1. Biochemistry and Chemical Biology
  2. Evolutionary Biology

Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes

  1. Florian Baier
  2. Nansook Hong
  3. Gloria Yang
  4. Anna Pabis
  5. Charlotte M Miton
  6. Alexandre Barrozo
  7. Paul D Carr
  8. Shina CL Kamerlin
  9. Colin J Jackson
  10. Nobuhiko Tokuriki  Is a corresponding author
  1. University of British Columbia, Canada
  2. Australian National University, Australia
  3. Uppsala University, Sweden
https://doi.org/10.7554/eLife.40789
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Cite this article
  1. Florian Baier
  2. Nansook Hong
  3. Gloria Yang
  4. Anna Pabis
  5. Charlotte M Miton
  6. Alexandre Barrozo
  7. Paul D Carr
  8. Shina CL Kamerlin
  9. Colin J Jackson
  10. Nobuhiko Tokuriki
(2019)
Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes
eLife 8:e40789.
https://doi.org/10.7554/eLife.40789
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  3. Download .RIS

Abstract

Genetic variation among orthologous proteins can cause cryptic phenotypic properties that only manifest in changing environments. Such variation may impact the evolvability of proteins, but the underlying molecular basis remains unclear. Here, we performed comparative directed evolution of four orthologous metallo-β-lactamases toward a new function and found that different starting genotypes evolved to distinct evolutionary outcomes. Despite a low initial fitness, one ortholog reached a significantly higher fitness plateau than its counterparts, via increasing catalytic activity. By contrast, the ortholog with the highest initial activity evolved to a less-optimal and phenotypically distinct outcome through changes in expression, oligomerization and activity. We show how cryptic molecular properties and conformational variation of active site residues in the initial genotypes cause epistasis, that could lead to distinct evolutionary outcomes. Our work highlights the importance of understanding the molecular details that connect genetic variation to protein function to improve the prediction of protein evolution.

Data availability

Diffraction data have been deposited in PDB under the accession code 5JQJ, 5K4M and 6BM9

The following data sets were generated

Article and author information

Author details

  1. Florian Baier

    Michael Smith Laboratory, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.

  2. Nansook Hong

    Research School of Chemistry, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.

  3. Gloria Yang

    Michael Smith Laboratory, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.

  4. Anna Pabis

    Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  5. Charlotte M Miton

    Michael Smith Laboratory, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2374-303X

  6. Alexandre Barrozo

    Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  7. Paul D Carr

    Research School of Chemistry, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.

  8. Shina CL Kamerlin

    Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3190-1173

  9. Colin J Jackson

    Research School of Chemistry, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6150-3822

  10. Nobuhiko Tokuriki

    Michael Smith Laboratory, University of British Columbia, Vancouver, Canada
    For correspondence
    tokuriki@msl.ubc.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8235-1829

Funding

Natural Sciences and Engineering Research Council of Canada (RGPIN 418262-12)

  • Nobuhiko Tokuriki

Canadian Institutes of Health Research (353714)

  • Nobuhiko Tokuriki

Natural Sciences and Engineering Research Council of Canada (RGPIN 2017-04909)

  • Nobuhiko Tokuriki

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrei N Lupas, Max Planck Institute for Developmental Biology, Germany

Version history

  1. Received: August 5, 2018
  2. Accepted: January 22, 2019
  3. Accepted Manuscript published: February 5, 2019 (version 1)
  4. Version of Record published: February 12, 2019 (version 2)

Copyright

© 2019, Baier et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Florian Baier
  2. Nansook Hong
  3. Gloria Yang
  4. Anna Pabis
  5. Charlotte M Miton
  6. Alexandre Barrozo
  7. Paul D Carr
  8. Shina CL Kamerlin
  9. Colin J Jackson
  10. Nobuhiko Tokuriki
(2019)
Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes
eLife 8:e40789.
https://doi.org/10.7554/eLife.40789

Share this article

https://doi.org/10.7554/eLife.40789

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