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Register a new userDiffusion Component Analysis: Unraveling Functional Topology in Biological Networks
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Complex biological systems have been successfully modeled by biochemical and genetic interaction networks, typically gathered from high-throughput (HTP) data. These networks can be used to infer functional relationships between genes or proteins. Using the intuition that the topological role of a gene in a network relates to its biological function, local or diffusion based guilt-by-association and graph-theoretic methods have had success in inferring gene functions. Here we seek to improve function prediction by integrating diffusion-based methods with a novel dimensionality reduction technique to overcome the incomplete and noisy nature of network data. In this paper, we introduce diffusion component analysis (DCA), a framework that plugs in a diffusion model and learns a low-dimensional vector representation of each node to encode the topological properties of a network. As a proof of concept, we demonstrate DCAs substantial improvement over state-of-the-art diffusion-based approaches in predicting protein function from molecular interaction networks. Moreover, our DCA framework can integrate multiple networks from heterogeneous sources, consisting of genomic information, biochemical experiments and other resources, to even further improve function prediction. Yet another layer of performance gain is achieved by integrating the DCA framework with support vector machines that take our node vector representations as features. Overall, our DCA framework provides a novel representation of nodes in a network that can be used as a plug-in architecture to other machine learning algorithms to decipher topological properties of and obtain novel insights into interactomes.
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Networks are ubiquitous in biology where they encode connectivity patterns at all scales of organization, from molecular to the biome. However, biological networks are noisy due to the limitations of measurement technology and inherent natural variation, which can hamper discovery of network patterns and dynamics. We propose Network Enhancement (NE), a method for improving the signal-to-noise ratio of undirected, weighted networks. NE uses a doubly stochastic matrix operator that induces sparsity and provides a closed-form solution that increases spectral eigengap of the input network. As a result, NE removes weak edges, enhances real connections, and leads to better downstream performance. Experiments show that NE improves gene function prediction by denoising tissue-specific interaction networks, alleviates interpretation of noisy Hi-C contact maps from the human genome, and boosts fine-grained identification accuracy of species. Our results indicate that NE is widely applicable for denoising biological networks.
The rapidly developing theory of complex networks indicates that real networks are not random, but have a highly robust large-scale architecture, governed by strict organizational principles. Here, we focus on the properties of biological networks, discussing their scale-free and hierarchical features. We illustrate the major network characteristics using examples from the metabolic network of the bacterium Escherichia coli. We also discuss the principles of network utilization, acknowledging that the interactions in a real network have unequal strengths. We study the interplay between topology and reaction fluxes provided by flux-balance analysis. We find that the cellular utilization of the metabolic network is both globally and locally highly inhomogeneous, dominated by hot-spots, representing connected high-flux pathways.
Information transmission in biological signaling circuits has often been described using the metaphor of a noise filter. Cellular systems need accurate, real-time data about their environmental conditions, but the biochemical reaction networks that propagate, amplify, and process signals work with noisy representations of that data. Biology must implement strategies that not only filter the noise, but also predict the current state of the environment based on information delayed due to the finite speed of chemical signaling. The idea of a biochemical noise filter is actually more than just a metaphor: we describe recent work that has made an explicit mathematical connection between signaling fidelity in cellular circuits and the classic theories of optimal noise filtering and prediction that began with Wiener, Kolmogorov, Shannon, and Bode. This theoretical framework provides a versatile tool, allowing us to derive analytical bounds on the maximum mutual information between the environmental signal and the real-time estimate constructed by the system. It helps us understand how the structure of a biological network, and the response times of its components, influences the accuracy of that estimate. The theory also provides insights into how evolution may have tuned enzyme kinetic parameters and populations to optimize information transfer.
Living systems are often described utilizing informational analogies. An important open question is whether information is merely a useful conceptual metaphor, or intrinsic to the operation of biological systems. To address this question, we provide a rigorous case study of the informational architecture of two representative biological networks: the Boolean network model for the cell-cycle regulatory network of the fission yeast S. pombe and that of the budding yeast S. cerevisiae. We compare our results for these biological networks to the same analysis performed on ensembles of two different types of random networks. We show that both biological networks share features in common that are not shared by either ensemble. In particular, the biological networks in our study, on average, process more information than the random networks. They also exhibit a scaling relation in information transferred between nodes that distinguishes them from either ensemble: even when compared to the ensemble of random networks that shares important topological properties, such as a scale-free structure. We show that the most biologically distinct regime of this scaling relation is associated with the dynamics and function of the biological networks. Information processing in biological networks is therefore interpreted as an emergent property of topology (causal structure) and dynamics (function). These results demonstrate quantitatively how the informational architecture of biologically evolved networks can distinguish them from other classes of network architecture that do not share the same informational properties.
Boolean networks have long been used as models of molecular networks and play an increasingly important role in systems biology. This paper describes a software package, Polynome, offered as a web service, that helps users construct Boolean network models based on experimental data and biological input. The key feature is a discrete analog of parameter estimation for continuous models. With only experimental data as input, the software can be used as a tool for reverse-engineering of Boolean network models from experimental time course data.
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