A computational framework for qualitative simulation of nonlinear dynamical models of gene-regulatory networks.
BACKGROUND
Due to the huge amount of information at genomic level made recently available by high-throughput experimental technologies, networks of regulatory interactions between genes and gene products, the so-called gene-regulatory networks, can be uncovered. Most networks of interest are quite intricate because of both the high dimension of interacting elements and the complexity of the kinds of interactions between them. Then, mathematical and computational modeling frameworks are a must to predict the network behavior in response to environmental stimuli. A specific class of Ordinary Differential Equations (ODE) has shown to be adequate to describe the essential features of the dynamics of gene-regulatory networks. But, deriving quantitative predictions of the network dynamics through the numerical simulation of such models is mostly impracticable as they are currently characterized by incomplete knowledge of biochemical reactions underlying regulatory interactions, and of numeric values of kinetic parameters.


RESULTS
This paper presents a computational framework for qualitative simulation of a class of ODE models, based on the assumption that gene regulation is threshold-dependent, i.e. only effective above or below a certain threshold. The simulation algorithm we propose assumes that threshold-dependent regulation mechanisms are modeled by continuous steep sigmoid functions, unlike other simulation tools that considerably simplifies the problem by approximating threshold-regulated response functions by step functions discontinuous in the thresholds. The algorithm results from the interplay between methods to deal with incomplete knowledge and to study phenomena that occur at different time-scales.


CONCLUSIONS
The work herein presented establishes the computational groundwork for a sound and a complete algorithm capable to capture the dynamical properties that depend only on the network structure and are invariant for ranges of values of kinetic parameters. At the current state of knowledge, the exploitation of such a tool is rather appropriate and useful to understand how specific activity patterns derive from given network structures, and what different types of dynamical behaviors are possible.
Ironi
Liliana
L
IMATI-Consiglio Nazionale delle Ricerche, via Ferrata 1, Pavia, Italy. ironi@imati.cnr.it
Panzeri
Luigi
L
D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D053263:Gene Regulatory Networks / Q000235:genetics*; D008957:Models, Genetic; D017711:Nonlinear Dynamics