryotes provides valuable statistics about the distribution of secretory and transmembrane proteins

The following paper summarizes a general analysis of the mouse proteome sets deduced from the transcriptome DNA sequences based on various algorithms and approaches. We used protein domain databases, namely InterPro (Apweiler et al. 2001) and Superfamily (Gough and Chothia 2002), to carry out initial functional annotation of the protein sequences and to classify these sequences according to existing biological resources, such as Gene Ontology (GO). The general coverage of proteins in the representative proteins set is about 92% for both InterPro and Superfamily, and this provides a comprehensive overview of the proteome. InterPro analysis has also been used for comparison of the different proteomes produced; this analysis highlights interesting differences between various mouse sequencing projects. New domains which are not included in existing resources have been detected using algorithms implemented in the MDS database (Kawaji et al. 2002), and seven new domain candidates have been discovered. Determination of the membrane organization within the secretory pathway, namely whether a protein is secreted into the extracellular media, a membrane-spanning protein (transmembrane protein), or a nonsecretory protein, is essential for understanding its function. This information complements other computational annotation projects, as it provides the context by determining the membrane topography of predicted functional protein units and is essential for the prediction of subcellular localization, which depends on the class of protein.

	RESULTS AND DISCUSSION

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Two protein sets have been produced as a result of the FANTOM2 sequencing project. The representative proteins set (RPS) is derived from the representative set of transcriptional units. The variant-based proteins set (VPS) combines RPS and complete protein sequences representing splice variants not included in RPS. The VPS includes variant forms of known genes identified by sequencing of the FANTOM2 clones. We summarized the characterization of the sets in the main FANTOM2 paper (FANTOM Consortium 2002). We describe here the different characteristics of the variants and provide comparisons with other available sequence data for mouse and human.

InterPro Matches Statistics
The major goal of the domain/site/motif composition analysis was to obtain a general functional overview of the proteome and to use these results for initial functional assignments. We used InterPro as a standard tool to determine the domain/site/motif composition of different mouse protein sequence data sets. In addition to the RPS and VPS described earlier, we also analyzed a mouse sequence data set of hypothetical proteins computationally predicted by Celera and the nonredundant mouse protein set produced as part of the International Protein Index (IPI) (http://www.ebi.ac.uk/IPI). The human protein set provided by IPI was also analyzed.

The general number of proteins for both FANTOM2 proteome sets having matches for InterPro entries is about 72% (92% for combined InterPro and Superfamily databases). This amount is quite similar to other existing proteomes analyzed in the Proteome Analysis Database (http://www.ebi.ac.uk/proteome); about 60%–75% for complete proteomes in the database. This provides some evidence of the high quality of the FANTOM2 data. We also analyzed amino-acid frequency distribution for the mouse protein sequences (data not shown). The difference in the frequencies between the different mouse datasets is only about 0.3%, which is far less than the difference between various eukaryotic proteomes (about 3%).

Comparative Proteomics
The algorithms implemented in the Proteome Analysis Database also include several InterPro-based statistical analyses, including a list of the top 20 InterPro entries. Table 1 presents statistics for the described mouse proteome data and also includes human IPI statistics. The analyses suggest that the general domain/site/motif composition is similar for all four mouse proteome sets. The statistics of the InterPro entries can be used to infer some functional information about the proteome. The most commonly represented functional groups are nucleic acid binding proteins and proteins belonging to the immunoglobulin family. The other major group of InterPro entries includes serine/threonine and tyrosine protein kinase domains. The RPS and VPS proteome sets have similar statistics for InterPro entry composition, which describes the protein sets from the point of view of functional domains/sites/motifs. This can be considered evidence of the relative stability of the functional potential of the transcriptome, which maintains a constant ratio of proteins of different functions despite the presence of splice variants. The InterPro entry-matches distribution is very similar for the human and mouse proteomes at the level of the top entries and can, therefore, provide valuable information about conserved functional domains/sites/motifs across different mammalian species.

