Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes
- University of British Columbia, Canada
- Australian National University, Australia
- Uppsala University, Sweden
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
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Data from: Cryptic genetic variation defines the adaptive evolutionary potential of enzymesDryad Digital Repository, doi.org/10.5061/dryad.qk653b3.
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Directed evolutionary changes in MBL super family - VIM-2 Round 10Protein Data Bank, 6BM9.
Article and author information
Author details
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.
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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Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes
eLife 8:e40789.
https://doi.org/10.7554/eLife.40789
