Bio::Homology::InterologWalk - A Perl module to build putative protein-protein interaction networks through interolog mapping
© Gallone et al; licensee BioMed Central Ltd. 2011
Received: 25 February 2011
Accepted: 18 July 2011
Published: 18 July 2011
Protein-protein interaction (PPI) data are widely used to generate network models that aim to describe the relationships between proteins in biological systems. The fidelity and completeness of such networks is primarily limited by the paucity of protein interaction information and by the restriction of most of these data to just a few widely studied experimental organisms. In order to extend the utility of existing PPIs, computational methods can be used that exploit functional conservation between orthologous proteins across taxa to predict putative PPIs or 'interologs'. To date most interolog prediction efforts have been restricted to specific biological domains with fixed underlying data sources and there are no software tools available that provide a generalised framework for 'on-the-fly' interolog prediction.
We introduce Bio::Homology::InterologWalk, a Perl module to retrieve, prioritise and visualise putative protein-protein interactions through an orthology-walk method. The module uses orthology and experimental interaction data to generate putative PPIs and optionally collates meta-data into an Interaction Prioritisation Index that can be used to help prioritise interologs for further analysis. We show the application of our interolog prediction method to the genomic interactome of the fruit fly, Drosophila melanogaster. We analyse the resulting interaction networks and show that the method proposes new interactome members and interactions that are candidates for future experimental investigation.
Our interolog prediction tool employs the Ensembl Perl API and PSICQUIC enabled protein interaction data sources to generate up to date interologs 'on-the-fly'. This represents a significant advance on previous methods for interolog prediction as it allows the use of the latest orthology and protein interaction data for all of the genomes in Ensembl. The module outputs simple text files, making it easy to customise the results by post-processing, allowing the putative PPI datasets to be easily integrated into existing analysis workflows. The Bio::Homology::InterologWalk module, sample scripts and full documentation are freely available from the Comprehensive Perl Archive Network (CPAN) under the GNU Public license.
In recent years, large protein-protein interaction (PPI) datasets have allowed the description of relationships between proteins in complex biological systems . These data are commonly derived from yeast two hybrid (Y2H), co-immunoprecipitation or tandem affinity purification (TAP) assays and have been obtained from a variety of unicellular and multicellular organisms [2–6]. Recent advances in high resolution mass spectrometry have further contributed to the rapid accumulation of PPI data [7–9]. Unfortunately, large scale experimental discovery of PPIs remains difficult, expensive and beyond the means of many experimentalists. Currently, PPI data is almost exclusively limited to a few popular model organisms and amongst these coverage of the captured interactions is often biased to a particular domain and incomplete. For many organisms, PPI data lags behind or is non-existent compared with genome sequence data.
In an attempt to address the relative paucity of data, a number of computational techniques have been proposed to predict and prioritise PPIs [10, 11]. While the number of such methods is large, we focus here on methods that transfer functional information using cross-species orthology projection [12, 13]. In essence, the rationale is that for interacting proteins x and y in organism we expect (under certain conditions) that their orthologues x' and y' in organism will also interact. Such conserved interaction pairs are called 'interologs' [14, 15]. The potential use of interolog mapping has been explored in several organisms including Homo sapiens[16–22], Helicobacter pylori, Saccharomyces cerevisiae, Plasmodium falciparum and Magnaporthe grisea. Additionally a number of quantification methods have been developed to assess the confidence of predicted interologs [27–29].
Several web interfaces to interolog databases have been developed (e.g. HomoMINT  and Ulysses ), but these are essentially ad hoc efforts. They consider a small set of organisms for interolog prediction in restricted biological domains, thus hindering more widespread use. Underlying data sets are often frozen at the moment of publication or curated for a limited period of time (e.g. InteroPORC ), are dependent on other projects that are not updated (e.g. Integr8 ) or are based on algorithms that are not state-of-the-art. Considering that both orthology projection methods and interaction data are continually updated, such static databases are destined to obsolescence. To date the only project that provides the option to discover interologs with up to date data is OpenPPI predictor . This represents a step forward, but relies on the user providing both the orthology relationships and known PPI data and only performs mappings between two species, without ranking or prioritising the putative PPI network obtained.
To address the lack of tools for performing multi-species interolog prediction 'on the fly' we created the Perl module Bio::Homology::InterologWalk. The tool relies on BioPerl , the Ensembl Perl Core and Compara APIs [33, 34] and the EBI-Intact PSI Common Query InterfaCe (PSICQUIC) enabled web service [35, 36] for its operation. Bio::Homology::InterologWalk is freely available under the GNU General Public Licence at the Comprehensive Perl Archive Network (CPAN) [37, 38].
