See-Kiong Ng

Computational approaches for detecting protein complexes from protein interaction networks: a survey

BackgroundMost proteins form macromolecular complexes to perform their biological functions. However, experimentally determined protein complex data, especially of those involving more than two protein partners, are relatively limited in the current state-of-the-art high-throughput experimental techniques. Nevertheless, many techniques (such as yeast-two-hybrid) have enabled systematic screening of pairwise protein-protein interactions en masse. Thus computational approaches for detecting protein complexes from protein interaction data are useful complements to the limited experimental methods. They can be used together with the experimental methods for mapping the interactions of proteins to understand how different proteins are organized into higher-level substructures to perform various cellular functions.ResultsGiven the abundance of pairwise protein interaction data from high-throughput genome-wide experimental screenings, a protein interaction network can be constructed from protein interaction data by considering individual proteins as the nodes, and the existence of a physical interaction between a pair of proteins as a link. This binary protein interaction graph can then be used for detecting protein complexes using graph clustering techniques. In this paper, we review and evaluate the state-of-the-art techniques for computational detection of protein complexes, and discuss some promising research directions in this field.ConclusionsExperimental results with yeast protein interaction data show that the interaction subgraphs discovered by various computational methods matched well with actual protein complexes. In addition, the computational approaches have also improved in performance over the years. Further improvements could be achieved if the quality of the underlying protein interaction data can be considered adequately to minimize the undesirable effects from the irrelevant and noisy sources, and the various biological evidences can be better incorporated into the detection process to maximize the exploitation of the increasing wealth of biological knowledge available.

InterDom: a database of putative interacting protein domains for validating predicted protein interactions and complexes

Advances in proteomics technology have enabled new proteins to be discovered at an unprecedented speed, and high throughput experimental methods have been developed to detect protein interactions and complexes en masse. Such bottom-up, data-driven approach has resulted in data that may be uninformative or potentially errorful, requiring further validation and annotation. The InterDom database focuses on providing supporting evidence for the detected protein interactions based on putative protein domain interactions. Using an integrative approach, InterDom derives potential domain interactions by combining data from multiple sources, ranging from domain fusions, protein interactions and complexes, to scientific literature. The InterDom database is available at http://InterDom.lit.org.sg.

DISCOVERING PROTEIN COMPLEXES IN DENSE RELIABLE NEIGHBORHOODS OF PROTEIN INTERACTION NETWORKS

Multiprotein complexes play central roles in many cellular pathways. Although many high-throughput experimental techniques have already enabled systematic screening of pairwise protein-protein interactions en masse, the amount of experimentally determined protein complex data has remained relatively lacking. As such, researchers have begun to exploit the vast amount of pairwise interaction data to help discover new protein complexes. However, mining for protein complexes in interaction networks is not an easy task because there are many data artefacts in the underlying protein-protein interaction data due to the limitations in the current high-throughput screening methods. We propose a novel DECAFF (Dense-neighborhood Extraction using Connectivity and conFidence Features) algorithm to mine for dense and reliable subgraphs in protein interaction networks. Our method is devised to address two major limitations in current high throughout protein interaction data, namely, incompleteness and high data noise. Experimental results with yeast protein interaction data show that the interaction subgraphs discovered by DECAFF matched significantly better with actual protein complexes than other existing approaches. Our results demonstrate that pairwise protein interaction networks can be effectively mined to discover new protein complexes, provided that the data artefacts in the underlying interaction data are taken into account adequately.