View this table: [in this window] [in a new window]   Table 1. Top 20 InterPro Entries for Different Mouse Protein Sequence Sets and Human Proteome

View larger version (71K): [in this window] [in a new window]   Figure 1 Comparative diagram of the GO Slim categories for different mouse and human proteomes. The y-axis indicates the number of proteins; the x-axis indicates the following GO categories: GO:0003676 nucleic_acid_binding; GO:0003754 chaperone; GO:0003774 motor; GO:0003793 defense/immunity_protein; GO:0003824 enzyme; GO:0004871 signal_transducer; GO:0005198 structural_molecule; GO:0005215 transporter; GO:0005488 binding; GO:0005554 molecular_function_unknown; GO:0015070 toxin; GO:0030234 enzyme_regulator; GO: 0030528 transcription_regulator.

View larger version (69K): [in this window] [in a new window]   Figure 2 Comparative diagram of the GO Slim categories for different eukaryotic proteomes. The y-axis shows the number of proteins; the x-axis shows GO categories (see Fig. 1).

The SUPERFAMILY analysis is used to detect and classify evolutionarily related groups of domains for which there is a known structural representative. All assigned domains are classified at the superfamily level. An accurate superfamily level of classification is obtained by a detailed hand analysis by an expert of structural, sequence, and functional evidence of a common evolutionary ancestor (Murzin et al. 1995). The superfamily classification used is that defined by the SCOP database.

Functional Annotation
These assignments provide information which has been used as part of the MATRICS, annotation of the FANTOM2 mouse cDNA sequences. Because proteins with the same structure usually have the same or a related function, the structural domain assignments are a useful component of the information used in the functional annotation. Furthermore, the SUPERFAMILY analysis provides assignments for many sequences where there is little or no other significant information. At least one domain was assigned to 59% of the sequences, and the domains cover 42% of all residues. This is close to the coverage of other eukaryote proteomes. The rest of the analysis shown in this section pertains to the subset of sequences and domains which were detected. The top 12 superfamilies are shown in Table 2. This is very similar to that which is observed in the human proteome based on gene predictions from the genomic sequence (Hubbard et al. 2002).

View this table: [in this window] [in a new window]   Table 2. The Top 12 Most Commonly Occurring Superfamily Domains

Evolutionary Overview
The evolutionary relationships can give us a meaningful overview of a large proportion of the genome. The ancestral domain from each superfamily represents a genetic building block. These building blocks have been duplicated, recombined, and mutated to create the proteins which are currently observed in the genome. The assigned domain architecture for each sequence (available at the URL at the beginning of this section) shows the recombination of ancestral domains which has taken place during evolution. It can be seen that a small number of domains have been duplicated a very large number of times (see Fig. 3), and that a large number of domains have been duplicated very few times (see Fig. 4). In fact, 98% of the identified domains have been produced by duplication from 716 ancestral domains. This is very close to the pattern observed in the human proteome.

View larger version (20K): [in this window] [in a new window]   Figure 3 Observed evolutionary domains. The ordered sizes of superfamilies with greater than 100 members.

View larger version (36K): [in this window] [in a new window]   Figure 4 Observed evolutionary domains. The distribution sizes of superfamilies with less than 100 members.

In addition, we performed, with the MDS motifs that were extracted from the FANTOM1 sequence set (Kawaji et al. 2002), Hidden Markov Model (HMM) searches against the FANTOM2 protein sequences and SWISS-PROT/TrEMBL nonredundant database (SWISS-PROT Release 40.27 of 30-Aug-2002, TrEMBL Release 21.12 of 13-Sep-2002, and TrEMBL_new of 13-Sep-2002). As a result, we obtained several new members with the FANTOM1 MDS motifs (see http://motif.ics.es.osaka-u.ac.jp/fantom2/). Proacrosin binding protein (E130112G13; AK053586 [GenBank] ) was detected as a new member of motif MDS001052 (the ING1-homolog subfamily motif)-containing proteins. The multiple alignment of the subfamily members (see http://motif.ics.es.osaka-u.ac.jp/fantom2/) shows that the clone is identical to a newly found splicing variant (mINGh-L, ING1-like protein long form; TrEMBL AAK63168 [GenBank] of the mouse ING1-homolog proteins (Ha et al. 2002).

