Dynamical complexity of discrete time regulatory networks

Genetic regulatory networks are usually modeled by systems of coupled differential equations and by finite state models, better known as logical networks, are also used. In this paper we consider a class of models of regulatory networks which present both discrete and continuous aspects. Our models consist of a network of units, whose states are quantified by a continuous real variable. The state of each unit in the network evolves according to a contractive transformation chosen from a finite collection of possible transformations, according to a rule which depends on the state of the neighboring units. As a first approximation to the complete description of the dynamics of this networks we focus on a global characteristic, the dynamical complexity, related to the proliferation of distinguishable temporal behaviors. In this work we give explicit conditions under which explicit relations between the topological structure of the regulatory network, and the growth rate of the dynamical complexity can be established. We illustrate our results by means of some biologically motivated examples.Comment: 28 pages, 4 figure

Discrete time piecewise affine models of genetic regulatory networks

We introduce simple models of genetic regulatory networks and we proceed to the mathematical analysis of their dynamics. The models are discrete time dynamical systems generated by piecewise affine contracting mappings whose variables represent gene expression levels. When compared to other models of regulatory networks, these models have an additional parameter which is identified as quantifying interaction delays. In spite of their simplicity, their dynamics presents a rich variety of behaviours. This phenomenology is not limited to piecewise affine model but extends to smooth nonlinear discrete time models of regulatory networks. In a first step, our analysis concerns general properties of networks on arbitrary graphs (characterisation of the attractor, symbolic dynamics, Lyapunov stability, structural stability, symmetries, etc). In a second step, focus is made on simple circuits for which the attractor and its changes with parameters are described. In the negative circuit of 2 genes, a thorough study is presented which concern stable (quasi-)periodic oscillations governed by rotations on the unit circle -- with a rotation number depending continuously and monotonically on threshold parameters. These regular oscillations exist in negative circuits with arbitrary number of genes where they are most likely to be observed in genetic systems with non-negligible delay effects.Comment: 34 page

Ensembles, Dynamics, and Cell Types: Revisiting the Statistical Mechanics Perspective on Cellular Regulation

Genetic regulatory networks control ontogeny. For fifty years Boolean networks have served as models of such systems, ranging from ensembles of random Boolean networks as models for generic properties of gene regulation to working dynamical models of a growing number of sub-networks of real cells. At the same time, their statistical mechanics has been thoroughly studied. Here we recapitulate their original motivation in the context of current theoretical and empirical research. We discuss ensembles of random Boolean networks whose dynamical attractors model cell types. A sub-ensemble is the critical ensemble. There is now strong evidence that genetic regulatory networks are dynamically critical, and that evolution is exploring the critical sub-ensemble. The generic properties of this sub-ensemble predict essential features of cell differentiation. In particular, the number of attractors in such networks scales as the DNA content raised to the 0.63 power. Data on the number of cell types as a function of the DNA content per cell shows a scaling relationship of 0.88. Thus, the theory correctly predicts a power law relationship between the number of cell types and the DNA contents per cell, and a comparable slope. We discuss these new scaling values and show prospects for new research lines for Boolean networks as a base model for systems biology.Comment: 22 pages, article will be included in a special issue of J. Theor. Biol. dedicated to the memory of Prof. Rene Thoma

Additive Functions in Boolean Models of Gene Regulatory Network Modules

Gene-on-gene regulations are key components of every living organism. Dynamical abstract models of genetic regulatory networks help explain the genome’s evolvability and robustness. These properties can be attributed to the structural topology of the graph formed by genes, as vertices, and regulatory interactions, as edges. Moreover, the actual gene interaction of each gene is believed to play a key role in the stability of the structure. With advances in biology, some effort was deployed to develop update functions in Boolean models that include recent knowledge. We combine real-life gene interaction networks with novel update functions in a Boolean model. We use two sub-networks of biological organisms, the yeast cell-cycle and the mouse embryonic stem cell, as topological support for our system. On these structures, we substitute the original random update functions by a novel threshold-based dynamic function in which the promoting and repressing effect of each interaction is considered. We use a third real-life regulatory network, along with its inferred Boolean update functions to validate the proposed update function. Results of this validation hint to increased biological plausibility of the threshold-based function. To investigate the dynamical behavior of this new model, we visualized the phase transition between order and chaos into the critical regime using Derrida plots. We complement the qualitative nature of Derrida plots with an alternative measure, the criticality distance, that also allows to discriminate between regimes in a quantitative way. Simulation on both real-life genetic regulatory networks show that there exists a set of parameters that allows the systems to operate in the critical region. This new model includes experimentally derived biological information and recent discoveries, which makes it potentially useful to guide experimental research. The update function confers additional realism to the model, while reducing the complexity and solution space, thus making it easier to investigate

The number and probability of canalizing functions

Canalizing functions have important applications in physics and biology. For example, they represent a mechanism capable of stabilizing chaotic behavior in Boolean network models of discrete dynamical systems. When comparing the class of canalizing functions to other classes of functions with respect to their evolutionary plausibility as emergent control rules in genetic regulatory systems, it is informative to know the number of canalizing functions with a given number of input variables. This is also important in the context of using the class of canalizing functions as a constraint during the inference of genetic networks from gene expression data. To this end, we derive an exact formula for the number of canalizing Boolean functions of n variables. We also derive a formula for the probability that a random Boolean function is canalizing for any given bias p of taking the value 1. In addition, we consider the number and probability of Boolean functions that are canalizing for exactly k variables. Finally, we provide an algorithm for randomly generating canalizing functions with a given bias p and any number of variables, which is needed for Monte Carlo simulations of Boolean networks

Boolean network model predicts cell cycle sequence of fission yeast

A Boolean network model of the cell-cycle regulatory network of fission yeast (Schizosaccharomyces Pombe) is constructed solely on the basis of the known biochemical interaction topology. Simulating the model in the computer, faithfully reproduces the known sequence of regulatory activity patterns along the cell cycle of the living cell. Contrary to existing differential equation models, no parameters enter the model except the structure of the regulatory circuitry. The dynamical properties of the model indicate that the biological dynamical sequence is robustly implemented in the regulatory network, with the biological stationary state G1 corresponding to the dominant attractor in state space, and with the biological regulatory sequence being a strongly attractive trajectory. Comparing the fission yeast cell-cycle model to a similar model of the corresponding network in S. cerevisiae, a remarkable difference in circuitry, as well as dynamics is observed. While the latter operates in a strongly damped mode, driven by external excitation, the S. pombe network represents an auto-excited system with external damping.Comment: 10 pages, 3 figure