Analysis of the impact degree distribution in metabolic networks using branching process approximation

Theoretical frameworks to estimate the tolerance of metabolic networks to various failures are important to evaluate the robustness of biological complex systems in systems biology. In this paper, we focus on a measure for robustness in metabolic networks, namely, the impact degree, and propose an approximation method to predict the probability distribution of impact degrees from metabolic network structures using the theory of branching process. We demonstrate the relevance of this method by testing it on real-world metabolic networks. Although the approximation method possesses a few limitations, it may be a powerful tool for evaluating metabolic robustness.Comment: 17 pages, 4 figures, 4 table

How to understand the cell by breaking it: network analysis of gene perturbation screens

Modern high-throughput gene perturbation screens are key technologies at the forefront of genetic research. Combined with rich phenotypic descriptors they enable researchers to observe detailed cellular reactions to experimental perturbations on a genome-wide scale. This review surveys the current state-of-the-art in analyzing perturbation screens from a network point of view. We describe approaches to make the step from the parts list to the wiring diagram by using phenotypes for network inference and integrating them with complementary data sources. The first part of the review describes methods to analyze one- or low-dimensional phenotypes like viability or reporter activity; the second part concentrates on high-dimensional phenotypes showing global changes in cell morphology, transcriptome or proteome.Comment: Review based on ISMB 2009 tutorial; after two rounds of revisio

Understanding interdependency through complex information sharing

The interactions between three or more random variables are often nontrivial, poorly understood, and yet, are paramount for future advances in fields such as network information theory, neuroscience, genetics and many others. In this work, we propose to analyze these interactions as different modes of information sharing. Towards this end, we introduce a novel axiomatic framework for decomposing the joint entropy, which characterizes the various ways in which random variables can share information. The key contribution of our framework is to distinguish between interdependencies where the information is shared redundantly, and synergistic interdependencies where the sharing structure exists in the whole but not between the parts. We show that our axioms determine unique formulas for all the terms of the proposed decomposition for a number of cases of interest. Moreover, we show how these results can be applied to several network information theory problems, providing a more intuitive understanding of their fundamental limits.Comment: 39 pages, 4 figure

Improving the iMM904 S. cerevisiae metabolic model using essentiality and synthetic lethality data

<p>Abstract</p> <p>Background</p> <p><it>Saccharomyces cerevisiae </it>is the first eukaryotic organism for which a multi-compartment genome-scale metabolic model was constructed. Since then a sequence of improved metabolic reconstructions for yeast has been introduced. These metabolic models have been extensively used to elucidate the organizational principles of yeast metabolism and drive yeast strain engineering strategies for targeted overproductions. They have also served as a starting point and a benchmark for the reconstruction of genome-scale metabolic models for other eukaryotic organisms. In spite of the successive improvements in the details of the described metabolic processes, even the recent yeast model (i.e., <it>i</it>MM904) remains significantly less predictive than the latest <it>E. coli </it>model (i.e., <it>i</it>AF1260). This is manifested by its significantly lower specificity in predicting the outcome of grow/no grow experiments in comparison to the <it>E. coli </it>model.</p> <p>Results</p> <p>In this paper we make use of the automated GrowMatch procedure for restoring consistency with single gene deletion experiments in yeast and extend the procedure to make use of synthetic lethality data using the genome-scale model <it>i</it>MM904 as a basis. We identified and vetted using literature sources 120 distinct model modifications including various regulatory constraints for minimal and YP media. The incorporation of the suggested modifications led to a substantial increase in the fraction of correctly predicted lethal knockouts (i.e., specificity) from 38.84% (87 out of 224) to 53.57% (120 out of 224) for the minimal medium and from 24.73% (45 out of 182) to 40.11% (73 out of 182) for the YP medium. Synthetic lethality predictions improved from 12.03% (16 out of 133) to 23.31% (31 out of 133) for the minimal medium and from 6.96% (8 out of 115) to 13.04% (15 out of 115) for the YP medium.</p> <p>Conclusions</p> <p>Overall, this study provides a roadmap for the computationally driven correction of multi-compartment genome-scale metabolic models and demonstrates the value of synthetic lethals as curation agents.</p

