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Robustness Can Evolve Gradually in Complex Regulatory Gene Networks with Varying Topology

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  • Stefano Ciliberti
  • Olivier C Martin
  • Andreas Wagner

Abstract

The topology of cellular circuits (the who-interacts-with-whom) is key to understand their robustness to both mutations and noise. The reason is that many biochemical parameters driving circuit behavior vary extensively and are thus not fine-tuned. Existing work in this area asks to what extent the function of any one given circuit is robust. But is high robustness truly remarkable, or would it be expected for many circuits of similar topology? And how can high robustness come about through gradual Darwinian evolution that changes circuit topology gradually, one interaction at a time? We here ask these questions for a model of transcriptional regulation networks, in which we explore millions of different network topologies. Robustness to mutations and noise are correlated in these networks. They show a skewed distribution, with a very small number of networks being vastly more robust than the rest. All networks that attain a given gene expression state can be organized into a graph whose nodes are networks that differ in their topology. Remarkably, this graph is connected and can be easily traversed by gradual changes of network topologies. Thus, robustness is an evolvable property. This connectedness and evolvability of robust networks may be a general organizational principle of biological networks. In addition, it exists also for RNA and protein structures, and may thus be a general organizational principle of all biological systems.Author Summary: Living things are astonishingly complex, yet unlike houses of cards they are also highly robust. That is, they have persisted for billions of years, despite being exposed to an endless stream of environmental stressors and random mutations. Is this robustness an evolvable property? Do different biological systems vary in their robustness? Has natural selection shaped this robustness? These questions are very difficult to answer experimentally for most systems, be they proteins or large gene networks. Here we address these questions with a model of the transcription regulation networks that regulate both cellular functions and embryonic development in many organisms. We examine millions of such networks that differ in the topology or architecture of their regulatory interactions, that is, in the “who interacts with whom” of a network. We find that radically different network architectures can show the same gene expression pattern. The networks' robustness to both mutations and gene expression noise shows a broad distribution: some network architectures are highly robust, whereas others are quite fragile. Importantly, the entire space of network architectures can be traversed through small changes of individual regulatory interactions, without changing a network's gene expression pattern. This means that high robustness in gene expression can evolve through gradual and neutral evolution in the space of network architectures. Our results show that the robustness of transcriptional regulation networks is an evolvable trait that natural selection can change like any other trait.

Suggested Citation

  • Stefano Ciliberti & Olivier C Martin & Andreas Wagner, 2007. "Robustness Can Evolve Gradually in Complex Regulatory Gene Networks with Varying Topology," PLOS Computational Biology, Public Library of Science, vol. 3(2), pages 1-10, February.
  • Handle: RePEc:plo:pcbi00:0030015
    DOI: 10.1371/journal.pcbi.0030015
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    References listed on IDEAS