Molecules interacting with CasL (MICALs; Suzuki et al. 2002; Terman et al. 2002) derived from human (TrEMBL Q8TDZ2), fruitfly (TrEMBL AAM55242 [GenBank] AAM55243 [GenBank] AAM55244 [GenBank] and MICAL-like protein, TrEMBL AAM55245 [GenBank] , and mouse (TrEMBL AAH34682 [GenBank] were detected as new members of the leucine zipper-like motif MDS00113containing proteins. Terman and coworkers (2002) showed that the fruitfly MICAL interacts with neuronal plexin A (PlexA) receptor in its C-terminal region including the MDS00113motif, confirming our previous prediction that this motif may act as a novel protein–protein interaction site.

Motif MDS00146 which previously comprised only hypothetical proteins, was expanded to the human Cdc42-activating protein zizimin1 (TrEMBL AAM90306 [GenBank] Meller et al. 2002). Zizimin1 contains a new domain named CDM (CED-5, DOCK180, MyoBlast city) zizimin homology domain 2 (CZH2) that mediates direct interaction with the Cdc42 Rho GTPase. Motif MDS00146is included within the CZH2 domain and appears to be a submotif of CZH2 that is specific for two of the four CZH2 domain-containing protein subfamilies, namely zizimin, KIAA1395, DOCK180, and KIAA0299. Our HMM search with motif MDS00146detected only members of the zizimin and KIAA1395 subfamilies.

Membrane Organization
In an attempt to annotate the membrane organization of entire proteomes from a range of species, we developed a computational strategy. Based on the prediction of two features, endoplasmic reticulum signal peptides (used for translocation into the secretory pathway) and membrane-spanning domains (transmembrane domains), the membrane organization of proteins can be classified. We have annotated 10 proteome databases from a range of species (see Table 3). Determination of the membrane organization of an individual protein is dependent on knowing the full-length protein open reading frame (ORF) and cannot be applied to partial protein ORFs. For each proteome dataset, we removed any readily identifiable partial protein sequences (see Table 3). As expected in both the human and mouse ENSEMBL proteome databases, significant numbers of partial ORFs were present (37% and 44% respectively.) This highlights the high level of partial protein sequences generated from predicted genes. These partial sequences would result in inaccurate predictions of their membrane organization if retained. Surprisingly, the M. musculus IPI proteome contained similar levels of partial sequences (45%), whereas the other proteomes analyzed contained less than 10%.

View this table: [in this window] [in a new window]   Table 3. Predicted Signal Peptides and Transmembrane Domains in Eukaryotic Proteomes

The results of this analysis using the various proteome datasets are presented in Table 3. The proportion of proteins predicted to contain signal peptides within the RIKEN RPS was 21.1%. Similar levels were annotated in the other higher eukaryotic proteomes (human and mouse). Lower proportions of signal peptides were annotated in the D. melanogaster (18.4%), C. elegans (19.3%), A. thaliana (14.6%), and S. cerevisiae (8.5%) proteome databases.

Prediction of the Membrane-Spanning Regions or Transmembrane Domains
Next we annotated the transmembrane domains for each protein. Although a consensus approach has been proposed (Nilsson et al. 2000), its application to entire genomes was not practical. To analyze all proteins, we selected two prediction methods that could be readily applied to large datasets. TMHMM 2.0, which was clearly the best performer in a recent comparative evaluation (Moller et al. 2001), was selected first. Secondly, SVMtm, a new transmembrane prediction method using a support vector machine (Z. Yuan and R. Teasdale, unpubl., http://microarray.imb.uq.edu.au/predictors/) was selected. When SVMtm was compared to TMHMM 2.0 it showed comparable accuracy levels (specificity 94.0% vs. 95.2% and sensitivity 91.8% vs. 90.8%, respectively).

