Developing a logical model of yeast metabolism

With the completion of the sequencing of genomes of increasing numbers of organisms, the focus of biology is moving to determining the role of these genes (functional genomics). To this end it is useful to view the cell as a biochemical machine: it consumes simple molecules to manufacture more complex ones by chaining together biochemical reactions into long sequences referred to as em metabolic pathways. Such metabolic pathways are not linear but often interesect to form complex networks. Genes play a fundamental role in these networks by providing the information to synthesise the enzymes that catalyse biochemical reactions. Although developing a complete model of metabolism is of fundamental importance to biology and medicine, the size and complexity of the network has proven beyond the capacity of human reasoning. This paper presents the first results of the Robot Scientist research programme that aims to automatically discover the function of genes in the metabolism of the yeast em Saccharomyces cerevisiae. Results include: (1) the first logical model of metabolism;(2) a method to predict phenotype by deductive inference; and (3) a method to infer reactions and gene function by aductive inference. We describe the em in vivo experimental set-up which will allow these em in silico predictions to be automatically tested by a laboratory robot

Using a logical model to predict the growth of yeast

<p>Abstract</p> <p>Background</p> <p>A logical model of the known metabolic processes in <it>S. cerevisiae </it>was constructed from iFF708, an existing Flux Balance Analysis (FBA) model, and augmented with information from the KEGG online pathway database. The use of predicate logic as the knowledge representation for modelling enables an explicit representation of the structure of the metabolic network, and enables logical inference techniques to be used for model identification/improvement.</p> <p>Results</p> <p>Compared to the FBA model, the logical model has information on an additional 263 putative genes and 247 additional reactions. The correctness of this model was evaluated by comparison with iND750 (an updated FBA model closely related to iFF708) by evaluating the performance of both models on predicting empirical minimal medium growth data/essential gene listings.</p> <p>Conclusion</p> <p>ROC analysis and other statistical studies revealed that use of the simpler logical form and larger coverage results in no significant degradation of performance compared to iND750.</p

Evolutionary discovery of multi-relational association rules from ontological knowledge bases

In the Semantic Web, OWL ontologies play the key role of domain conceptualizations, while the corresponding assertional knowledge is given by the heterogeneousWeb resources referring to them. However, being strongly decoupled, ontologies and assertional knowledge can be out of sync. In particular, an ontology may be incomplete, noisy, and sometimes inconsistent with the actual usage of its conceptual vocabulary in the assertions. Despite of such problematic situations, we aim at discovering hidden knowledge patterns from ontological knowledge bases, in the form of multi-relational association rules, by exploiting the evidence coming from the (evolving) assertional data. The final goal is to make use of such patterns for (semi-)automatically enriching/completing existing ontologies. An evolutionary search method applied to populated ontological knowledge bases is proposed for the purpose. The method is able to mine intensional and assertional knowledge by exploiting problemaware genetic operators, echoing the refinement operators of inductive logic programming, and by taking intensional knowledge into account, which allows to restrict the search space and direct the evolutionary process. The discovered rules are represented in SWRL, so that they can be straightforwardly integrated within the ontology, thus enriching its expressive power and augmenting the assertional knowledge that can be derived from it. Discovered rules may also suggest new (schema) axioms to be added to the ontology. We performed experiments on publicly available ontologies, validating the performances of our approach and comparing them with the main state-of-the-art systems

Functional genomic hypothesis generation and experimentation by a robot scientist

The question of whether it is possible to automate the scientific process is of both great theoretical interest and increasing practical importance because, in many scientific areas, data are being generated much faster than they can be effectively analysed. We describe a physically implemented robotic system that applies techniques from artificial intelligence to carry out cycles of scientific experimentation. The system automatically originates hypotheses to explain observations, devises experiments to test these hypotheses, physically runs the experiments using a laboratory robot, interprets the results to falsify hypotheses inconsistent with the data, and then repeats the cycle. Here we apply the system to the determination of gene function using deletion mutants of yeast (Saccharomyces cerevisiae) and auxotrophic growth experiments. We built and tested a detailed logical model (involving genes, proteins and metabolites) of the aromatic amino acid synthesis pathway. In biological experiments that automatically reconstruct parts of this model, we show that an intelligent experiment selection strategy is competitive with human performance and significantly outperforms, with a cost decrease of 3-fold and 100-fold (respectively), both cheapest and random-experiment selection