Generalised Measures of Multivariate Information Content

The entropy of a pair of random variables is commonly depicted using a Venn diagram. This representation is potentially misleading, however, since the multivariate mutual information can be negative. This paper presents new measures of multivariate information content that can be accurately depicted using Venn diagrams for any number of random variables. These measures complement the existing measures of multivariate mutual information and are constructed by considering the algebraic structure of information sharing. It is shown that the distinct ways in which a set of marginal observers can share their information with a non-observing third party corresponds to the elements of a free distributive lattice. The redundancy lattice from partial information decomposition is then subsequently and independently derived by combining the algebraic structures of joint and shared information content.Comment: 31 pages, 11 figure

Genome-scale models of bacterial metabolism: reconstruction and applications

Genome-scale metabolic models bridge the gap between genome-derived biochemical information and metabolic phenotypes in a principled manner, providing a solid interpretative framework for experimental data related to metabolic states, and enabling simple in silico experiments with whole-cell metabolism. Models have been reconstructed for almost 20 bacterial species, so far mainly through expert curation efforts integrating information from the literature with genome annotation. A wide variety of computational methods exploiting metabolic models have been developed and applied to bacteria, yielding valuable insights into bacterial metabolism and evolution, and providing a sound basis for computer-assisted design in metabolic engineering. Recent advances in computational systems biology and high-throughput experimental technologies pave the way for the systematic reconstruction of metabolic models from genomes of new species, and a corresponding expansion of the scope of their applications. In this review, we provide an introduction to the key ideas of metabolic modeling, survey the methods, and resources that enable model reconstruction and refinement, and chart applications to the investigation of global properties of metabolic systems, the interpretation of experimental results, and the re-engineering of their biochemical capabilities

A New Framework for Decomposing Multivariate Information

What are the distinct ways in which a set of predictor variables can provide information about a target variable? When does a variable provide unique information, when do variables share redundant information, and when do variables combine synergistically to provide complementary information? The redundancy lattice from the partial information decomposition of Williams and Beer provided a promising glimpse at the answer to these questions. However, this structure was constructed using a much-criticised measure of redundant information, and despite sustained research, no completely satisfactory replacement measure has been proposed. This thesis presents a new framework for information decomposition that is based upon the decomposition of pointwise mutual information rather than mutual information. The framework is derived in two separate ways. The first of these derivations is based upon a modified version of the original axiomatic approach taken by Williams and Beer. However, to overcome the difficulty associated with signed pointwise mutual information, the decomposition is applied separately to the unsigned entropic components of pointwise mutual information which are referred to as the specificity and ambiguity. This yields a separate redundancy lattice for each component. Based upon an operational interpretation of redundancy, measures of redundant specificity and redundant ambiguity are defined which enables one to evaluate the partial information atoms separately for each lattice. These separate atoms can then be recombined to yield the sought-after multivariate information decomposition. This framework is applied to canonical examples from the literature and the results and various properties of the decomposition are discussed. In particular, the pointwise decomposition using specificity and ambiguity is shown to satisfy a chain rule over target variables, which provides new insights into the so-called two-bit-copy example. The second approach begins by considering the distinct ways in which two marginal observers can share their information with the non-observing individual third party. Several novel measures of information content are introduced, namely the union, intersection and unique information contents. Next, the algebraic structure of these new measures of shared marginal information is explored, and it is shown that the structure of shared marginal information is that of a distributive lattice. Furthermore, by using the fundamental theorem of distributive lattices, it is shown that these new measures are isomorphic to a ring of sets. Finally, by combining this structure together with the semi-lattice of joint information, the redundancy lattice form partial information decomposition is found to be embedded within this larger algebraic structure. However, since this structure considers information contents, it is actually equivalent to the specificity lattice from the first derivation of pointwise partial information decomposition. The thesis then closes with a discussion about whether or not one should combine the information contents from the specificity and ambiguity lattices