Modelling the Evolution of Dynamic Regulatory Networks: Some Critical Insights

  • Anton CrombachEmail author


Regulatory networks are at the centre of cellular decision-making, and understanding their structure and dynamics is a goal in many areas of the life sciences. In this chapter, I present recent studies that, in my opinion, demonstrate how thinking in terms of networks is enriching our understanding of evolution. By studying abstract models of regulatory networks, evolutionary concepts such as robustness, evolvability, modularity, and hierarchy have been clarified. Moreover, models are helping us probe the relationship between network structure, function, and evolution. Models can also be closely linked to experimental systems. I discuss two such data-driven studies, which highlight how combining theory and data allows us to understand how evolution has proceeded on Earth. Finally, I present several open challenges in the field of network evolution, and I suggest how to tackle them.



I thank Elise Parey for critical reading and comments. And I kindly acknowledge Foundation Bettencourt Schueller.


  1. Abou-Jaoud W, Traynard P, Monteiro PT, Saez-Rodriguez J, Helikar T, Thieffry D, Chaouiya C (2016) Logical modeling and dynamical analysis of cellular networks. Front Genet 7:94Google Scholar
  2. Alberch P (1991) From genes to phenotype: dynamical systems and evolvability. Genetica 84(1):5–11CrossRefPubMedGoogle Scholar
  3. Bergman A, Siegal ML (2003) Evolutionary capacitance as a general feature of complex gene networks. Nature 424(6948):549–552CrossRefPubMedGoogle Scholar
  4. Bertolino E, Reinitz J, Manu (2016) The analysis of novel distal Cebpa enhancers and silencers using a transcriptional model reveals the complex regulatory logic of hematopoietic lineage specification. Dev Biol 413(1):128–144Google Scholar
  5. Borrell V, Reillo I (2012) Emerging roles of neural stem cells in cerebral cortex development and evolution. Dev Neurobiol 72(7):955–971CrossRefPubMedGoogle Scholar
  6. Britten RJ, Davidson EH (1969) Gene regulation for higher cells: a theory. Science 165(3891):349–357CrossRefPubMedGoogle Scholar
  7. Catalan P, Arias CF, Cuesta JA, Manrubia S (2017) Adaptive multiscapes: an up-to-date metaphor to visualize molecular adaptation. Biol Direct 12(1):7CrossRefPubMedPubMedCentralGoogle Scholar
  8. Clark E (2017) Dynamic patterning by the Drosophila pair-rule network reconciles long-germ and short-germ segmentation. bioRxiv, p 099671Google Scholar
  9. Clark E, Akam M (2016) Odd-paired controls frequency doubling in Drosophila segmentation by altering the pair-rule gene regulatory network. eLife 5Google Scholar
  10. Clune J, Mouret JB, Lipson H (2013) The evolutionary origins of modularity. Proc Biol Sci 280(1755):20122863Google Scholar
  11. Cordero OX, Hogeweg P (2006) Feed-forward loop circuits as a side effect of genome evolution. Mol Biol Evol 23(10):1931–1936CrossRefPubMedGoogle Scholar
  12. Corominas-Murtra B, Goi J, Sol RV, Rodrguez-Caso C (2013) On the origins of hierarchy in complex networks. Proc Natl Acad Sci USA 110(33):13316–13321CrossRefPubMedPubMedCentralGoogle Scholar
  13. Cotterell J, Sharpe J (2010) An atlas of gene regulatory networks reveals multiple three-gene mechanisms for interpreting morphogen gradients. Mol Syst Biol 6:425CrossRefPubMedPubMedCentralGoogle Scholar
  14. Cotterell J, Sharpe J (2013) Mechanistic explanations for restricted evolutionary paths that emerge from gene regulatory networks. PLoS ONE 8(4):e61178Google Scholar
  15. Crombach A, Hogeweg P (2008) Evolution of evolvability in gene regulatory networks. PLoS Comput Biol 4(7):e1000112Google Scholar
  16. Crombach A, Wotton KR, Jimenez-Guri E, Jaeger J (2016) Gap gene regulatory dynamics evolve along a genotype network. Mol Biol Evol 33(5):1293–1307CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ellis LL, Huang W, Quinn AM, Ahuja A, Alfrejd B, Gomez FE, Hjelmen CE, Moore KL, Mackay TFC, Johnston JS, Tarone AM (2014) Intrapopulation genome size variation in D. melanogaster reflects life history variation and plasticity. PLoS Genet 10(7):e1004522Google Scholar
