A Factor Graph Approach to Automated GO Annotation

As volume of genomic data grows, computational methods become essential for providing a first glimpse onto gene annotations. Automated Gene Ontology (GO) annotation methods based on hierarchical ensemble classification techniques are particularly interesting when interpretability of annotation results is a main concern. In these methods, raw GO-term predictions computed by base binary classifiers are leveraged by checking the consistency of predefined GO relationships. Both formal leveraging strategies, with main focus on annotation precision, and heuristic alternatives, with main focus on scalability issues, have been described in literature. In this contribution, a factor graph approach to the hierarchical ensemble formulation of the automated GO annotation problem is presented. In this formal framework, a core factor graph is first built based on the GO structure and then enriched to take into account the noisy nature of GO-term predictions. Hence, starting from raw GO-term predictions, an iterative message passing algorithm between nodes of the factor graph is used to compute marginal probabilities of target GO-terms. Evaluations on Saccharomyces cerevisiae, Arabidopsis thaliana and Drosophila melanogaster protein sequences from the GO Molecular Function domain showed significant improvements over competing approaches, even when protein sequences were naively characterized by their physicochemical and secondary structure properties or when loose noisy annotation datasets were considered. Based on these promising results and using Arabidopsis thaliana annotation data, we extend our approach to the identification of most promising molecular function annotations for a set of proteins of unknown function in Solanum lycopersicum.Fil: Spetale, Flavio Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas. Universidad Nacional de Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas; ArgentinaFil: Krsticevic, Flavia Jorgelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas. Universidad Nacional de Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas; ArgentinaFil: Roda, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas. Universidad Nacional de Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas; ArgentinaFil: Bulacio, Pilar Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas. Universidad Nacional de Rosario. Centro Internacional Franco Argentino de Ciencias de la Información y de Sistemas; Argentin

Identifying regulatory targets of cell cycle transcription factors using gene expression and ChIP-chip data

Abstract Background ChIP-chip data, which indicate binding of transcription factors (TFs) to DNA regions in vivo, are widely used to reconstruct transcriptional regulatory networks. However, the binding of a TF to a gene does not necessarily imply regulation. Thus, it is important to develop methods to identify regulatory targets of TFs from ChIP-chip data. Results We developed a method, called Temporal Relationship Identification Algorithm (TRIA), which uses gene expression data to identify a TF's regulatory targets among its binding targets inferred from ChIP-chip data. We applied TRIA to yeast cell cycle microarray data and identified many plausible regulatory targets of cell cycle TFs. We validated our predictions by checking the enrichments for functional annotation and known cell cycle genes. Moreover, we showed that TRIA performs better than two published methods (MA-Network and MFA). It is known that co-regulated genes may not be co-expressed. TRIA has the ability to identify subsets of highly co-expressed genes among the regulatory targets of a TF. Different functional roles are found for different subsets, indicating the diverse functions a TF could have. Finally, for a control, we showed that TRIA also performs well for cell-cycle irrelevant TFs. Conclusion Finding the regulatory targets of TFs is important for understanding how cells change their transcription program to adapt to environmental stimuli. Our algorithm TRIA is helpful for achieving this purpose.</p

Control of stochastic and induced switching in biophysical networks

Noise caused by fluctuations at the molecular level is a fundamental part of intracellular processes. While the response of biological systems to noise has been studied extensively, there has been limited understanding of how to exploit it to induce a desired cell state. Here we present a scalable, quantitative method based on the Freidlin-Wentzell action to predict and control noise-induced switching between different states in genetic networks that, conveniently, can also control transitions between stable states in the absence of noise. We apply this methodology to models of cell differentiation and show how predicted manipulations of tunable factors can induce lineage changes, and further utilize it to identify new candidate strategies for cancer therapy in a cell death pathway model. This framework offers a systems approach to identifying the key factors for rationally manipulating biophysical dynamics, and should also find use in controlling other classes of noisy complex networks.Comment: A ready-to-use code package implementing the method described here is available from the authors upon reques

Multi-scale genetic network inference based on time series gene expression profiles

This work integrates multi-scale clustering and short-time correlation to estimate genetic networks with different time resolutions and detail levels. Gene expression data are noisy and large scale. Clustering is widely used to group genes with similar pattern. The cluster centers can be used to infer the genetic networks among these clusters. This work introduces the Multi-scale Fuzzy K-means clustering algorithm to uncover groups of coregulated genes and capture the networks in different levels of detail.;Time series expression profiles provide dynamic information for inferring gene regulatory relationships. Large scale network inference, identifying the transient interactions and feedback loops as well as differentiating direct and indirect interactions are among the major challenges of genetic network inference. Time correlation can estimate the time delay and edge direction. Partial correlation and directed-separation theory help differentiate direct and indirect interactions and identify feedback loops. This work introduces the constraint-based time-correlation (CBTC) network inference algorithm that combines these methods with time correlation estimation to more fully characterize genetic networks. Gene expression regulation can happen in specific time periods and conditions instead of across the whole expression profile. Short-time correlation can capture transient interactions.;The network discovery algorithm was mainly validated using yeast cell cycle data. The algorithm successfully identified the yeast cell cycle development stages, cell cycle and negative feedback loops, and indicated how the networks dynamically changes over time. The inferred networks reflect most interactions previously identified by genome-wide location analysis and match the extant literature. At detailed network level, the inferred networks provide more detailed information about genes (or clusters) and the interactions among them. Interesting genes, clusters and interactions were identified, which match the literature and the gene ontology information and provide hypotheses for further studies

A fast and efficient gene-network reconstruction method from multiple over-expression experiments

<p>Abstract</p> <p>Background</p> <p>Reverse engineering of gene regulatory networks presents one of the big challenges in systems biology. Gene regulatory networks are usually inferred from a set of single-gene over-expressions and/or knockout experiments. Functional relationships between genes are retrieved either from the steady state gene expressions or from respective time series.</p> <p>Results</p> <p>We present a novel algorithm for gene network reconstruction on the basis of steady-state gene-chip data from over-expression experiments. The algorithm is based on a straight forward solution of a linear gene-dynamics equation, where experimental data is fed in as a first predictor for the solution. We compare the algorithm's performance with the NIR algorithm, both on the well known <it>E. coli </it>experimental data and on in-silico experiments.</p> <p>Conclusion</p> <p>We show superiority of the proposed algorithm in the number of correctly reconstructed links and discuss computational time and robustness. The proposed algorithm is not limited by combinatorial explosion problems and can be used in principle for large networks.</p