article published yes Mato Lagator author 345D25EC-F248-11E8-B48F-1D18A9856A87 Srdjan Sarikas author 35F0286E-F248-11E8-B48F-1D18A9856A87 Hande Acar author 2DDF136A-F248-11E8-B48F-1D18A9856A870000-0003-1986-9753 Jonathan P Bollback author 2C6FA9CC-F248-11E8-B48F-1D18A9856A870000-0002-4624-4612 Calin C Guet author 47F8433E-F248-11E8-B48F-1D18A9856A870000-0001-6220-2052 CaGu department JoBo department NiBa department International IST Postdoc Fellowship Programme project Selective Barriers to Horizontal Gene Transfer project Most phenotypes are determined by molecular systems composed of specifically interacting molecules. However, unlike for individual components, little is known about the distributions of mutational effects of molecular systems as a whole. We ask how the distribution of mutational effects of a transcriptional regulatory system differs from the distributions of its components, by first independently, and then simultaneously, mutating a transcription factor and the associated promoter it represses. We find that the system distribution exhibits increased phenotypic variation compared to individual component distributions - an effect arising from intermolecular epistasis between the transcription factor and its DNA-binding site. In large part, this epistasis can be qualitatively attributed to the structure of the transcriptional regulatory system and could therefore be a common feature in prokaryotes. Counter-intuitively, intermolecular epistasis can alleviate the constraints of individual components, thereby increasing phenotypic variation that selection could act on and facilitating adaptive evolution. https://research-explorer.ista.ac.at/download/570/5096/IST-2017-918-v1+1_elife-28921-figures-v3.pdf application/pdfno https://research-explorer.ista.ac.at/download/570/5097/IST-2017-918-v1+2_elife-28921-v3.pdf application/pdfno https://creativecommons.org/licenses/by/4.0/ eLife Sciences Publications2017 eng 2050-084X 00042586820000110.7554/eLife.28921 6 Lagator M, Sarikas S, Acar H, Bollback JP, Guet CC. 2017. Regulatory network structure determines patterns of intermolecular epistasis. eLife. 6, e28921. Lagator, Mato, Srdjan Sarikas, Hande Acar, Jonathan P Bollback, and Calin C Guet. “Regulatory Network Structure Determines Patterns of Intermolecular Epistasis.” <i>ELife</i>. eLife Sciences Publications, 2017. <a href="https://doi.org/10.7554/eLife.28921">https://doi.org/10.7554/eLife.28921</a>. Lagator M, Sarikas S, Acar H, Bollback JP, Guet CC. Regulatory network structure determines patterns of intermolecular epistasis. <i>eLife</i>. 2017;6. doi:<a href="https://doi.org/10.7554/eLife.28921">10.7554/eLife.28921</a> Lagator, M., Sarikas, S., Acar, H., Bollback, J. P., &#38; Guet, C. C. (2017). Regulatory network structure determines patterns of intermolecular epistasis. <i>ELife</i>. eLife Sciences Publications. <a href="https://doi.org/10.7554/eLife.28921">https://doi.org/10.7554/eLife.28921</a> M. Lagator, S. Sarikas, H. Acar, J. P. Bollback, and C. C. Guet, “Regulatory network structure determines patterns of intermolecular epistasis,” <i>eLife</i>, vol. 6. eLife Sciences Publications, 2017. Lagator, Mato, et al. “Regulatory Network Structure Determines Patterns of Intermolecular Epistasis.” <i>ELife</i>, vol. 6, e28921, eLife Sciences Publications, 2017, doi:<a href="https://doi.org/10.7554/eLife.28921">10.7554/eLife.28921</a>. M. Lagator, S. Sarikas, H. Acar, J.P. Bollback, C.C. Guet, ELife 6 (2017). 5702018-12-11T11:47:14Z2025-09-11T07:40:30Z