Regulatory network structure determines patterns of intermolecular epistasis

Lagator, Mato; Sarikas, Srdjan; Kirit, Hande Acar; Bollback, Jonathan P.; Guet, Călin C.

doi:10.7554/elife.28921

Cited by 18 publications

(38 citation statements)

References 39 publications

(47 reference statements)

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“…Our results suggest that these epistatic interactions can also be predicted if the corresponding GRN, its regulatory mechanism and the effect of mutations in single regulatory regions are known. This observation complements a recent study suggesting that epistatic interactions between mutations in transcription factors and DNA binding sites are determined by regulatory network structure (Lagator et al , 2017b). Ultimately, understanding the nonlinearities inherent in complex biological systems will be essential to understand how such systems constrain the production of phenotypes.…”

Section: Discussionsupporting

confidence: 89%

Synthetic circuits reveal how mechanisms of gene regulatory networks constrain evolution

Schaerli

Jiménez

Duarte

et al. 2018

Molecular Systems Biology

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Phenotypic variation is the raw material of adaptive Darwinian evolution. The phenotypic variation found in organismal development is biased towards certain phenotypes, but the molecular mechanisms behind such biases are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most pertinent evidence is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits expressed in Escherichia coli that produce a gene expression stripe—a pivotal pattern in embryonic development. The two parental circuits produce the same phenotype, but create it through different regulatory mechanisms. We show that mutations cause distinct novel phenotypes in the two networks and use a combination of experimental measurements, mathematical modelling and DNA sequencing to understand why mutations bring forth only some but not other novel gene expression phenotypes. Our results reveal that the regulatory mechanisms of networks restrict the possible phenotypic variation upon mutation. Consequently, seemingly equivalent networks can indeed be distinct in how they constrain the outcome of further evolution.

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Section: Discussionsupporting

confidence: 89%

Synthetic circuits reveal how mechanisms of gene regulatory networks constrain evolution

Schaerli

Jiménez

Duarte

et al. 2018

Molecular Systems Biology

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“…Table 1 ). The shape of the DFE in our experiment was similar to DFEs observed in other biological systems, such as mutations in bacterial promoters [ 19 , 20 ], viral sequences [ 21 ], transcription factors [ 22 ], and random transposon insertions [ 18 ]. The effect of the deleterious transferred genes is well described by a log-normal distribution ( μ = − 3.562 and σ = 1.693), as previously observed for DMEs of mutations [ 23 ].…”

Section: Resultssupporting

confidence: 78%

Experimental determination of evolutionary barriers to horizontal gene transfer

2020

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Background Horizontal gene transfer, the acquisition of genes across species boundaries, is a major source of novel phenotypes that enables microbes to rapidly adapt to new environments. How the transferred gene alters the growth – fitness – of the new host affects the success of the horizontal gene transfer event and how rapidly the gene spreads in the population. Several selective barriers – factors that impact the fitness effect of the transferred gene – have been suggested to impede the likelihood of horizontal transmission, however experimental evidence is scarce. The objective of this study was to determine the fitness effects of orthologous genes transferred from Salmonella enterica serovar Typhimurium to Escherichia coli to identify the selective barriers using highly precise experimental measurements. Results We found that most gene transfers result in strong fitness costs. Previously identified evolutionary barriers — gene function and the number of protein-protein interactions — did not predict the fitness effects of transferred genes. In contrast, dosage sensitivity, gene length, and the intrinsic protein disorder significantly impact the likelihood of a successful horizontal transfer. Conclusion While computational approaches have been successful in describing long-term barriers to horizontal gene transfer, our experimental results identified previously underappreciated barriers that determine the fitness effects of newly transferred genes, and hence their short-term eco-evolutionary dynamics.

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“…Our results suggest that these epistatic interactions can also be predicted, if the corresponding GRN, its regulatory mechanism, and the effect of mutations in single regulatory regions are known. This observation complements a recent study suggesting that epistatic interactions between mutations in transcription factors and DNA-binding sites are determined by regulatory network structure (Lagator et al, 2017b). Ultimately, understanding the nonlinearities inherent in complex biological systems will be essential to understand how such systems constrain the production of phenotypes.…”

Section: Discussionsupporting

confidence: 88%

The mechanisms of gene regulatory networks constrain evolution: A lesson from synthetic circuits

Schaerli

Jiménez

et al. 2017

Preprint

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Phenotypic variation is the raw material of adaptive Darwinian evolution. The phenotypic variation found in organismal development is biased towards certain phenotypes, but the molecular mechanisms behind such restrictions are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most of the evidence for this is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits expressed in E. coli that produce a gene expression stripe - a pivotal pattern in embryonic development. The two parental circuits produce the same phenotype, but create it through different regulatory mechanisms. We show that mutations cause distinct novel phenotypes in the two networks and use a combination of experimental measurements, mathematical modelling and DNA sequencing to understand why mutations bring forth only some but not other novel gene expression phenotypes. Our results reveal that the regulatory mechanisms of networks restrict the possible phenotypic variation upon mutation. Consequently, seemingly equivalent networks can indeed be distinct in how they constrain the outcome of further evolution.

show abstract

Regulatory network structure determines patterns of intermolecular epistasis

Cited by 18 publications

References 39 publications

Synthetic circuits reveal how mechanisms of gene regulatory networks constrain evolution

Synthetic circuits reveal how mechanisms of gene regulatory networks constrain evolution

Experimental determination of evolutionary barriers to horizontal gene transfer

The mechanisms of gene regulatory networks constrain evolution: A lesson from synthetic circuits

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