Increasing confidence of protein interactomes using network topological metrics

MOTIVATION Experimental limitations in high-throughput protein-protein interaction detection methods have resulted in low quality interaction datasets that contained sizable fractions of false positives and false negatives. Small-scale, focused experiments are then needed to complement the high-throughput methods to extract true protein interactions. However, the naturally vast interactomes would require much more scalable approaches. RESULTS We describe a novel method called IRAP* as a computational complement for repurification of the highly erroneous experimentally derived protein interactomes. Our method involves an iterative process of removing interactions that are confidently identified as false positives and adding interactions detected as false negatives into the interactomes. Identification of both false positives and false negatives are performed in IRAP* using interaction confidence measures based on network topological metrics. Potential false positives are identified amongst the detected interactions as those with very low computed confidence values, while potential false negatives are discovered as the undetected interactions with high computed confidence values. Our results from applying IRAP* on large-scale interaction datasets generated by the popular yeast-two-hybrid assays for yeast, fruit fly and worm showed that the computationally repurified interaction datasets contained potentially lower fractions of false positive and false negative errors based on functional homogeneity. AVAILABILITY The confidence indices for PPIs in yeast, fruit fly and worm as computed by our method can be found at our website http://www.comp.nus.edu.sg/~chenjin/fpfn.

NeMoFinder: dissecting genome-wide protein-protein interactions with meso-scale network motifs

Recent works in network analysis have revealed the existence of network motifs in biological networks such as the protein-protein interaction (PPI) networks. However, existing motif mining algorithms are not sufficiently scalable to find meso-scale network motifs. Also, there has been little or no work to systematically exploit the extracted network motifs for dissecting the vast interactomes.We describe an efficient network motif discovery algorithm, NeMoFinder, that can mine meso-scale network motifs that are repeated and unique in large PPI networks. Using NeMoFinder, we successfully discovered, for the first time, up to size-12 network motifs in a large whole-genome S. cerevisiae (Yeast) PPI network. We also show that such network motifs can be systematically exploited for indexing the reliability of PPI data that were generated via highly erroneous high-throughput experimental methods.

Inferring gene-phenotype associations via global protein complex network propagation.

Background Phenotypically similar diseases have been found to be caused by functionally related genes, suggesting a modular organization of the genetic landscape of human diseases that mirrors the modularity observed in biological interaction networks. Protein complexes, as molecular machines that integrate multiple gene products to perform biological functions, express the underlying modular organization of protein-protein interaction networks. As such, protein complexes can be useful for interrogating the networks of phenome and interactome to elucidate gene-phenotype associations of diseases. Methodology/Principal Findings We proposed a technique called RWPCN (Random Walker on Protein Complex Network) for predicting and prioritizing disease genes. The basis of RWPCN is a protein complex network constructed using existing human protein complexes and protein interaction network. To prioritize candidate disease genes for the query disease phenotypes, we compute the associations between the protein complexes and the query phenotypes in their respective protein complex and phenotype networks. We tested RWPCN on predicting gene-phenotype associations using leave-one-out cross-validation; our method was observed to outperform existing approaches. We also applied RWPCN to predict novel disease genes for two representative diseases, namely, Breast Cancer and Diabetes. Conclusions/Significance Guilt-by-association prediction and prioritization of disease genes can be enhanced by fully exploiting the underlying modular organizations of both the disease phenome and the protein interactome. Our RWPCN uses a novel protein complex network as a basis for interrogating the human phenome-interactome network. As the protein complex network can capture the underlying modularity in the biological interaction networks better than simple protein interaction networks, RWPCN was found to be able to detect and prioritize disease genes better than traditional approaches that used only protein-phenotype associations.

A correlated motif approach for finding short linear motifs from protein interaction networks

