Reverse engineering genetic networks using nonlinear saturation kinetics.

ABSTRACT

A gene regulatory network (GRN) represents a set of genes along with their regulatory interactions. Cellular behavior is driven by genetic level interactions. Dynamics of such systems show nonlinear saturation kinetics which can be best modeled by Michaelis-Menten (MM) and Hill equations. Although MM equation is being widely used for modeling biochemical processes, it has been applied rarely for reverse engineering GRNs. In this paper, we develop a complete framework for a novel model for GRN inference using MM kinetics. A set of coupled equations is first proposed for modeling GRNs. In the coupled model, Michaelis-Menten constant associated with regulation by a gene is made invariant irrespective of the gene being regulated. The parameter estimation of the proposed model is carried out using an evolutionary optimization method, namely, trigonometric differential evolution (TDE). Subsequently, the model is further improved and the regulations of different genes by a given gene are made distinct by allowing varying values of Michaelis-Menten constants for each regulation. Apart from making the model more relevant biologically, the improvement results in a decoupled GRN model with fast estimation of model parameters. Further, to enhance exploitation of the search, we propose a local search algorithm based on hill climbing heuristics. A novel mutation operation is also proposed to avoid population stagnation and premature convergence. Real life benchmark data sets generated in vivo are used for validating the proposed model. Further, we also analyze realistic in silico datasets generated using GeneNetweaver. The comparison of the performance of proposed model with other existing methods shows the potential of the proposed model.