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Pervasive epistasis exposes intramolecular networks in adaptive enzyme evolution.

ABSTRACT: Enzyme evolution is characterized by constant alterations of the intramolecular residue networks supporting their functions. The rewiring of these network interactions can give rise to epistasis. As mutations accumulate, the epistasis observed across diverse genotypes may appear idiosyncratic, that is, exhibit unique effects in different genetic backgrounds. Here, we unveil a quantitative picture of the prevalence and patterns of epistasis in enzyme evolution by analyzing 41 fitness landscapes generated from seven enzymes. We show that >94% of all mutational and epistatic effects appear highly idiosyncratic, which greatly distorted the functional prediction of the evolved enzymes. By examining seemingly idiosyncratic changes in epistasis along adaptive trajectories, we expose several instances of higher-order, intramolecular rewiring. Using complementary structural data, we outline putative molecular mechanisms explaining higher-order epistasis along two enzyme trajectories. Our work emphasizes the prevalence of epistasis and provides an approach to exploring this phenomenon through a molecular lens.

SUBMITTER: Buda K

PROVIDER: S-EPMC10739712 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Pervasive epistasis exposes intramolecular networks in adaptive enzyme evolution.

Buda Karol K Miton Charlotte M CM Tokuriki Nobuhiko N

Nature communications 20231221 1

Enzyme evolution is characterized by constant alterations of the intramolecular residue networks supporting their functions. The rewiring of these network interactions can give rise to epistasis. As mutations accumulate, the epistasis observed across diverse genotypes may appear idiosyncratic, that is, exhibit unique effects in different genetic backgrounds. Here, we unveil a quantitative picture of the prevalence and patterns of epistasis in enzyme evolution by analyzing 41 fitness landscapes g ...[more]

PMID: 38129396

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Project description:In Drosophila, multiple lines of evidence converge in suggesting that beneficial substitutions to the genome may be common. All suffer from confounding factors, however, such that the interpretation of the evidence-in particular, conclusions about the rate and strength of beneficial substitutions-remains tentative. Here, we use genome-wide polymorphism data in D. simulans and sequenced genomes of its close relatives to construct a readily interpretable characterization of the effects of positive selection: the shape of average neutral diversity around amino acid substitutions. As expected under recurrent selective sweeps, we find a trough in diversity levels around amino acid but not around synonymous substitutions, a distinctive pattern that is not expected under alternative models. This characterization is richer than previous approaches, which relied on limited summaries of the data (e.g., the slope of a scatter plot), and relates to underlying selection parameters in a straightforward way, allowing us to make more reliable inferences about the prevalence and strength of adaptation. Specifically, we develop a coalescent-based model for the shape of the entire curve and use it to infer adaptive parameters by maximum likelihood. Our inference suggests that ∼13% of amino acid substitutions cause selective sweeps. Interestingly, it reveals two classes of beneficial fixations: a minority (approximately 3%) that appears to have had large selective effects and accounts for most of the reduction in diversity, and the remaining 10%, which seem to have had very weak selective effects. These estimates therefore help to reconcile the apparent conflict among previously published estimates of the strength of selection. More generally, our findings provide unequivocal evidence for strongly beneficial substitutions in Drosophila and illustrate how the rapidly accumulating genome-wide data can be leveraged to address enduring questions about the genetic basis of adaptation.

Dataset Information

Pervasive epistasis exposes intramolecular networks in adaptive enzyme evolution.

Publications

Pervasive epistasis exposes intramolecular networks in adaptive enzyme evolution.

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