Each protein within the different proteome databases was analyzed with both TMHMM 2.0 and SVMtm. Transmembrane domains were annotated when both methods positively predicted a membrane-spanning domain. Sequences containing conflicting predictions were further analyzed using three additional transmembrane prediction tools (SOSUI, HMMTOP, and MEMSAT). Only membrane-spanning regions that were positively predicted by more than two of these additional methods were annotated as transmembrane domains. Between 14% and 20% of the total number of transmembrane domains annotated were assigned by this method. In addition, an initial prediction was considered a false-positive prediction when not supported by any of the other transmembrane prediction methods. This approach is similar to the "majority vote" consensus method recently used by others (Nilsson et al. 2000; Ikeda et al. 2002).

Transmembrane domain prediction methods are known to incorrectly predict signal peptides as transmembrane domains. Therefore we adopted a filter for predicted N-terminal transmembrane segments: If the predicted transmembrane domain's starting point was within the first 15 residues of the ORF and a signal peptide was predicted, then this region was regarded as a signal peptide instead of a transmembrane domain. This filtering procedure was applied to the results of all transmembrane prediction tools. The results from this analysis using the various proteome datasets are presented in Table 3.

In contrast to the signal peptide analysis, the proportion of proteins with predicted transmembrane domains varied little between proteomes, (21.6%–26.6%), with the exception of the C. elegans proteome, where the proportion was higher (31.5%). These results are consistent with the similar attempts to annotate membrane-spanning domains in eukaryotes (Wallin and von Heijne 1998; Krogh et al. 2001; Liu and Rost 2001; Ward 2001). For example, using an earlier version of TMHMM, Krogh and others predicted transmembrane domains for S. ceresiviae, D. melanogaster, and C. elegans, at 20.7%, 20.1%, and 30.3% respectively.

Classification of Proteins Into Distinct Classes Based on Their Predicted Membrane Organization
Here we propose an alternative broad classification scheme for protein classes based on their predicted membrane organization. This approach utilizes the combined annotation within individual full-length protein ORFs of both signal peptides and transmembrane domains (see Table 4). Transmembrane-negative soluble proteins are classified as intracellular or extracellular based on the signal peptide predictions. Transmembrane-positive proteins are classified into three groups. The topology of single membrane-spanning proteins, Type I (Nout/Cin), or Type II (Nin/Cout), is assigned based on the presence or absence of a signal peptide. Proteins with more than one membrane-spanning domain are classified as multi-span membrane proteins. Based on the above annotation of signal peptides and membrane-spanning regions, we obtained six groups of proteins (see Table 4).

View this table: [in this window] [in a new window]   Table 4. Membrane Organization of Protein Classes Assigned Based on the Prediction of Signal Peptides and Transmembrane Domains

	METHODS

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Databases
We analyzed the following proteome databases available from EBI on June 15th 2002 (http://www.ebi.ac.uk/proteome/; Apweiler et al. 2001): Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens (International Protein Index, IPI), Mus musculus (IPI), and Saccharomyces cerevisiae. In addition, we analyzed the RIKEN Mouse Representative Transcript and Protein Sets (Riken RPS; http://genome.gsc.riken.go.jp/), RIKEN Mouse Variable Protein Set (Riken VPS; http://genome.gsc.riken.go.jp/), and the predicted protein ORFs from the ENSMBL human genome database (Human Build 29) and mouse genome database (MGSC Mouse Assembly 3; http://www.ensembl.org/; Hubbard et al. 2002). The sequences were filtered so that partial ORFs that did not contain a methionine at position 1 or were clearly annotated as partial or fragments were removed.

The set of predicted proteins produced by Celera (Release R13b, April 2002, http://www.celeradiscoverysystem.com/) was used as one of the whole-genome sets of computational predictions. The Celera sequencing, assembly, and transcript prediction methods are described (Mural et al. 2002). The complete Celera protein set contained 47,256 transcripts and protein sequences, corresponding to 46,941 gene predictions. Of this set, 14,994 weak-confidence predictions were excluded for compatibility with the analyses of the Ensembl set and of the Chr.16 (Mural et al. 2002). The remaining 32,262 high- to medium-confidence protein predictions were used in this study; 15,548 of these hypothetical proteins had BLAST hits to the publicly available protein sequences, 7085 were in common with the RefSeq(Pruitt and Maglott 2001) mouse protein set, and 19,089 had InterPro assignments.

