title: Nonlinear Dynamics in Gene Regulation Promote Robustness and Evolvability of Gene Expression Levels.
abstract: Cellular phenotypes underpinned by regulatory networks need to respond to evolutionary pressures to allow adaptation, but at the same time be robust to perturbations. This creates a conflict in which mutations affecting regulatory networks must both generate variance but also be tolerated at the phenotype level. Here, we perform mathematical analyses and simulations of regulatory networks to better understand the potential trade-off between robustness and evolvability. Examining the phenotypic effects of mutations, we find an inverse correlation between robustness and evolvability that breaks only with nonlinearity in the network dynamics, through the creation of regions presenting sudden changes in phenotype with small changes in genotype. For genotypes embedding low levels of nonlinearity, robustness and evolvability correlate negatively and almost perfectly. By contrast, genotypes embedding nonlinear dynamics allow expression levels to be robust to small perturbations, while generating high diversity (evolvability) under larger perturbations. Thus, nonlinearity breaks the robustness-evolvability trade-off in gene expression levels by allowing disparate responses to different mutations. Using analytical derivations of robustness and system sensitivity, we show that these findings extend to a large class of gene regulatory network architectures and also hold for experimentally observed parameter regimes. Further, the effect of nonlinearity on the robustness-evolvability trade-off is ensured as long as key parameters of the system display specific relations irrespective of their absolute values. We find that within this parameter regime genotypes display low and noisy expression levels. Examining the phenotypic effects of mutations, we find an inverse correlation between robustness and evolvability that breaks only with nonlinearity in the network dynamics. Our results provide a possible solution to the robustness-evolvability trade-off, suggest an explanation for the ubiquity of nonlinear dynamics in gene expression networks, and generate useful guidelines for the design of synthetic gene circuits.
authors.affiliation: MRC Biostatistics Unit, Cambridge, United Kingdom.
authors.forename: Arno
authors.initials: A
authors.lastname: Steinacher
authors.affiliation: School of Engineering, University of Warwick, Warwick, United Kingdom.
authors.forename: Declan G
authors.initials: DG
authors.lastname: Bates
authors.affiliation: College of Engineering, Mathematics, and Physical Sciences, University of Exeter, Exeter, United Kingdom.
authors.forename: Ozgur E
authors.initials: OE
authors.lastname: Akman
authors.affiliation: School of Life Sciences, University of Warwick, Warwick, United Kingdom.
authors.forename: Orkun S
authors.initials: OS
authors.lastname: Soyer
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D003198:Computer Simulation; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D056084:Genetic Fitness; D014644:Genetic Variation; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D017711:Nonlinear Dynamics; D012641:Selection, Genetic