Negative Feedback in Genetic Circuits Confers Evolutionary Resilience and Capacitance

Marciano, David C.; Lua, Rhonald C.; Katsonis, Panagiotis; Amin, Shivas R.; Herman, Christophe; Lichtarge, Olivier

doi:10.1016/j.celrep.2014.05.018

Cited by 22 publications

(21 citation statements)

References 46 publications

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“…S.3 and S.4 in the Supplemental Material [18]). The calculated Hill coefficient observed ( h obs ) for P lexA of 1.5 ± 0.2 in this system agrees with previous estimates of LexA cooperativity ranging from 1 to 2.4 [17,36,38]. Surprisingly, addition of three SOS boxes upstream of the RNA polymerase binding site in the P lexA –SOS5 construct had the effect of lowering h obs to 1.2 ± 0.2.…”

Section: Experimental Validationsupporting

confidence: 90%

“…3(a)]. P lexA has two SOS boxes and, although not experimentally quantified, it has been reported to have moderate cooperativity [17,36,38]. By adding more SOS boxes ( P lexA –SOS3 and P lexA –SOS5 ), we expected to increase the cooperativity.…”

Section: Experimental Validationmentioning

confidence: 99%

“…This plasmid panel was transformed into E. coli cells with a chromosomally encoded P sulA - gfp reporter that is repressed by LexA to allow assessment of LexA repressor function via monitoring of GFP fluorescence levels. Next, we progressively introduced specific mutations into the lexA gene that severely attenuate repressor function in the cell by increasing degradation rate [17,40]. Any one of these substitutions is highly deleterious and their combination would be expected to render the LexA function irrecoverable.…”

Section: Experimental Validationmentioning

confidence: 99%

“…However, the same perturbations, when crossed into a line wherein calcium-mediated negative feedback is absent, produced larger alterations in single-photon responses, showing that negative feedback enables a more robust, stereotyped response that promotes reliable signal transmission through the visual pathway. In more recent work in bacteria, NAR was shown to impart robustness to TF mutations and stabilize expression levels [17]. However, it is an open question as to which components of NAR can influence mutational robustness.…”

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confidence: 99%

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Cooperativity of Negative Autoregulation Confers Increased Mutational Robustness

et al. 2016

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Negative autoregulation is universally found across organisms. In the bacterium Escherichia coli, transcription factors often repress their own expression to form a negative feedback network motif that enables robustness to changes in biochemical parameters. Here we present a simple phenomenological model of a negative feedback transcription factor repressing both itself and another target gene. The strength of the negative feedback is characterized by three parameters: the cooperativity in self-repression, the maximal expression rate of the transcription factor, and the apparent dissociation constant of the transcription factor binding to its own promoter. Analysis of the model shows that the target gene levels are robust to mutations in the transcription factor, and that the robustness improves as the degree of cooperativity in self-repression increases. The prediction is tested in the LexA transcriptional network of E. coli by altering cooperativity in self-repression and promoter strength. Indeed, we find robustness is correlated with the former. Considering the proposed importance of gene regulation in speciation, parameters governing a transcription factor’s robustness to mutation may have significant influence on a cell or organism’s capacity to evolve.

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Section: Experimental Validationsupporting

confidence: 90%

Section: Experimental Validationmentioning

confidence: 99%

Section: Experimental Validationmentioning

confidence: 99%

mentioning

confidence: 99%

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Cooperativity of Negative Autoregulation Confers Increased Mutational Robustness

et al. 2016

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“…"Evolutionary capacitance," on the other hand, is a term reserved for instances when an adaptive role is demonstrated. Phenotypic capacitance has been known in fruit flies since the 1950s (5), but demonstrations of adaptive potential (4,6), and the various molecular mechanisms behind it (7)(8)(9)(10)(11) have been reported only relatively recently.…”

mentioning

confidence: 99%

Intramolecular phenotypic capacitance in a modular RNA molecule

Hayden

Bendixsen

Wagner

2015

Proc. Natl. Acad. Sci. U.S.A.

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Phenotypic capacitance refers to the ability of a genome to accumulate mutations that are conditionally hidden and only reveal phenotype-altering effects after certain environmental or genetic changes. Capacitance has important implications for the evolution of novel forms and functions, but experimentally studied mechanisms behind capacitance are mostly limited to complex, multicomponent systems often involving several interacting protein molecules. Here we demonstrate phenotypic capacitance within a much simpler system, an individual RNA molecule with catalytic activity (ribozyme). This naturally occurring RNA molecule has a modular structure, where a scaffold module acts as an intramolecular chaperone that facilitates folding of a second catalytic module. Previous studies have shown that the scaffold module is not absolutely required for activity, but dramatically decreases the concentration of magnesium ions required for the formation of an active site. Here, we use an experimental perturbation of magnesium ion concentration that disrupts the folding of certain genetic variants of this ribozyme and use in vitro selection followed by deep sequencing to identify genotypes with altered phenotypes (catalytic activity). We identify multiple conditional mutations that alter the wild-type ribozyme phenotype under a stressful environmental condition of low magnesium ion concentration, but preserve the phenotype under more relaxed conditions. This conditional buffering is confined to the scaffold module, but controls the catalytic phenotype, demonstrating how modularity can enable phenotypic capacitance within a single macromolecule. RNA's ancient role in life suggests that phenotypic capacitance may have influenced evolution since life's origins. modularity | epistasis | phenotypic capacitance | ribozyme | evolution

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Adaptive evolvability through direct selection instead of indirect, second‐order selection

Wagner

2021

J Exp Zool Pt B

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Can evolvability itself be the product of adaptive evolution? To answer this question is challenging, because any DNA mutation that alters only evolvability is subject to indirect, “second order” selection on the future effects of this mutation. Such indirect selection is weaker than “first‐order” selection on mutations that alter fitness, in the sense that it can operate only under restrictive conditions. Here I discuss a route to adaptive evolvability that overcomes this challenge. Specifically, a recent evolution experiment showed that some mutations can enhance both fitness and evolvability through a combination of direct and indirect selection. Unrelated evidence from gene duplication and the evolution of gene regulation suggests that mutations with such dual effects may not be rare. Through such mutations, evolvability may increase at least in part because it provides an adaptive advantage. These observations suggest a research program on the adaptive evolution of evolvability, which aims to identify such mutations and to disentangle their direct fitness effects from their indirect effects on evolvability. If evolvability is itself adaptive, Darwinian evolution may have created more than life's diversity. It may also have helped create the very conditions that made the success of Darwinian evolution possible.

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Negative Feedback in Genetic Circuits Confers Evolutionary Resilience and Capacitance

Cited by 22 publications

References 46 publications

Cooperativity of Negative Autoregulation Confers Increased Mutational Robustness

Cooperativity of Negative Autoregulation Confers Increased Mutational Robustness

Intramolecular phenotypic capacitance in a modular RNA molecule

Adaptive evolvability through direct selection instead of indirect, second‐order selection

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