    as
    1. William J. Blake & Mads KÆrn & Charles R. Cantor & J. J. Collins, 2003. "Noise in eukaryotic gene expression," Nature, Nature, vol. 422(6932), pages 633-637, April.
    2. Ángel Raya & Yasuhiko Kawakami & Concepción Rodríguez-Esteban & Marta Ibañes & Diego Rasskin-Gutman & Joaquín Rodríguez-León & Dirk Büscher & José A. Feijó & Juan Carlos Izpisúa Belmonte, 2004. "Notch activity acts as a sensor for extracellular calcium during vertebrate left–right determination," Nature, Nature, vol. 427(6970), pages 121-128, January.
    3. U. Alon & M. G. Surette & N. Barkai & S. Leibler, 1999. "Robustness in bacterial chemotaxis," Nature, Nature, vol. 397(6715), pages 168-171, January.
    4. Attila Becskei & Luis Serrano, 2000. "Engineering stability in gene networks by autoregulation," Nature, Nature, vol. 405(6786), pages 590-593, June.
    5. Ricardo B. R. Azevedo & Rolf Lohaus & Suraj Srinivasan & Kristen K. Dang & Christina L. Burch, 2006. "Sexual reproduction selects for robustness and negative epistasis in artificial gene networks," Nature, Nature, vol. 440(7080), pages 87-90, March.
    6. Naama Barkai & Stanislas Leibler, 2000. "Circadian clocks limited by noise," Nature, Nature, vol. 403(6767), pages 267-268, January.
    7. George von Dassow & Eli Meir & Edwin M. Munro & Garrett M. Odell, 2000. "The segment polarity network is a robust developmental module," Nature, Nature, vol. 406(6792), pages 188-192, July.
    8. Johannes Jaeger & Svetlana Surkova & Maxim Blagov & Hilde Janssens & David Kosman & Konstantin N. Kozlov & Manu & Ekaterina Myasnikova & Carlos E. Vanario-Alonso & Maria Samsonova & David H. Sharp & J, 2004. "Dynamic control of positional information in the early Drosophila embryo," Nature, Nature, vol. 430(6997), pages 368-371, July.
    9. Matthew Freeman, 2000. "Feedback control of intercellular signalling in development," Nature, Nature, vol. 408(6810), pages 313-319, November.
    10. Eric van Nimwegen & James P. Crutchfield & Martijn Huynen, 1999. "Neutral Evolution of Mutational Robustness," Working Papers 99-03-021, Santa Fe Institute.
    11. Michael B. Elowitz & Stanislas Leibler, 2000. "A synthetic oscillatory network of transcriptional regulators," Nature, Nature, vol. 403(6767), pages 335-338, January.
    12. Timothy S. Gardner & Charles R. Cantor & James J. Collins, 2000. "Construction of a genetic toggle switch in Escherichia coli," Nature, Nature, vol. 403(6767), pages 339-342, January.
    13. Aviv Bergman & Mark L. Siegal, 2003. "Evolutionary capacitance as a general feature of complex gene networks," Nature, Nature, vol. 424(6948), pages 549-552, July.
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    Cited by:

    1. Emmert-Streib, Frank & Dehmer, Matthias, 2009. "Fault tolerance of information processing in gene networks," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 388(4), pages 541-548.
    2. Sam F Greenbury & Steffen Schaper & Sebastian E Ahnert & Ard A Louis, 2016. "Genetic Correlations Greatly Increase Mutational Robustness and Can Both Reduce and Enhance Evolvability," PLOS Computational Biology, Public Library of Science, vol. 12(3), pages 1-27, March.
    3. Krishnan, Arun & Tomita, Masaru & Giuliani, Alessandro, 2008. "Evolution of gene regulatory networks: Robustness as an emergent property of evolution," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 387(8), pages 2170-2186.
    4. Shintaro Nagata & Macoto Kikuchi, 2020. "Emergence of cooperative bistability and robustness of gene regulatory networks," PLOS Computational Biology, Public Library of Science, vol. 16(6), pages 1-24, June.
    5. Tadamune Kaneko & Macoto Kikuchi, 2022. "Evolution enhances mutational robustness and suppresses the emergence of a new phenotype: A new computational approach for studying evolution," PLOS Computational Biology, Public Library of Science, vol. 18(1), pages 1-20, January.
    6. Javier Santos-Moreno & Eve Tasiudi & Hadiastri Kusumawardhani & Joerg Stelling & Yolanda Schaerli, 2023. "Robustness and innovation in synthetic genotype networks," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Payne, Joshua L., 2016. "No tradeoff between versatility and robustness in gene circuit motifs," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 449(C), pages 192-199.
    8. Zang, Hong & Zhang, Tonghua & Zhang, Yanduo, 2015. "Bifurcation analysis of a mathematical model for genetic regulatory network with time delays," Applied Mathematics and Computation, Elsevier, vol. 260(C), pages 204-226.
    9. Nasimul Noman & Taku Monjo & Pablo Moscato & Hitoshi Iba, 2015. "Evolving Robust Gene Regulatory Networks," PLOS ONE, Public Library of Science, vol. 10(1), pages 1-21, January.

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