BackgroundAn important class of interaction switches for biological circuits and disease pathways are short binding motifs. However, the biological experiments to find these binding motifs are often laborious and expensive. With the availability of protein interaction data, novel binding motifs can be discovered computationally: by applying standard motif extracting algorithms on protein sequence sets each interacting with either a common protein or a protein group with similar properties. The underlying assumption is that proteins with common interacting partners will share some common binding motifs. Although novel binding motifs have been discovered with such approach, it is not applicable if a protein interacts with very few other proteins or when prior knowledge of protein group is not available or erroneous. Experimental noise in input interaction data can further deteriorate the dismal performance of such approaches.ResultsWe propose a novel approach of finding correlated short sequence motifs from protein-protein interaction data to effectively circumvent the above-mentioned limitations. Correlated motifs are those motifs that consistently co-occur only in pairs of interacting protein sequences, and could possibly interact with each other directly or indirectly to mediate interactions. We adopted the (l, d)-motif model and formulate finding the correlated motifs as an (l, d)-motif pair finding problem. We present both an exact algorithm, D-MOTIF, as well as its approximation algorithm, D-STAR to solve this problem. Evaluation on extensive simulated data showed that our approach not only eliminated the need for any prior protein grouping, but is also more robust in extracting motifs from noisy interaction data. Application on two biological datasets (SH3 interaction network and TGFβ signaling network) demonstrates that the approach can extract correlated motifs that correspond to actual interacting subsequences.ConclusionThe correlated motif approach outlined in this paper is able to find correlated linear motifs from sparse and noisy interaction data. This, in turn, will expedite the discovery of novel linear binding motifs, and facilitate the studies of biological pathways mediated by them.

Integrative approach for computationally inferring protein domain interactions

The current need for high-throughput protein interaction detection has resulted in interaction data being generated en masse, using experimental methods such as yeast-two-hybrids and protein chips. Such data can be errorful and they often do not provide adequate functional information for the detected interactions; it is therefore useful to develop an in silico approach to further validate and annotate the detected protein interactions. Given that protein-protein interactions involve physical interactions between protein domains, domain-domain interaction information can be useful for validating, annotating, and even predicting protein interactions. However, large-scale experimentally determined domain-domain interaction data do not exist; as such, we describe an integrative approach to computationally derive putative domain interactions from multiple data sources, including rosetta stone sequences, protein interactions, and protein complexes. We show the usefulness of such an integrative approach by applying the derived domain interactions to predict and validate protein-protein interactions.

Searching for Rising Stars in Bibliography Networks

Identifying the rising stars is an important but difficult human resource exercise in all organizations. Rising stars are those who currently have relatively low profiles but may eventually emerge as prominent contributors to the organizations. In this paper, we propose a novel PubRank algorithm to identify rising stars in research communities by mining the social networks of researchers in terms of their co-authorship relationships. Experimental results show that PubRank algorithm can be used to effectively mine the bibliography networks to search for rising stars in the research communities.

Ensemble Positive Unlabeled Learning for Disease Gene Identification

An increasing number of genes have been experimentally confirmed in recent years as causative genes to various human diseases. The newly available knowledge can be exploited by machine learning methods to discover additional unknown genes that are likely to be associated with diseases. In particular, positive unlabeled learning (PU learning) methods, which require only a positive training set P (confirmed disease genes) and an unlabeled set U (the unknown candidate genes) instead of a negative training set N, have been shown to be effective in uncovering new disease genes in the current scenario. Using only a single source of data for prediction can be susceptible to bias due to incompleteness and noise in the genomic data and a single machine learning predictor prone to bias caused by inherent limitations of individual methods. In this paper, we propose an effective PU learning framework that integrates multiple biological data sources and an ensemble of powerful machine learning classifiers for disease gene identification. Our proposed method integrates data from multiple biological sources for training PU learning classifiers. A novel ensemble-based PU learning method EPU is then used to integrate multiple PU learning classifiers to achieve accurate and robust disease gene predictions. Our evaluation experiments across six disease groups showed that EPU achieved significantly better results compared with various state-of-the-art prediction methods as well as ensemble learning classifiers. Through integrating multiple biological data sources for training and the outputs of an ensemble of PU learning classifiers for prediction, we are able to minimize the potential bias and errors in individual data sources and machine learning algorithms to achieve more accurate and robust disease gene predictions. In the future, our EPU method provides an effective framework to integrate the additional biological and computational resources for better disease gene predictions.