MOfinder: A Novel Algorithm for Detecting Overlapping Modules from Protein-Protein Interaction Network

Since organism development and many critical cell biology processes are organized in modular patterns, many algorithms have been proposed to detect modules. In this study, a new method, MOfinder, was developed to detect overlapping modules in a protein-protein interaction (PPI) network. We demonstrate that our method is more accurate than other 5 methods. Then, we applied MOfinder to yeast and human PPI network and explored the overlapping information. Using the overlapping modules of human PPI network, we constructed the module-module communication network. Functional annotation showed that the immune-related and cancer-related proteins were always together and present in the same modules, which offer some clues for immune therapy for cancer. Our study around overlapping modules suggests a new perspective on the analysis of PPI network and improves our understanding of disease

Recent advances in clustering methods for protein interaction networks

The increasing availability of large-scale protein-protein interaction data has made it possible to understand the basic components and organization of cell machinery from the network level. The arising challenge is how to analyze such complex interacting data to reveal the principles of cellular organization, processes and functions. Many studies have shown that clustering protein interaction network is an effective approach for identifying protein complexes or functional modules, which has become a major research topic in systems biology. In this review, recent advances in clustering methods for protein interaction networks will be presented in detail. The predictions of protein functions and interactions based on modules will be covered. Finally, the performance of different clustering methods will be compared and the directions for future research will be discussed

Biological Networks: Modeling and Structural Analysis

Biological networks are receiving increased attention due to their importance in understanding life at the cellular level. There exist many different kinds of biological networks, and different models have been proposed for them. In this dissertation we focus on suitable network models for representing experimental data on protein interaction networks and protein complex networks (protein complexes are groups of proteins that associate to accomplish some function in the cell), and to design algorithms for exploring such networks. Our goal is to enable biologists to identify the general principles that govern the organization of protein-protein interaction networks and protein complex networks. For protein complex networks, we propose a hypergraph model which more accurately represents the data than earlier models. We define the concept of k-cores in hypergraphs, which are highly connected subhypergraphs, and design an algorithm for computing k -cores in hypergraphs. A major challenge in computational systems biology is to understand the modular structure of biological networks. We construct computational models for predicting functional modules through the use of graph clustering techniques. The application of earlier graph clustering techniques to proteomic networks does not yield good results due to the high error rates present, and the small-world and power-law properties of these networks. We discuss the various requirements that clusterings of biological networks are required to satisfy, design an algorithm for computing a clustering, and show that our clustering approach is robust and scalable. Moreover, we design a new algorithm to compute overlapping clustering rather than exclusive clustering. Our approach identifies a set of clusters and a set of bridge proteins that form the overlap among the clusters. Finally we assess the quality of our proposed clusterings using different reference sets

Bridging topological and functional information in protein interaction networks by short loops profiling

Protein-protein interaction networks (PPINs) have been employed to identify potential novel interconnections between proteins as well as crucial cellular functions. In this study we identify fundamental principles of PPIN topologies by analysing network motifs of short loops, which are small cyclic interactions of between 3 and 6 proteins. We compared 30 PPINs with corresponding randomised null models and examined the occurrence of common biological functions in loops extracted from a cross-validated high-confidence dataset of 622 human protein complexes. We demonstrate that loops are an intrinsic feature of PPINs and that specific cell functions are predominantly performed by loops of different lengths. Topologically, we find that loops are strongly related to the accuracy of PPINs and define a core of interactions with high resilience. The identification of this core and the analysis of loop composition are promising tools to assess PPIN quality and to uncover possible biases from experimental detection methods. More than 96% of loops share at least one biological function, with enrichment of cellular functions related to mRNA metabolic processing and the cell cycle. Our analyses suggest that these motifs can be used in the design of targeted experiments for functional phenotype detection.This research was supported by the Biotechnology and Biological Sciences Research Council (BB/H018409/1 to AP, ACCC and FF, and BB/J016284/1 to NSBT) and by the Leukaemia & Lymphoma Research (to NSBT and FF). SSC is funded by a Leukaemia & Lymphoma Research Gordon Piller PhD Studentship

Detecting Cohesive and 2-mode Communities in Directed and Undirected Networks

Networks are a general language for representing relational information among objects. An effective way to model, reason about, and summarize networks, is to discover sets of nodes with common connectivity patterns. Such sets are commonly referred to as network communities. Research on network community detection has predominantly focused on identifying communities of densely connected nodes in undirected networks. In this paper we develop a novel overlapping community detection method that scales to networks of millions of nodes and edges and advances research along two dimensions: the connectivity structure of communities, and the use of edge directedness for community detection. First, we extend traditional definitions of network communities by building on the observation that nodes can be densely interlinked in two different ways: In cohesive communities nodes link to each other, while in 2-mode communities nodes link in a bipartite fashion, where links predominate between the two partitions rather than inside them. Our method successfully detects both 2-mode as well as cohesive communities, that may also overlap or be hierarchically nested. Second, while most existing community detection methods treat directed edges as though they were undirected, our method accounts for edge directions and is able to identify novel and meaningful community structures in both directed and undirected networks, using data from social, biological, and ecological domains.Comment: Published in the proceedings of WSDM '1

Network Analysis of Microarray Data

DNA microarrays are widely used to investigate gene expression. Even though the classical analysis of microarray data is based on the study of differentially expressed genes, it is well known that genes do not act individually. Network analysis can be applied to study association patterns of the genes in a biological system. Moreover, it finds wide application in differential coexpression analysis between different systems. Network based coexpression studies have for example been used in (complex) disease gene prioritization, disease subtyping, and patient stratification.Peer reviewe

Computational Labeling, Partitioning, and Balancing of Molecular Networks

Recent advances in high throughput techniques enable large-scale molecular quantification with high accuracy, including mRNAs, proteins and metabolites. Differential expression of these molecules in case and control samples provides a way to select phenotype-associated molecules with statistically significant changes. However, given the significance ranking list of molecular changes, how those molecules work together to drive phenotype formation is still unclear. In particular, the changes in molecular quantities are insufficient to interpret the changes in their functional behavior. My study is aimed at answering this question by integrating molecular network data to systematically model and estimate the changes of molecular functional behaviors. We build three computational models to label, partition, and balance molecular networks using modern machine learning techniques. (1) Due to the incompleteness of protein functional annotation, we develop AptRank, an adaptive PageRank model for protein function prediction on bilayer networks. By integrating Gene Ontology (GO) hierarchy with protein-protein interaction network, our AptRank outperforms four state-of-the-art methods in a comprehensive evaluation using benchmark datasets. (2) We next extend our AptRank into a network partitioning method, BioSweeper, to identify functional network modules in which molecules share similar functions and also densely connect to each other. Compared to traditional network partitioning methods using only network connections, BioSweeper, which integrates the GO hierarchy, can automatically identify functionally enriched network modules. (3) Finally, we conduct a differential interaction analysis, namely difFBA, on protein-protein interaction networks by simulating protein fluxes using flux balance analysis (FBA). We test difFBA using quantitative proteomic data from colon cancer, and demonstrate that difFBA offers more insights into functional changes in molecular behavior than does protein quantity changes alone. We conclude that our integrative network model increases the observational dimensions of complex biological systems, and enables us to more deeply understand the causal relationships between genotypes and phenotypes