Pervasive epistasis exposes intramolecular networks in adaptive enzyme evolution
Karol Buda1, Charlotte M Miton1, Nobuhiko Tokuriki2
1Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
Nature Communications
|December 21, 2023
Summary
Enzyme evolution shows that most mutations have unique effects across different genetic backgrounds, complicating functional predictions. This study quanties epistasis, revealing intramolecular rewiring mechanisms.
Area of Science:
- Biochemistry
- Evolutionary Biology
- Molecular Biology
Background:
- Enzyme function relies on intricate intramolecular residue networks.
- Alterations in these networks during evolution can lead to epistasis, where mutations have context-dependent effects.
- Epistasis can appear idiosyncratic, varying significantly across different genetic backgrounds.
Purpose of the Study:
- To quantitatively assess the prevalence and patterns of epistasis in enzyme evolution.
- To investigate the role of idiosyncratic epistasis in distorting functional predictions.
- To uncover molecular mechanisms underlying higher-order epistasis during enzyme adaptation.
Main Methods:
- Analysis of 41 fitness landscapes from seven distinct enzymes.
- Examination of mutational and epistatic effects across diverse genotypes.
- Integration of structural data to elucidate molecular mechanisms of epistasis.
Main Results:
- >94% of mutational and epistatic effects were found to be highly idiosyncratic.
- Idiosyncratic epistasis significantly distorted the functional predictions of evolved enzymes.
- Instances of higher-order, intramolecular rewiring were identified along adaptive trajectories.
Conclusions:
- Epistasis is highly prevalent and often idiosyncratic in enzyme evolution.
- Understanding idiosyncratic epistasis is crucial for accurate functional prediction.
- Molecular and structural analyses provide insights into the mechanisms of enzyme evolution and epistasis.
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