IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v444y2006i7121d10.1038_nature05385.html
   My bibliography  Save this article

Robustness–epistasis link shapes the fitness landscape of a randomly drifting protein

Author

Listed:
  • Shimon Bershtein

    (Weizmann Institute of Science)

  • Michal Segal

    (Weizmann Institute of Science)

  • Roy Bekerman

    (Weizmann Institute of Science)

  • Nobuhiko Tokuriki

    (Weizmann Institute of Science)

  • Dan S. Tawfik

    (Weizmann Institute of Science)

Abstract

The distribution of fitness effects of protein mutations is still unknown1,2. Of particular interest is whether accumulating deleterious mutations interact, and how the resulting epistatic effects shape the protein’s fitness landscape. Here we apply a model system in which bacterial fitness correlates with the enzymatic activity of TEM-1 β-lactamase (antibiotic degradation). Subjecting TEM-1 to random mutational drift and purifying selection (to purge deleterious mutations) produced changes in its fitness landscape indicative of negative epistasis; that is, the combined deleterious effects of mutations were, on average, larger than expected from the multiplication of their individual effects. As observed in computational systems3,4,5, negative epistasis was tightly associated with higher tolerance to mutations (robustness). Thus, under a low selection pressure, a large fraction of mutations was initially tolerated (high robustness), but as mutations accumulated, their fitness toll increased, resulting in the observed negative epistasis. These findings, supported by FoldX stability computations of the mutational effects6, prompt a new model in which the mutational robustness (or neutrality) observed in proteins, and other biological systems, is due primarily to a stability margin, or threshold, that buffers the deleterious physico-chemical effects of mutations on fitness. Threshold robustness is inherently epistatic—once the stability threshold is exhausted, the deleterious effects of mutations become fully pronounced, thereby making proteins far less robust than generally assumed.

Suggested Citation

  • Shimon Bershtein & Michal Segal & Roy Bekerman & Nobuhiko Tokuriki & Dan S. Tawfik, 2006. "Robustness–epistasis link shapes the fitness landscape of a randomly drifting protein," Nature, Nature, vol. 444(7121), pages 929-932, December.
  • Handle: RePEc:nat:nature:v:444:y:2006:i:7121:d:10.1038_nature05385
    DOI: 10.1038/nature05385
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature05385
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/nature05385?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Zachary R Sailer & Sarah H Shafik & Robert L Summers & Alex Joule & Alice Patterson-Robert & Rowena E Martin & Michael J Harms, 2020. "Inferring a complete genotype-phenotype map from a small number of measured phenotypes," PLOS Computational Biology, Public Library of Science, vol. 16(9), pages 1-27, September.
    2. Steve O'Hagan & Joshua Knowles & Douglas B Kell, 2012. "Exploiting Genomic Knowledge in Optimising Molecular Breeding Programmes: Algorithms from Evolutionary Computing," PLOS ONE, Public Library of Science, vol. 7(11), pages 1-14, November.
    3. Jingzhi Lou & Weiwen Liang & Lirong Cao & Inchi Hu & Shi Zhao & Zigui Chen & Renee Wan Yi Chan & Peter Pak Hang Cheung & Hong Zheng & Caiqi Liu & Qi Li & Marc Ka Chun Chong & Yexian Zhang & Eng-kiong , 2024. "Predictive evolutionary modelling for influenza virus by site-based dynamics of mutations," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Steven Schulz & Sébastien Boyer & Matteo Smerlak & Simona Cocco & Rémi Monasson & Clément Nizak & Olivier Rivoire, 2021. "Parameters and determinants of responses to selection in antibody libraries," PLOS Computational Biology, Public Library of Science, vol. 17(3), pages 1-24, March.
    5. Jordan Yang & Nandita Naik & Jagdish Suresh Patel & Christopher S Wylie & Wenze Gu & Jessie Huang & F Marty Ytreberg & Mandar T Naik & Daniel M Weinreich & Brenda M Rubenstein, 2020. "Predicting the viability of beta-lactamase: How folding and binding free energies correlate with beta-lactamase fitness," PLOS ONE, Public Library of Science, vol. 15(5), pages 1-26, May.
    6. Manhart, Michael & Haldane, Allan & Morozov, Alexandre V., 2012. "A universal scaling law determines time reversibility and steady state of substitutions under selection," Theoretical Population Biology, Elsevier, vol. 82(1), pages 66-76.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:444:y:2006:i:7121:d:10.1038_nature05385. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.