Canalizing Functions Research Articles

Proof for Minimum Sensitivity of Nested Canalizing Functions, a Fractal Bound, and Implications for Biology.

We prove that nested canalizing functions are the minimum-sensitivity Boolean functions for any activity ratio and we determine the functional form of this boundary which has a nontrivial fractal structure. We further observe that the majority of the gene regulatory functions found in known biological networks (submitted to the Cell Collective database) lie on the line of minimum sensitivity which paradoxically remains largely in the unstable regime. Our results provide a quantitative basis for the argument that an evolutionary preference for nested canalizing functions in gene regulation (e.g., for higher robustness) and for plasticity of gene activity are sufficient for concentration of such systems near the "edge of chaos."

Critical dynamics in biological Boolean networks follows from symmetric response to input genes

A recent observation on an extensive collection of biological gene regulatory networks suggests that the regulatory dynamics is tuned to remain close to the order-chaos boundary in the Lyapunov sense [1]. We here investigate, from a mathematical perspective, the structural/functional constraints which give rise to such accumulation around criticality in these systems. While the role of canalizing functions in this respect is well established, we find that critical sensitivity to small input variations also follows from an over-abundance of symmetrical inputs, i.e. regulatory genes invoking identical or complementary responses on their common target. A random network ensemble constructed to have the same distribution of symmetric inputs as in the above collection of biological networks captures the dependence of the sensitivity on mean activity bias, a nontrivial characteristic which the canalizing ensemble fails to fully reproduce.

Certificate complexity and symmetry of nested canalizing functions

Boolean nested canalizing functions (NCFs) have important applications in molecular regulatory networks, engineering and computer science. In this paper, we study their certificate complexity. For both Boolean values $b\in\{0,1\}$, we obtain a formula for $b$-certificate complexity and consequently, we develop a direct proof of the certificate complexity formula of an NCF. Symmetry is another interesting property of Boolean functions and we significantly simplify the proofs of some recent theorems about partial symmetry of NCFs. We also describe the algebraic normal form of $s$-symmetric NCFs. We obtain the general formula of the cardinality of the set of $n$-variable $s$-symmetric Boolean NCFs for $s=1,\dots,n$. In particular, we enumerate the strongly asymmetric Boolean NCFs.

Quantifying the total effect of edge interventions in discrete multistate networks

Developing efficient computational methods to assess the impact of external interventions on the dynamics of a network model is an important problem in systems biology. This paper focuses on quantifying the global changes that result from the application of an intervention to produce a desired effect, which we define as the total effect of the intervention. The type of mathematical models that we will consider are discrete dynamical systems which include the widely used Boolean networks and their generalizations. The potential interventions can be represented by a set of nodes and edges that can be manipulated to produce a desired effect on the system. We use a class of regulatory rules called nested canalizing functions that frequently appear in published models and were inspired by the concept of canalization in evolutionary biology. In this paper, we provide a polynomial normal form based on the canalizing properties of regulatory functions. Using this polynomial normal form, we give a set of formulas for counting the maximum number of transitions that will change in the state space upon an edge deletion in the wiring diagram. These formulas rely on the canalizing structure of the target function since the number of changed transitions depends on the canalizing layer that includes the input to be deleted. We also present computations on random networks to compare the exact number of changes with the upper bounds provided by our formulas. Finally, we provide statistics on the sharpness of these upper bounds in random networks.

Maximal sensitivity of Boolean nested canalizing functions

Boolean nested canalizing functions (NCF) have important applications in molecular regulatory networks, engineering and computer science. In the literature, there are two sensitivities to measure the complexity of a Boolean function. One is average sensitivity, the other one is maximal sensitivity. We follow the tradition and omit the word “maximal”. In other words, in this paper, sensitivity is always maximal sensitivity. Using the past work of the authors and their coauthors on a characterization of NCF, we obtain the formula of the sensitivity of any NCF. We find that the sensitivity of any NCF is between ⌈n+22⌉ and n. Both lower and upper bounds are tight. We prove that the block sensitivity, hence the l-block sensitivity, is the same as the sensitivity for NCF. It is well known that monotone Boolean functions (MBF) also have this property. We characterize all functions which are both monotone and nested canalizing (MNCF). The closed formula of the cardinality of the set of MNCFs is also provided.

The influence of canalization on the robustness of Boolean networks

Time- and state-discrete dynamical systems are frequently used to model molecular networks. This paper provides a collection of mathematical and computational tools for the study of robustness in Boolean network models. The focus is on networks governed by k-canalizing functions, a recently introduced class of Boolean functions that contains the well-studied class of nested canalizing functions. The variable activities and sensitivity of a function quantify the impact of input changes on the function output. This paper generalizes the latter concept to c-sensitivity and provides formulas for the activities and c-sensitivity of general k-canalizing functions as well as canalizing functions with more precisely defined structure. A popular measure for the robustness of a network, the Derrida value, can be expressed as a weighted sum of the c-sensitivities of the governing canalizing functions, and can also be calculated for a stochastic extension of Boolean networks. These findings provide a computationally efficient way to obtain Derrida values of Boolean networks, deterministic or stochastic, that does not involve simulation.