  18. Fierst JL, Phillips PC (2015) Modeling the evolution of complex genetic systems: the gene network family tree. J Exp Zool B Mol Dev Evol 324(1):1–12CrossRefPubMedPubMedCentralGoogle Scholar
  19. Fontana W, Schuster P (1998a) Continuity in evolution: on the nature of transitions. Science 280(5368):1451–1455CrossRefPubMedGoogle Scholar
  20. Fontana W, Schuster P (1998b) Shaping space: the possible and the attainable in RNA genotype--phenotype mapping. J Theor Biol 194(4):491–515Google Scholar
  21. Franois P, Hakim V (2004) Design of genetic networks with specified functions by evolution in silico. Proc Natl Acad Sci USA 101(2):580–585CrossRefGoogle Scholar
  22. Friedlander T, Mayo AE, Tlusty T, Alon U (2013) Mutation rules and the evolution of sparseness and modularity in biological systems. PLoS ONE 8(8):e70444Google Scholar
  23. Furusawa C, Kaneko K (2013) Epigenetic feedback regulation accelerates adaptation and evolution. PLoS ONE 8(5):e61251Google Scholar
  24. Garca-Solache M, Jaeger J, Akam M (2010) A systematic analysis of the gap gene system in the moth midge Clogmia albipunctata. Dev Biol 344(1):306–318Google Scholar
  25. Gjuvsland AB, Hayes BJ, Omholt SW, Carlborg O (2007a) Statistical epistasis is a generic feature of gene regulatory networks. Genetics 175(1):411–420CrossRefPubMedPubMedCentralGoogle Scholar
  26. Gjuvsland AB, Plahte E, Omholt SW (2007b) Threshold-dominated regulation hides genetic variation in gene expression networks. BMC Syst Biol 1:57CrossRefPubMedPubMedCentralGoogle Scholar
  27. Gjuvsland AB, Wang Y, Plahte E, Omholt SW (2013) Monotonicity is a key feature of genotype-phenotype maps. Front Genet 4:216CrossRefPubMedPubMedCentralGoogle Scholar
  28. Glass L, Kauffman SA (1973) The logical analysis of continuous, non-linear biochemical control networks. J Theor Biol 39(1):103–129CrossRefPubMedGoogle Scholar
  29. Hogeweg P (2012) Toward a theory of multilevel evolution: long-term information integration shapes the mutational landscape and enhances evolvability. Adv Exp Med Biol 751:195–224CrossRefPubMedGoogle Scholar
  30. Hoyos E, Kim K, Milloz J, Barkoulas M, Pnigault JB, Munro E, Felix MA (2011) Quantitative variation in autocrine signaling and pathway crosstalk in the Caenorhabditis vulval network. Curr Biol 21(7):527–538CrossRefPubMedPubMedCentralGoogle Scholar
  31. Huynen MA, Hogeweg P (1994) Pattern generation in molecular evolution: exploitation of the variation in RNA landscapes. J Mol Evol 39(1):71–79CrossRefPubMedGoogle Scholar
  32. Ingram PJ, Stumpf MPH, Stark J (2006) Network motifs: structure does not determine function. BMC Genom 7:108CrossRefGoogle Scholar
  33. Jaeger J (2011) The gap gene network. Cell Mol Life Sci 68(2):243–274CrossRefPubMedGoogle Scholar
  34. Jaeger J, Crombach A (2012) Life’s attractors: understanding developmental systems through reverse engineering and in silico evolution. Adv Exp Med Biol 751:93–119CrossRefPubMedGoogle Scholar
  35. Jiang P, Ludwig MZ, Kreitman M, Reinitz J (2015) Natural variation of the expression pattern of the segmentation gene even-skipped in Drosophila melanogaster. Dev Biol 405(1):173–181Google Scholar
  36. Jimenez A, Cotterell J, Munteanu A, Sharpe J (2015) Dynamics of gene circuits shapes evolvability. Proc Natl Acad Sci USA 112(7):2103–2108CrossRefPubMedPubMedCentralGoogle Scholar
  37. Jimenez A, Cotterell J, Munteanu A, Sharpe J (2017) A spectrum of modularity in multifunctional gene circuits. Mol Syst Biol 13(4):925CrossRefPubMedPubMedCentralGoogle Scholar
  38. Jimenez-Guri E, Huerta-Cepas J, Cozzuto L, Wotton KR, Kang H, Himmelbauer H, Roma G, Gabaldn T, Jaeger J (2013) Comparative transcriptomics of early dipteran development. BMC Genom 14:123CrossRefGoogle Scholar
  39. Kashtan N, Alon U (2005) Spontaneous evolution of modularity and network motifs. Proc Natl Acad Sci USA 102(39):13773–13778CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kauffman SA (1969) Metabolic stability and epigenesis in randomly constructed genetic nets. J Theor Biol 22(3):437–467CrossRefPubMedGoogle Scholar
