A Novel Knowledge-Driven Systems Biology Approach for Phenotype Prediction upon Genetic Intervention

摘要

Deciphering the biological networks underlying complex phenotypic traits, e.g., human disease is undoubtedly crucial to understand the underlying molecular mechanisms and to develop effective therapeutics. Due to the network complexity and the relatively small number of available experiments, data-driven modeling is a great challenge for deducing the functions of genes/proteins in the network and in phenotype formation. We propose a novel knowledge-driven systems biology method that utilizes qualitative knowledge to construct a Dynamic Bayesian network (DBN) to represent the biological network underlying a specific phenotype. Edges in this network depict physical interactions between genes and/or proteins. A qualitative knowledge model first translates typical molecular interactions into constraints when resolving the DBN structure and parameters. Therefore, the uncertainty of the network is restricted to a subset of models which are consistent with the qualitative knowledge. All models satisfying the constraints are considered as candidates for the underlying network. These consistent models are used to perform quantitative inference. By in silico inference, we can predict phenotypic traits upon genetic interventions and perturbing in the network. We applied our method to analyze the puzzling mechanism of breast cancer cell proliferation network and we accurately predicted cancer cell growth rate upon manipulating (anti)cancerous marker genes/proteins.