12,716 research outputs found
Nonlinear dynamics in gene regulation promote robustness and evolvability of gene expression levels
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
Nonlinear Dynamics in Gene Regulation Promote Robustness and Evolvability of Gene Expression Levels
This is the final version of the article. Available from Public Library of Science via the DOI in this record.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.This work was funded by the UK Engineering and Physical Sciences Research Council, grant number EP/I017445/1
Gene autoregulation via intronic microRNAs and its functions
Background: MicroRNAs, post-transcriptional repressors of gene expression,
play a pivotal role in gene regulatory networks. They are involved in core
cellular processes and their dysregulation is associated to a broad range of
human diseases. This paper focus on a minimal microRNA-mediated regulatory
circuit, in which a protein-coding gene (host gene) is targeted by a microRNA
located inside one of its introns. Results: Autoregulation via intronic
microRNAs is widespread in the human regulatory network, as confirmed by our
bioinformatic analysis, and can perform several regulatory tasks despite its
simple topology. Our analysis, based on analytical calculations and
simulations, indicates that this circuitry alters the dynamics of the host gene
expression, can induce complex responses implementing adaptation and Weber's
law, and efficiently filters fluctuations propagating from the upstream network
to the host gene. A fine-tuning of the circuit parameters can optimize each of
these functions. Interestingly, they are all related to gene expression
homeostasis, in agreement with the increasing evidence suggesting a role of
microRNA regulation in conferring robustness to biological processes. In
addition to model analysis, we present a list of bioinformatically predicted
candidate circuits in human for future experimental tests. Conclusions: The
results presented here suggest a potentially relevant functional role for
negative self-regulation via intronic microRNAs, in particular as a homeostatic
control mechanism of gene expression. Moreover, the map of circuit functions in
terms of experimentally measurable parameters, resulting from our analysis, can
be a useful guideline for possible applications in synthetic biology.Comment: 29 pages and 7 figures in the main text, 18 pages of Supporting
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