Multistate nested canalizing functions and their networks

This paper provides a collection of mathematical and computational tools for the study of robustness in nonlinear gene regulatory networks, represented by time- and state-discrete dynamical systems taking on multiple states. The focus is on networks governed by nested canalizing functions (NCFs), first introduced in the Boolean context by S. Kauffman. After giving a general definition of NCFs we analyze the class of such functions. We derive a formula for the normalized average c-sensitivities of multistate NCFs, which enables the calculation of the Derrida plot, a popular measure of network stability. We also provide a unique canonical parametrized polynomial form of NCFs. This form has several consequences. We can easily generate NCFs for varying parameter choices, and derive a closed form formula for the number of such functions in a given number of variables, as well as an asymptotic formula. Finally, we compute the number of equivalence classes of NCFs under permutation of variables. Together, the results of the paper represent a useful mathematical framework for the study of NCFs and their dynamic networks.

Stratification and enumeration of Boolean functions by canalizing depth

Boolean network models have gained popularity in computational systems biology over the last dozen years. Many of these networks use canalizing Boolean functions, which has led to increased interest in the study of these functions. The canalizing depth of a function describes how many canalizing variables can be recursively “picked off”, until a non-canalizing function remains. In this paper, we show how every Boolean function has a unique algebraic form involving extended monomial layers and a well-defined core polynomial. This generalizes recent work on the algebraic structure of nested canalizing functions, and it yields a stratification of all Boolean functions by their canalizing depth. As a result, we obtain closed formulas for the number of n-variable Boolean functions with depth k, which simultaneously generalizes enumeration formulas for canalizing, and nested canalizing functions.

Canalizing Boolean Functions Maximize Mutual Information

Information processing in biologically motivated Boolean networks is of interest in recent information theoretic research. One measure to quantify this ability is the well-known mutual information. Using Fourier analysis, we show that canalizing functions maximize mutual information between a single input variable and the outcome of a function with fixed expectation. A similar result can be obtained for the mutual information between a set of input variables and the output. Further, if the expectation of the function is not fixed, we obtain that the mutual information is maximized by a function only dependent on this single variable, i.e., the dictatorship function. We prove our findings for Boolean functions with uniformly distributed as well as product distributed input variables.

Phase transition of Boolean networks with partially nested canalizing functions

We generate the critical condition for the phase transition of a Boolean network governed by partially nested canalizing functions for which a fraction of the inputs are canalizing, while the remaining non-canalizing inputs obey a complementary threshold Boolean function. Past studies have considered the stability of fully or partially nested canalizing functions paired with random choices of the complementary function. In some of those studies conflicting results were found with regard to the presence of chaotic behavior. Moreover, those studies focus mostly on ergodic networks in which initial states are assumed equally likely. We relax that assumption and find the critical condition for the sensitivity of the network under a non-ergodic scenario. We use the proposed mathematical model to determine parameter values for which phase transitions from order to chaos occur. We generate Derrida plots to show that the mathematical model matches the actual network dynamics. The phase transition diagrams indicate that both order and chaos can occur, and that certain parameters induce a larger range of values leading to order versus chaos. The edge-of-chaos curves are identified analytically and numerically. It is shown that the depth of canalization does not cause major dynamical changes once certain thresholds are reached; these thresholds are fairly small in comparison to the connectivity of the nodes.

Bounds on the average sensitivity of nested canalizing functions.

Nested canalizing Boolean functions (NCF) play an important role in biologically motivated regulatory networks and in signal processing, in particular describing stack filters. It has been conjectured that NCFs have a stabilizing effect on the network dynamics. It is well known that the average sensitivity plays a central role for the stability of (random) Boolean networks. Here we provide a tight upper bound on the average sensitivity of NCFs as a function of the number of relevant input variables. As conjectured in literature this bound is smaller than . This shows that a large number of functions appearing in biological networks belong to a class that has low average sensitivity, which is even close to a tight lower bound.

Boolean nested canalizing functions: A comprehensive analysis

Boolean network models of molecular regulatory networks have been used successfully in computational systems biology. The Boolean functions that appear in published models tend to have special properties, in particular the property of being nested canalizing, a concept inspired by the concept of canalization in evolutionary biology. It has been shown that networks comprised of nested canalizing functions have dynamic properties that make them suitable for modeling molecular regulatory networks, namely a small number of (large) attractors, as well as relatively short limit cycles.This paper contains a detailed analysis of this class of functions, based on a novel normal form as polynomial functions over the Boolean field. The concept of layer is introduced that stratifies variables into different classes depending on their level of dominance. Using this layer concept a closed form formula is derived for the number of nested canalizing functions with a given number of variables. Additional metrics considered include Hamming weight, the activity number of any variable, and the average sensitivity of the function. It is also shown that the average sensitivity of any nested canalizing function is between 0 and 2. This provides a rationale for why nested canalizing functions are stable, since a random Boolean function in n variables has average sensitivity n2. The paper also contains experimental evidence that the layer number is an important factor in network stability.

