Models and algorithms applied to metabolism: From revealing the responses to perturbations towards the design of microbial consortia

Abstract : In this PhD work, we proposed to model metabolism. Our focus was to develop generic models, that are not specific to one organism or condition, but are instead based on general assumptions that we tried to validate using data from the literature.We first present TOTORO that uses a qualitative measurement of concentrations in two steady-states to infer the reaction changes that lead to differences in metabolite pools in both conditions.TOTORO enumerates all sub-(hyper)graphs that represent a sufficient explanation for the observed differences in concentrations. We exploit a dataset of Yeast (Saccharomyces cerevisiae) exposed to cadmium and show that we manage to retrieve the known pathways used by the organisms. We then address the same issue, but using a constraint-based programming framework, called KOTOURA, that allows to infer more quantitatively the reaction changes during the perturbed state. We use in this case exact concentration measurements and the stoichiometric matrix, and show on simulated datasets that the overall variations of reaction fluxes can be captured by our formulation.Finally, we propose MULTIPUS, a method to infer microbial communities and metabolic roads to produce specific target compounds from a set of defined substrates. We use in this case a weighted directed hypergraph. We apply MULTIPUS to the production of antibiotics using a consortium composed of an archae and an actinobacteria and show hat their metabolic capacities are complementary. We then infer for another community the excretion of an inhibitory product (acetate) by a 1,3-propanediol (PDO) producer and its consumption by a methanogene archae
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Alice Julien-Laferriere. Models and algorithms applied to metabolism: From revealing the responses to perturbations towards the design of microbial consortia. Bioinformatics [q-bio.QM]. Université de Lyon, 2016. English. ⟨NNT : 2016LYSE1260⟩. ⟨tel-01394113v2⟩

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