Bio::Homology::InterologWalk accepts as input a list of Ensembl gene accession numbers from any of the vertebrate or metazoan genomes in Ensembl and also for all species in the Ensembl pan-taxonomic Compara database. The tool searches the Ensembl Core and Compara databases and the PSICQUIC-enabled EBI-Intact PPI database to collect and analyse gene orthology and PPI data, together with ancillary information. It then provides the option of filtering the putative interactions to retain those with strong experimental or phylogenetic support. In addition the user can query the PPI database directly to collect all known interactions for the input gene list. This allows the ready comparison of putative PPIs from interolog projection to known PPIs. The software outputs plain text tab-separated files and can also output network representations of the PPI data and their attributes in a format compatible with the widely used biological network analysis tool Cytoscape .
We demonstrate the use of the software to investigate the potential of interolog projection on the genome of the fruit fly, Drosophila melanogaster. The analysis (a) generates a novel putative PPI network that strengthens the connectivity of the known PPI network (b) proposes new interaction candidates. We further calculate an Interaction Prioritisation indeX (IPX) for each of the PPIs and use these to create a sub-network centred on a core of 10 DNA replication proteins.
The procedure is organised as a pipeline of related data-processing activities. The output of the basic pipeline can be further processed with the help of other methods in the module: it is possible to scan the results and compute counts, check for duplicate entries, isolate new gene IDs (not part of the original dataset) and generate Cytoscape-compatible network representations of the data. The package documentation gives a detailed account of post-processing options.
An additional stand-alone functionality of the module is the direct PPI pipeline: it is possible to use Bio::Homology::InterologWalk to mine all the experimental PPIs involving the initial gene list in the genome of interest (without mapping to reference genomes using orthology). This dataset is a 'snapshot' of the current experimental PPI network for the input dataset. As such it is useful both by itself, because it tells what is currently know about the PPIs involving the initial genes, and as a term of comparison for the putative PPI - because it can be used to evaluate the amount of overlap between the known and putative networks, as well as the novelty of the putative data. Additional file 1: 'Simplified schematics of the Interolog Walk Pipeline' illustrates both the putative and the experimental pipeline in detail.
One of the defining features of Bio::Homology::InterologWalk is that the retrieval of both orthology data and protein interaction data happens on-the-fly. The user inputs a list of gene IDs plus a number of set-up parameters, and the data will be downloaded through web-service interfaces each time the program is run.
Orthology Predictions from Ensembl Compara
Bio::Homology::InterologWalk uses the Ensembl Perl API http://www.ensembl.org/info/data/api.html to access the comparative biology data provided by the Ensembl Project through Ensembl Compara. The orthology prediction method used by Ensembl Compara is described by Vilella et al.  and identifies several classes of homology association between genes (Additional file 2: 'Definitions').
PPI Data from EBI-IntAct
Bio::Homology::InterologWalk currently uses EBI IntAct  as its source of experimental interactions. As of June 2011, v. 1.1.7 of the IntAct database contains more than 267,000 curated binary protein interaction evidences . Bio::Homology::InterologWalk queries Intact using the RESTful-based PSICQUIC [Aranda et al., in preparation] implementation and retrieves data in PSI-MI MITAB25 tab-delimited format  (Additional file 2: 'Definitions').
Options for Prioritisation of Putative Interactions
Spoke interactions: the user can choose whether to return any 'spoke' interactions when using interaction retrieval functions. Spoke interactions are binary interactions that are inferred from a complex of proteins that have been isolated together and as such the evidence for the interaction is indirect. Several of the most widely used protein-protein interaction data repositories including the two largest IntAct and BioGrid explicitly draw the user's attention to the presence of spoke (or co-existence) interactions and provide the option of excluding them at an early stage.
One-to-one orthology: for each of the orthology mapping functions the user can choose whether to restrict the mapping to explicit 1:1 relationships. This is likely to significantly reduce the number of orthologues retrieved as the evolutionary distance between mapped species increases. Restricting mappings to direct orthologues increases the likelihood that the mapped proteins retain some common functionality. Conversely considering 1-to-many or many-to-many relationships that have arisen through duplication events risks connecting proteins and interactions whose functions have diverged [51, 52].
Experimental interactions: the user can specify whether to restrict the interactions retrieved to those that have been identified by experimental methods rather than by inference or prediction (Additional File 2: 'Definitions').
Physical interactions: the user can choose to retrieve only those interactions that test for direct physical association between proteins (Additional File 2: 'Definitions').