InterPro version 5.1 (May 2002) and InterProScan version 3.1 (Zdobnov and Apweiler 2001) were used for the functional sites and domains composition analysis.

Prediction Methods
Signal P V2 (NN and HMM; Nielsen and Krogh 1998), SPScan (von Heijne 1987), TMHMM 2.0 (Krogh et al. 2001), SVMtm (Z. Yuan and R. Teasdale, in prep.; http://microarray.imb.uq.edu.au/predictors/), MEMSAT 1.5 (Jones et al. 1994), HMMTOP (Tusnady and Simon 2001), and SOSUI (Hirokawa et al. 1998) were applied using their default values except for selection of organism group. SPScan analysis was performed using the Genetics Computer Group (GCG) Wisconsin Package (version 8.1) located at the Australian National Genomic Information Service (ANGIS). SOSUI analysis was performed using its Web interface (http://sosui.proteome.bio.tuat.ac.jp/sosui/proteome/welcomeE.html).

	Acknowledgements

 
We thank N. Mulder and W. Fleischmann (European Bioinformatics Institute) for consultations and support, A. Krogh and S. Brunak (Technical University of Denmark) for providing the TMHMM and SignalP software packages, G.E. Tusnady (Hungarian Academy of Sciences) for providing the HMMTOP software package, D.T. Jones (University College) for providing the MEMSAT software package, and K. Miranda (IMB, University of Queensland) for technical assistance. This work was supported in part by the Australian Research Council and the National Health and Medical Research Council of Australia; also in part by ACT-JST of JST (Japan Science and Technology Corp.), and a Grant-in-Aid for Scientific Research on Priority Areas "Genome Information Science" from the Ministry of Education, Culture, Sports, Science and Technology of Japan to H.M.

	Footnotes

 
Article and publication are at http://www.genome.org/cgi/doi/10.1101/gr.978703.

¹¹ Corresponding author.
E-MAIL alex{at}ebi.ac.uk; FAX 44 0 1223 494610.

¹⁰ Takahiro Arakawa, Piero Carninci, Jun Kawai, and Yoshihide Hayashizaki.

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Hirokawa, T., Boon-Chieng, S., and Mitaku, S. 1998. SOSUI: Classification and secondary structure prediction system for membrane proteins. Bioinformatics 14:378 -379.[Abstract/Free Full Text]

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	WEB SITE REFERENCES

Top ABSTRACT RESULTS AND DISCUSSION METHODS REFERENCES WEB SITE REFERENCES

 

http://www.celeradiscoverysystem.com; Celera Corporation.

http://www.ensembl.org/; ENSEMBL genome databases.

http://www.ebi.ac.uk/IPI; International Protein Index.

http://www.ebi.ac.uk/proteome; Proteome Analysis Database.

http://genome.gsc.riken.go.jp/; RIKEN Mouse Representative Transcript and Protein Sets.

http://sosui.proteome.bio.tuat.ac.jp/sosui/proteome/welcomeE.html; SOSUI Web Interface.

http://supfam.org/SUPERFAMILY/cgi-bin/gen_list.cgi?genome=mr; SUPERFAMILY Database.

http://supfam.org/FANTOM2/domcombs.html; SUPERFAMILY FANTOM2 data.

http://microarray.imb.uq.edu.au/predictors; SVMtm Support Vector Machines to predict transmembrane domains.

http://motif.ics.es.osaka-u.ac.jp/fantom2/; MDS Motif Database for FANTOM2.

http://microarray.imb.uq.edu.au/predictors/proteome/; SRC microarray facility—Proteome supplementary material.

Received November 11, 2002; accepted in revised format March 5, 2003.
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