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ANALYSIS OF LARGE-SCALE BIOLOGICAL NETWORKS WITH CONSTRAINT-BASED APPROACHES OVER STATIC MODELS

By  and CARITO GUZIOLOWSKI and CARITO GUZIOLOWSKI

Abstract

To this date many approaches exist that model a genetic regulatory network in order to elucidate the dynamics of the system. These rnethods focus, however, mainly on small-scale regulatory models. In this thesis we use a formal approach over qualitative large-scale regulatory networks, that models the equilibrium shift of the cell molecules between two steady states. We test the coherency between the network topology and gene expression data, by using a general ínteraction logical causal rule. The outputs of our approach are to measure the consistency of our data, diagnose inconsistent regions of the network with respect to the experimental data, and infer the qualitative variation of new network molecules. Our method reasons over the whole network of interactions using efficient algorithms based either on decision diagrams, dependency graphs, or answer set programming. We proposed programs and bioinformatic tools that, based on these efficient implementations, automatize this reasoning. We validated this approach using the transcriptional networks of E. coli and S. cerevisiae, and the signaling network of the EWS-FLI1 human oncogene. Our main results were: (1) high prediction accuracy of the shifts of the network molecules, (2) effective manual and autornatic corrections of the model and/or data, (3) automatíc inference of the role of transcription factors, and (4) automatic reasoning over the causes that influence important phenotypes on a signaling networl. All in all, we provided a methodology that can be applied to complete regulatory networks built at different molecular levels, by exploiting the constantly incrcasing high-throughput outputs.To this date many approaches exist that model a genetic regulatory network in order to elucidate the dynamics of the system. These rnethods focus, however, mainly onsmall-scale regulatory models. In this thesis we use a formal approach over qualitativela

Topics: INGENIERIA Y TECNOLOGIA, INFORMATICA
Year: 2010
OAI identifier: oai:dspace2.conicyt.cl:10533/76407
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