Abstract
In prokaryotic genomes the number of transcriptional regulators is known to be proportional to the square of the total number of protein-coding genes. A toolbox model of evolution was recently proposed to explain this empirical scaling for metabolic enzymes and their regulators. According to its rules, the metabolic network of an organism evolves by horizontal transfer of pathways from other species. These pathways are part of a larger “universal” network formed by the union of all species-specific networks. It remained to be understood, however, how the topological properties of this universal network influence the scaling law of functional content of genomes in the toolbox model. Here we answer this question by first analyzing the scaling properties of the toolbox model on arbitrary tree-like universal networks. We prove that critical branching topology, in which the average number of upstream neighbors of a node is equal to one, is both necessary and sufficient for quadratic scaling. We further generalize the rules of the model to incorporate reactions with multiple substrates/products as well as branched and cyclic metabolic pathways. To achieve its metabolic tasks, the new model employs evolutionary optimized pathways with minimal number of reactions. Numerical simulations of this realistic model on the universal network of all reactions in the KEGG database produced approximately quadratic scaling between the number of regulated pathways and the size of the metabolic network. To quantify the geometrical structure of individual pathways, we investigated the relationship between their number of reactions, byproducts, intermediate, and feedback metabolites. Our results validate and explain the ubiquitous appearance of the quadratic scaling for a broad spectrum of topologies of underlying universal metabolic networks. They also demonstrate why, in spite of “small-world” topology, real-life metabolic networks are characterized by a broad distribution of pathway lengths and sizes of metabolic regulons in regulatory networks.
Highlights
In prokaryotic genomes the number of transcriptional regulators is known to quadratically scale with the total number of proteincoding genes [1]
The universality of the exponent a~2 was corroborated [2] by numerical simulations of the toolbox model with linearized pathways on the universal network formed by the union of all metabolic reactions in the KEGG database
It has been previously reported that in prokaryotic genomes the number of transcriptional regulators is proportional to the square of the total number of genes
Summary
In prokaryotic genomes the number of transcriptional regulators is known to quadratically scale with the total number of proteincoding genes [1]. The toolbox model of co-evolution of metabolic and regulatory networks was recently proposed [2] to explain this scaling in parts of the genome responsible for metabolic functions In this model prokaryotes acquire new metabolic capabilities by horizontal transfer of entire metabolic pathways from other organisms. The number of pathways and by extension the number of their transcriptional regulators grows faster than linearly with the number of non-regulatory genes in the genome While this qualitative explanation is rather general and does not depend on specific details such as topology of the universal network, the exact value of the exponent a connecting the number of transcription factors (equal to NL- the number of pathways or leaves of the network) to the number of metabolites in the metabolic network of an organism NM , as NL*NMa , is in general model-dependent. While the agreement between the values of the exponent a in these two cases hinted at underlying general principles at work, the detailed understanding of these principles remained elusive
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