We have created an Interaction Prioritisation indeX (IPX) and a PPI Conservation Score (PCS) that can optionally be used to aid in the prioritisation of putative interactions.
The IPX summarises the contribution of several pieces of heterogeneous information that are collected during orthology projection and interaction retrieval. It is not intended to be a quantitative measure of interaction reliability, but rather an integration of biological information such as orthology type, phylogenetic distance (FSA), percentage identity (OPI), interaction type and detection method (including multi-method). This is similar to the work of Huang et al.  and Yu et al. . Yu et al. used sequence similarity between the orthologous proteins to build a join similarity score, while Huang et al. proposed a scoring framework based on GO functional annotation, domain information, tissue specificity and sub-cellular localisation to rank interolog-based human putative PPIs obtained from six eukaryotes. Some of the indicators evaluated to create the IPX are:
Orthology Type. The kind of orthology relationship existing between an ID in the genome of interest and its orthologue in the reference genome. This feature indicates if there is a one-to-one mapping of orthologues, or if in-paralogy events in one or both sides mean we are considering a one-to-many, many-to-one or many-to-many orthologous mapping. As explained in the filtering section, we particularly value putative PPIs where both orthology relationships are of the one-to-one kind. It has been shown  that gene duplication is correlated with sub-functionalisation and neo-functionalisation. When the two orthologous pairs in the interolog walk are of the one-to-one kind we set a boolean variable, Θ, to a non-negative value in the score. We set Θ = 0 otherwise.
Expanded Complex. Indicates whether the binary interaction has been extracted from a complex using the spoke expansion model. A boolean non-negative term, ∑, is added to the score to reward each true binary interaction. ∑ = 0 for spoke-expanded binary interactions.
OPI. Overall Percentage Identity. A numerical index representing the percentage identity of the conserved columns between the two orthology members' sequences. Given N total samples, we define a Joint OPI as the geometric mean of the two OPIs (forward and backward orthology projection)
Node to Node Distance. A numerical indicator of the node-to-node distance in the consensus phylogenetic/species tree built by Ensembl Compara using Genetrees  (Figure 2B). We consider
Interaction Type & Interaction Detection Method. Features based on PSI-MI controlled vocabulary terms indicating, respectively, the type of interaction and the detection method used, within the HUPO PSI-MI hierarchy (Additional File 2: 'Definitions', Table S1).
PPI obtained with Multiple Methods & annotated in Multiple Organisms. Experimental PPIs reconfirmed through the usage of further detection methods and/or observed in multiple reference genomes are acknowledged by this feature (Figures 2C and 2D).
We set ω i ,= ω o = 1. Optimisation of these two weights based on training data will allow to reward either the interaction component or the orthology component of the score to optimise performance on a case-by-case basis. Lastly, ∑ and Θ are boolean terms and we set ∑ = 0 whenever the putative PPI has been inferred from a binary PPI derived from a spoke-expanded complex (∑ = n, where n > 0 is an integer, otherwise), while Θ = n whenever the putative PPI has been inferred based exclusively on one-to-one orthology paths (Θ = 0 otherwise).
∑ and Θ are boolean flags not normalised in the IPX expression. This is done to obtain a gross selection of putative PPI samples based on co-orthology/no co-orthology and spoke/no spoke information, prior to looking at other secondary metadata features. The value n was chosen to be the smallest integer bigger than the maximum spread of the distribution of the normalised IPX features. The IPX is composed of 6 features, f = [i, d, m dm , mtaxa, JOPI, JnnD], where 0 ≤ fi ≤ 1, ∀ i ∈ 1, ..., 6 and so n = 7.
∑ = 0, Θ = 0 (Low Tier) - the experimental interaction is spoke-expanded and at least one of the two orthology projections is not one-to-one.
(∑ = n, Θ = 0) Θ (∑ = 0; Θ = n) (Mid Tier) - either the experimental interaction is spoke-expanded or at least one of the two orthology projections is not one-to-one.
∑ = n, Θ = n (High Tier) - the experimental interaction is not expanded from a spoke-complex and the orthology projections are both one-to-one.
Visual inspection of the modes in the IPX distribution can be used as strategy to filter out different sets of putative PPIs, depending on the dataset considered and on the distribution of samples within the modes of the histogram. The choice of n provides good visual separation of the modes in the IPX distribution to facilitate inspection. We refer to the module code for further details.
where γ = 2 · E/[N · (N - 1)] and N and E are, respectively, the number of nodes and edges in the sub-network. Since the γ-connectedness measure is biased towards maximally connected small sub-networks, is relaxed by weighting it with the number of edges E.