Properties of Boolean networks and methods for their tests

Transcriptional regulation networks are often modeled as Boolean networks. We discuss certain properties of Boolean functions (BFs), which are considered as important in such networks, namely, membership to the classes of unate or canalizing functions. Of further interest is the average sensitivity (AS) of functions. In this article, we discuss several algorithms to test the properties of interest. To test canalizing properties of functions, we apply spectral techniques, which can also be used to characterize the AS of functions as well as the influences of variables in unate BFs. Further, we provide and review upper and lower bounds on the AS of unate BFs based on the spectral representation. Finally, we apply these methods to a transcriptional regulation network of Escherichia coli, which controls central parts of the E. coli metabolism. We find that all functions are unate. Also the analysis of the AS of the network reveals an exceptional robustness against transient fluctuations of the binary variables.a

Mean-field Boolean network model of a signal transduction network

In this paper we provide a mean-field Boolean network model for a signal transduction network of a generic fibroblast cell. The network consists of several main signaling pathways, including the receptor tyrosine kinase, the G-protein coupled receptor, and the Integrin signaling pathway. The network consists of 130 nodes, each representing a signaling molecule (mainly proteins). Nodes are governed by Boolean dynamics including canalizing functions as well as totalistic Boolean functions that depend only on the overall fraction of active nodes. We categorize the Boolean functions into several different classes. Using a mean-field approach we generate a mathematical formula for the probability of a node becoming active at any time step. The model is shown to be a good match for the actual network. This is done by iterating both the actual network and the model and comparing the results numerically. Using the Boolean model it is shown that the system is stable under a variety of parameter combinations. It is also shown that this model is suitable for assessing the dynamics of the network under protein mutations. Analytical results support the numerical observations that in the long-run at most half of the nodes of the network are active.

The phase diagram of random Boolean networks with nested canalizing functions

We obtain the phase diagram of random Boolean networks with nested canalizing functions. Using the annealed approximation, we obtain the evolution of the number b t of nodes with value one, and the network sensitivity λ, and compare with numerical simulations of quenched networks. We find that, contrary to what was reported by Kauffman et al. [Proc. Natl. Acad. Sci. 101, 17102 (2004)], these networks have a rich phase diagram, were both the “chaotic" and frozen phases are present, as well as an oscillatory regime of the value of b t . We argue that the presence of only the frozen phase in the work of Kauffman et al. was due simply to the specific parametrization used, and is not an inherent feature of this class of functions. However, these networks are significantly more stable than the variant where all possible Boolean functions are allowed.

The structure of canalizing functions

The structure of a canalizing function is discussed. Using a new matrix product, namely semitensor product, the logical function is expressed in its matrix form. From its matrix expression, a criterion is obtained to test whether a logical function is a canalizing function. Then a formula is obtained to calculate the number of canalizing functions. Moreover, an algorithm is presented to generate canalizing functions. Finally, some results obtained are extended to seminested canalizing functions.

Order or chaos in Boolean gene networks depends on the mean fraction of canalizing functions

We explore the connection between order/chaos in Boolean networks and the naturally occurring fraction of canalizing functions in such systems. This fraction turns out to give a very clear indication of whether the system possesses ordered or chaotic dynamics, as measured by Derrida plots, and also the degree of order when we compare different networks with the same number of vertices and edges. By studying also a wide distribution of indegrees in a network, we show that the mean probability of canalizing functions is a more reliable indicator of the type of dynamics for a finite network than the classical result on stability relating the bias to the mean indegree. Finally, we compare by direct simulations two biologically derived networks with networks of similar sizes but with power-law and Poisson distributions of indegrees, respectively. The biologically motivated networks are not more ordered than the latter, and in one case the biological network is even chaotic while the others are not.

Evolution of canalizing Boolean networks

Boolean networks with canalizing functions are used to model gene regulatory networks. In order to learn how such networks may behave under evolutionary forces, we simulate the evolution of a single Boolean network by means of an adaptive walk, which allows us to explore the fitness landscape. Mutations change the connections and the functions of the nodes. Our fitness criterion is the robustness of the dynamical attractors against small perturbations. We find that with this fitness criterion the global maximum is always reached and that there is a huge neutral space of 100% fitness. Furthermore, in spite of having such a high degree of robustness, the evolved networks still share many features with "chaotic" networks.

Canalizing Kauffman networks: nonergodicity and its effect on their critical behavior.

Boolean networks have been used to study numerous phenomena, including gene regulation, neural networks, social interactions, and biological evolution. Here, we propose a general method for determining the critical behavior of Boolean systems built from arbitrary ensembles of Boolean functions. In particular, we solve the critical condition for systems of units operating according to canalizing functions and present strong numerical evidence that our approach correctly predicts the phase transition from order to chaos in such systems.

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.