July 31, 2015
Gene Regulatory Networks (GRNs) consisting of combinations of transcription factors (TFs) and their cis promoters are assumed to be sufficient to direct the development of organisms. Mutations in GRNs are assumed to be the primary drivers for the evolution of multicellular life. Here it is proven that neither of these assumptions is correct. They are inconsistent with fundamental principles of combinatorics of bounded encoded networks. It is shown there are inherent complexity and control capacity limits for any gene regulatory network that is based solely on protein coding genes such as transcription factors. This result has significant practical consequences for understanding development, evolution, the Cambrian Explosion, as well as multi-cellular diseases such as cancer. If the arguments are sound, then genes cannot explain the development of complex multicellular organisms and genes cannot explain the evolution of complex multicellular life.
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December 19, 2013
A proof is presented that gene regulatory networks (GRNs) based solely on transcription factors cannot control the development of complex multicellular life. GRNs alone cannot explain the evolution of multicellular life in the Cambrian Explosion. Networks are based on addressing systems which are used to construct network links. The more complex the network the greater the number of links and the larger the required address space. It has been assumed that combinations of tran...
Developing and maintaining life requires a lot of computation. This is done by gene regulatory networks. But we have little understanding of how this computation is organized. I show that there is a direct correspondence between the structural and functional building blocks of regulatory networks, which I call regulatory motifs. I derive a simple bound on the range of function that these motifs can perform, in terms of the local network structure. I prove that this range is a...
September 26, 2021
Networks of gene regulation govern morphogenesis, determine cell identity and regulate cell function. But we have little understanding, at the local level, of which logics are biologically preferred or even permitted. To solve this puzzle, we studied the consequences of a fundamental aspect of gene regulatory networks: genes and transcription factors talk to each other but not themselves. Remarkably, this bipartite structure severely restricts the number of logical dependenci...
June 23, 2015
Gene regulation relies on the specificity of transcription factor (TF) - DNA interactions. In equilibrium, limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF-DNA interactions or remains erroneously inactive. We present a tractable biophysical model of global crosstalk, where many genes are simultaneously regulated by many TFs. We show that in the simplest regulatory scenario, a lower bound on cros...
February 15, 2005
Identity, response to external stimuli, and spatial architecture of a living system are central topics of molecular biology. Presently, they are largely seen as a result of the interplay between a gene repertoire and the regulatory machinery of the cell. At the transcriptional level, the cis-regulatory regions establish sets of interdependencies between transcription factors and genes, including other transcription factors. These ``transcription networks'' are too large to be...
January 21, 2011
Genetic regulatory networks enable cells to respond to the changes in internal and external conditions by dynamically coordinating their gene expression profiles. Our ability to make quantitative measurements in these biochemical circuits has deepened our understanding of what kinds of computations genetic regulatory networks can perform and with what reliability. These advances have motivated researchers to look for connections between the architecture and function of geneti...
October 10, 2016
Regulatory networks consist of interacting molecules with a high degree of mutual chemical specificity. How can these molecules evolve when their function depends on maintenance of interactions with cognate partners and simultaneous avoidance of deleterious "crosstalk" with non-cognate molecules? Although physical models of molecular interactions provide a framework in which co-evolution of network components can be analyzed, most theoretical studies have focused on the evolu...
November 15, 2003
Increased biological complexity is generally associated with the addition of new genetic information, which must be integrated into the existing regulatory network that operates within the cell. General arguments on network control, as well as several recent genomic observations, indicate that regulatory gene number grows disproportionally fast with increasing genome size. We present two models for the growth of regulatory networks. Both predict that the number of transcripti...
October 21, 2009
Gene regulatory networks typically have low in-degrees, whereby any given gene is regulated by few of the genes in the network. What mechanisms might be responsible for these low in-degrees? Starting with an accepted framework of the binding of transcription factors to DNA, we consider a simple model of gene regulatory dynamics. In this model, we show that the constraint of having a given function leads to the emergence of minimum connectivities compatible with function. We e...
July 27, 2021
In this paper, we conduct theoretical analyses on inferring the structure of gene regulatory networks. Depending on the experimental method and data type, the inference problem is classified into 20 different scenarios. For each scenario, we discuss the problem that with enough data, under what assumptions, what can be inferred about the structure. For scenarios that have been covered in the literature, we provide a brief review. For scenarios that have not been covered in li...