  41. Klingler E (2017) Development and organization of the evolutionarily conserved three-layered olfactory cortex. eNeuro 4(1)Google Scholar
  42. Kouvaris K, Clune J, Kounios L, Brede M, Watson RA (2017) How evolution learns to generalise: Using the principles of learning theory to understand the evolution of developmental organisation. PLoS Comput Biol 13(4):e1005358Google Scholar
  43. Lim WA, Lee CM, Tang C (2013) Design principles of regulatory networks: searching for the molecular algorithms of the cell. Mol Cell 49(2):202–212CrossRefPubMedPubMedCentralGoogle Scholar
  44. Loreto V, Servedio VDP, Strogatz SH, Tria F (2016) Dynamics on expanding spaces: modeling the emergence of novelties. In: Esposti MD, Altmann EG, Pachet F (eds) Creativity and universality in language, lecture notes in morphogenesis. Springer International Publishing, pp 59–83Google Scholar
  45. Ma W, Trusina A, El-Samad H, Lim WA, Tang C (2009) Defining network topologies that can achieve biochemical adaptation. Cell 138(4):760–773CrossRefPubMedPubMedCentralGoogle Scholar
  46. Mangan S, Alon U (2003) Structure and function of the feed-forward loop network motif. Proc Natl Acad Sci USA 100(21):11980–11985CrossRefPubMedPubMedCentralGoogle Scholar
  47. Mangan S, Zaslaver A, Alon U (2003) The coherent feedforward loop serves as a sign-sensitive delay element in transcription networks. J Mol Biol 334(2):197–204CrossRefPubMedGoogle Scholar
  48. Mengistu H, Huizinga J, Mouret JB, Clune J (2016) The evolutionary origins of hierarchy. PLoS Comput Biol 12(6):e1004829Google Scholar
  49. Milo R, Itzkovitz S, Kashtan N, Levitt R, Shen-Orr S, Ayzenshtat I, Sheffer M, Alon U (2004) Superfamilies of evolved and designed networks. Science 303(5663):1538–1542CrossRefPubMedGoogle Scholar
  50. Milo R, Shen-Orr S, Itzkovitz S, Kashtan N, Chklovskii D, Alon U (2002) Network motifs: simple building blocks of complex networks. Science 298(5594):824–827CrossRefPubMedGoogle Scholar
  51. Miyamoto T, Furusawa C, Kaneko K (2015) Pluripotency, differentiation, and reprogramming: a gene expression dynamics model with epigenetic feedback regulation. PLoS Comput Biol 11(8):e1004476Google Scholar
  52. Niklas KJ, Bondos SE, Dunker AK, Newman SA (2015) Rethinking gene regulatory networks in light of alternative splicing, intrinsically disordered protein domains, and posttranslational modifications. Front Cell Dev Biol 3:8CrossRefPubMedPubMedCentralGoogle Scholar
  53. van Nimwegen E, Crutchfield JP, Huynen M (1999) Neutral evolution of mutational robustness. Proc Natl Acad Sci USA 96(17):9716–9720CrossRefPubMedPubMedCentralGoogle Scholar
  54. O’Malley MA (2012) Evolutionary systems biology: historical and philosophical perspectives on an emerging synthesis. Adv Exp Med Biol 751:1–28CrossRefPubMedGoogle Scholar
  55. Omholt SW, Plahte E, Oyehaug L, Xiang K (2000) Gene regulatory networks generating the phenomena of additivity, dominance and epistasis. Genetics 155(2):969–980PubMedPubMedCentralGoogle Scholar
  56. Onimaru K, Marcon L, Musy M, Tanaka M, Sharpe J (2016) The fin-to-limb transition as the re-organization of a Turing pattern. Nat Commun 7:11582Google Scholar
  57. Palsson A, Wesolowska N, Reynisdttir S, Ludwig MZ, Kreitman M (2014) Naturally occurring deletions of Hunchback binding sites in the even-skipped stripe 3 + 7 enhancer. PLoS ONE 9(5):e91924Google Scholar
  58. Parter M, Kashtan N, Alon U (2008) Facilitated variation: how evolution learns from past environments to generalize to new environments. PLoS Comput Biol 4(11):e1000206Google Scholar
  59. Pavlicev M, Wagner GP (2012) A model of developmental evolution: selection, pleiotropy and compensation. Trends Ecol Evol (Amst) 27(6):316–322CrossRefGoogle Scholar
  60. Payne JL, Wagner A (2014) The robustness and evolvability of transcription factor binding sites. Science 343(6173):875–877CrossRefPubMedGoogle Scholar