There are many ways that an interolog could be prioritised. We aim for Bio::Homology::InterologWalk to be compatible with a diverse range of data and useful for many different kinds of users. Any prioritisation metric will be context-dependent and for this reason we offer a number of options to configure the process to suit the users requirements and the coverage and quality of the data available to them. As such the generalised and customisable prioritisation scheme we provide here should provide the necessary exibility to allow application across a broad range of biological domains.
Results and Discussion
Retrieving known interactions through orthology walking
where ortho(·) is the orthology operator. is the set of all binary PPIs in G i that match through orthology in G j (Figure 3A).
Bio::Homology::InterologWalk successfully retrieves 100% of the positive PPIs in all cases considered. In addition, putative PPI predictions are retrieved, which are candidates that can be prioritised for experimental evaluation. Interestingly, the known positive sets appear smaller than might be expected between closely related organisms like human and mouse. This might be due to a combination of factors such as (1) the parameters for orthology classification used by Ensembl are very stringent, (2) there are biases in experimental research across organisms (the bulk of experimental predictions in each of the two species might come from experiments in different cellular domain and sub-systems) (3) experimental PPI data will likely contain false positive interactions, which will not map through orthology.
It is also interesting to note that in the case of the yeast-worm pair (Figure 4I and 4J) the number of novel IDs and novel PPIs retrieved is one order of magnitude smaller than in the other four cases. This is consistent with the relatively limited amount of experimental PPI data available for C. elegans.
Assessing the IPX using Receiver Operating Curves (ROC)
It is important to stress that the IPX is not a necessary and sufficient condition to assess the reliability of a putative PPI: a highly ranking interolog may not turn out to be an interesting candidate, but as the index is calculated using both experimental and phylogenetic measures, it would be logical to assess such interologs as candidates before those with lower values. As is the case with any biological scoring metric, a feature with a low score may turn out to be a good candidate and should not be excluded solely on the basis of the score alone.
Example — Exploring the protein interactome of Drosophila melanogaster
To demonstrate the use of Bio::Homology::InterologWalk, we retrieved a list of all Drosophila melanogaster genes (DS_DMEL) from Ensembl-Compara Release 61. For the interolog walk the reference genomes were not restricted to any specific species, but included all 53 available taxa even though we expected a proportion of the species in the sets to provide 'dead end' orthologues where no significant experimental PPI data existed.
For the interolog walk we filtered by retrieving only one-to-one orthologues in the orthology mapping phases and discarded (a) all interactions that were inferred from complexes (spoke) and (b) all interactions that were not experimental physical associations. As a reference we also performed a direct mine of known interactions for the starting gene list with the same interactions filters.
DS_DMEL - Data for putative and known networks obtained with Bio::Homology::InterologWalk
PPIs in Reference Genomes
Unique PP Pairs
Surviving IDs (% Gene IDs)
NET_DS_DMEL_known (7779 nodes, 26622 edges) - the network consisting of all the experimentally-obtained physical associations involving genes in DS_DMEL, according to EBI-Intact;
NET_DS_DMEL_putative (2188 nodes, 4428 edges) - the network consisting of putative interactions involving genes in DS_DMEL according to Bio::Homology::InterologWalk (filtered as described above);
NET_DS_DMEL_union (8270 nodes, 31050 edges) - the network obtained computing the union of (1) and (2) where:
each node is a node of NET_DS_DMEL_known, NET_DS_DMEL_putative, or both;
each edge is either an edge of NET_DS_DMEL_known or an edge of NET_DS_DMEL_putative (Note: duplicate edges were not collapsed into one).
To illustrate the utility of the interolog walk we performed the same procedure as above using NET_DS_DMEL_union. In this case we retrieved a set of 68 'DNA replication' genes, a superset of the 65 found before, meaning that 3 additional DNA replication genes are drawn in through the putative pipeline. As before, we selected the sub-network of NET_DS_DMEL_union composed of the 10 core DNA replication genes and their nearest neighbours. The resulting sub-network, NET_DNArep, composed of 68 nodes and 165 edges (Figure 7B and for clarity in higher resolution see Additional File 6: 'NET_DNArep') has greatly increased connectivity (compare Figure 7A to 7B). Indeed the main connected component in NET_DNArep now comprises 55 genes and 153 interactions, and wires together 7 of the 10 core DNA replication genes. A broad analysis of NET_DNArep reveals that the introduction of putative PPI data has allowed us to:
collect evidence about new genes, not known to be related to DNA replication before;
increase the connectivity of the GO-annotated DNA replication proteins.
