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Evolutionary potential of transcription factors for gene regulatory rewiring

Nature Ecology & Evolutionvolume 2pages16331643 (2018) | Download Citation


Gene regulatory networks evolve through rewiring of individual components—that is, through changes in regulatory connections. However, the mechanistic basis of regulatory rewiring is poorly understood. Using a canonical gene regulatory system, we quantify the properties of transcription factors that determine the evolutionary potential for rewiring of regulatory connections: robustness, tunability and evolvability. In vivo repression measurements of two repressors at mutated operator sites reveal their contrasting evolutionary potential: while robustness and evolvability were positively correlated, both were in trade-off with tunability. Epistatic interactions between adjacent operators alleviated this trade-off. A thermodynamic model explains how the differences in robustness, tunability and evolvability arise from biophysical characteristics of repressor–DNA binding. The model also uncovers that the energy matrix, which describes how mutations affect repressor–DNA binding, encodes crucial information about the evolutionary potential of a repressor. The biophysical determinants of evolutionary potential for regulatory rewiring constitute a mechanistic framework for understanding network evolution.

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We thank S. Abedon, R. Grah, K. Jain, C. Nizak, T. Paixão, M. Pleska, E. Reichhart and S. Sarikas for helpful discussions. This work was supported by the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. [291734] to M.L., and European Research Council under the Horizon 2020 Framework Programme (FP/2007-2013) / ERC grant agreement no. [648440] to J.P.B. C.I. is the recipient of a DOC (Doctoral Fellowship Programme of the Austrian Academy of Sciences) Fellowship of the Austrian Academy of Sciences.

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  1. These authors contributed equally: Claudia Igler, Mato Lagator.


  1. IST Austria, Am Campus 1, Klosterneuburg, Austria

    • Claudia Igler
    • , Mato Lagator
    • , Gašper Tkačik
    • , Jonathan P. Bollback
    •  & Călin C. Guet
  2. Institute of Integrative Biology, University of Liverpool, Liverpool, UK

    • Jonathan P. Bollback


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All authors conceived the study together. C.I. and M.L. designed and carried out the experiments and analysed the data. C.I. wrote the code and ran the model. C.I. and M.L. wrote the initial draft of the manuscript and revised it together with G.T., J.P.B and C.C.G.

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The authors declare no competing interests.

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Correspondence to Călin C. Guet.

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