  61. Payne JL, Wagner A (2015) Function does not follow form in gene regulatory circuits. Sci Rep 5:13015Google Scholar
  62. Pigliucci M (2008) Is evolvability evolvable? Nat Rev Genet 9(1):75–82CrossRefPubMedGoogle Scholar
  63. Pigliucci M (2010) Genotype-phenotype mapping and the end of the ‘genes as blueprint’ metaphor. Philos Trans R Soc Lond B Biol Sci 365(1540):557–566Google Scholar
  64. Raspopovic J, Marcon L, Russo L, Sharpe J (2014) Modeling digits. Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients. Science 345(6196):566–570CrossRefPubMedGoogle Scholar
  65. Salazar-Ciudad I (2012) Tooth patterning and evolution. Curr Opin Genet Dev 22(6):585–592CrossRefPubMedGoogle Scholar
  66. Salazar-Ciudad I, Jernvall J (2010) A computational model of teeth and the developmental origins of morphological variation. Nature 464(7288):583–586CrossRefPubMedGoogle Scholar
  67. Salazar-Ciudad I, Marín-Riera M (2013) Adaptive dynamics under development-based genotypephenotype maps. Nature 497(7449):361–364CrossRefPubMedGoogle Scholar
  68. Schuster P, Fontana W, Stadler PF, Hofacker IL (1994) From sequences to shapes and back: a case study in RNA secondary structures. Proc Biol Sci 255(1344):279–284CrossRefPubMedGoogle Scholar
  69. Siegal ML, Bergman A (2002) Waddington’s canalization revisited: developmental stability and evolution. Proc Natl Acad Sci USA 99(16):10528–10532CrossRefPubMedPubMedCentralGoogle Scholar
  70. Siegal ML, Promislow DEL, Bergman A (2007) Functional and evolutionary inference in gene networks: does topology matter? Genetica 129(1):83–103CrossRefPubMedGoogle Scholar
  71. Sommer RJ (2012) Evolution of regulatory networks: nematode vulva induction as an example of developmental systems drift. Adv Exp Med Biol 751:79–91CrossRefPubMedGoogle Scholar
  72. Sorrells TR, Johnson AD (2015) Making sense of transcription networks. Cell 161(4):714–723CrossRefPubMedPubMedCentralGoogle Scholar
  73. Toma K, Hanashima C (2015) Switching modes in corticogenesis: mechanisms of neuronal subtype transitions and integration in the cerebral cortex. Front Neurosci 9:274CrossRefPubMedPubMedCentralGoogle Scholar
  74. True JR, Haag ES (2001) Developmental system drift and flexibility in evolutionary trajectories. Evol Dev 3(2):109–119CrossRefPubMedGoogle Scholar
  75. ten Tusscher KH, Hogeweg P (2011) Evolution of networks for body plan patterning; interplay of modularity, robustness and evolvability. PLoS Comput Biol 7(10):e1002208Google Scholar
  76. Wagner A (2008) Robustness and evolvability: a paradox resolved. Proc Biol Sci 275(1630):91–100CrossRefPubMedGoogle Scholar
  77. Wagner A (2011) The origins of evolutionary innovations: a theory of transformative change in living systems. Oxford University PressGoogle Scholar
  78. Wall ME (2011) Structure-function relations are subtle in genetic regulatory networks. Math Biosci 231(1):61–68CrossRefPubMedGoogle Scholar
  79. Wall ME, Dunlop MJ, Hlavacek WS (2005) Multiple functions of a feed-forward-loop gene circuit. J Mol Biol 349(3):501–514CrossRefPubMedGoogle Scholar
  80. Weiss KM (2005) The phenogenetic logic of life. Nat Rev Genet 6(1):36–45CrossRefPubMedGoogle Scholar
  81. Weiss KM, Fullerton SM (2000) Phenogenetic drift and the evolution of genotype-phenotype relationships. Theor Popul Biol 57(3):187–195CrossRefPubMedGoogle Scholar
  82. Wilke CO, Wang JL, Ofria C, Lenski RE, Adami C (2001) Evolution of digital organisms at high mutation rates leads to survival of the flattest. Nature 412(6844):331–333CrossRefPubMedGoogle Scholar
  83. Wotton KR, Jimenez-Guri E, Crombach A, Janssens H, Alcaine-Colet A, Lemke S, Schmidt-Ott U, Jaeger J (2015) Quantitative system drift compensates for altered maternal inputs to the gap gene network of the scuttle fly Megaselia abdita. eLife 4Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Centre for Interdisciplinary Research in BiologyCollege de France, CNRS, INSERM, PSL ResearchParisFrance

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