Proteins that were known to be involved in DNA replication now interact with proteins for which no evidence for DNA replication involvement existed, meaning new potential candidates are drawn in to build a more complete picture of the domain.
Using the IPX to refine the Sub-Network
Given the relatively high number of interactions and participating genes in NET_DNArep, we carried out a refinement of the interaction candidates obtained, using the IPX. As described earlier, Bio::Homology::InterologWalk can optionally calculate a prioritisation index for each of the putative PPIs produced. These can be employed to define a 'core' network for which there is strong biological and experimental evidence by removing nodes that are connected by putative PPIs with low IPX indices.
In order to look at the composition of putative PPIs in NET_DNArep, we set , and mapped score values to edge thickness in NET_DNArep (Figure 7B-D). Figure 7D shows the sub-network backbone possessing the highest confidence according to the algorithm. Interestingly, the connectedness of the main component still remains at this threshold level. Four putative PPIs survive the strict threshold: (Orc2, Mcm10), (MCM5, MCM3), (MCM10, MCM6) and (crn, CG6905). All these pairs, apart from (MCM6, MCM10), are known to interact experimentally (black edge) and the putative interaction (red edge) reconfirms these results. The (MCM6, MCM10) pair, on the other hand, has not been shown to interact in Drosophila melanogaster and represents a candidate for lab validation.
In this paper, we present Bio::Homology::InterologWalk, a Perl module to retrieve, prioritise and visualise putative Protein-Protein Interactions using interolog mapping. Unlike previous efforts, this Perl library (a) automatically connects to orthology/PPI data web-services to generate up-to-date predictions 'on the fly'. (b) outputs its predictions in the form of simple text files, allowing to use its methods, or the data it produces, within the context of pipeline-based work flows of wider scope (c) optionally flags the predictions on the basis of related biological metadata through a prioritisation index, allowing the selection of a subset of candidates for in vivo validation.
We formally validate the efficacy of the tool and present ROC curves to assess the association between the IPX and 'true-positive' interactions across several inter-species 'true-positive' sets. We test the potential of the tool to retrieve putative PPIs on the Drosophila melanogaster genome and look more closely at one DNA replication related sub-network identifying several novel nodes and interactions. We conclude by using IPX thresholds to create a 'core' network for which there is strong biological and experimental support.
Our interaction prioritisation index (IPX) is designed to encapsulate biologically relevant principles that relate directly to the assessments currently made manually by many researchers using interaction data. We stress, however, that the IPX measure for an interaction is not fully explored here and that a full validation is not possible due to the current poor coverage of PPI data across species. In our experience the IPX has proven to be a useful summary of biological metadata for PPIs. When performing an interolog walk we recommend the user first uses filtering options to restrict the interactions retrieved and then uses the IPX as a pragmatic aid to candidate prioritisation.
Bio::Homology::InterologWalk is freely available for non-commercial purposes on the Comprehensive Perl Archive Network (CPAN) and modifiable under the GNU GPL license. The package includes full documentation and example scripts to simplify usage.
Availability and requirements
Project name : Bio::Homology::InterologWalk
Project home page : http://search.cpan.org/~ggallone/Bio-Homology-InterologWalk/
Programming Language : Perl
Other requirements : Bioperl, Ensembl API. The module also relies on a number of pre-requisite Perl libraries. See manual on website.
License : GNU GPL
List of abbreviations
- API :
Application Programming Interface
- COG :
Cluster Of Orthologs
- CPAN :
Comprehensive Perl Archive Network
- EBI :
European Bioinformatics Institute
- IPX :
Interolog Prioritisation indeX
- GO :
- HUPO-PSI :
HUman Proteome Organisation - Proteomics Standards Initiative
- MITAB :
Molecular Interactions TAB delimited data exchange format
- PCS :
PPI Conservation Score
- PPI :
- PSICQUIC :
Protemics Standard Initiative Common QUery InterfaCe
- PSI-MI :
Proteomics Standard Initiative - Molecular Interactions
- REST :
Representational State Transfer
- ROC :
Receiver Operating Characteristic
- TAP :
Tandem Affinity Purification
- TreeBeST :
(gene) Tree Building guided by Species Tree.
Acknowledgements and Funding
Funding was provided by the Wellcome Trust (TIS, JDA, APJ) under grant number 077266, by the ERASysBio+ scheme (TIS) and by an MRC Capacity Building Studentship in Systems Biology (GG), number G68293X. This work has made use of resources provided by Ensembl http://www.ensembl.org and the EBI http://www.ebi.ac.uk. GG wishes to thank Lysimachos Zografos for interesting discussions.
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