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Delayed commitment to evolutionary fate in antibiotic resistance fitness landscapes

Author

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  • Adam C. Palmer

    (Harvard Medical School
    Laboratory of Systems Pharmacology, Harvard Medical School
    Present address: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia)

  • Erdal Toprak

    (Harvard Medical School
    Green Center for Systems Biology, University of Texas Southwestern Medical Center)

  • Michael Baym

    (Harvard Medical School)

  • Seungsoo Kim

    (Harvard Medical School
    Present address: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA)

  • Adrian Veres

    (Harvard Medical School)

  • Shimon Bershtein

    (Ben-Gurion University of the Negev)

  • Roy Kishony

    (Harvard Medical School
    Technion-Israel Institute of Technology)

Abstract

Predicting evolutionary paths to antibiotic resistance is key for understanding and controlling drug resistance. When considering a single final resistant genotype, epistatic contingencies among mutations restrict evolution to a small number of adaptive paths. Less attention has been given to multi-peak landscapes, and while specific peaks can be favoured, it is unknown whether and how early a commitment to final fate is made. Here we characterize a multi-peaked adaptive landscape for trimethoprim resistance by constructing all combinatorial alleles of seven resistance-conferring mutations in dihydrofolate reductase. We observe that epistatic interactions increase rather than decrease the accessibility of each peak; while they restrict the number of direct paths, they generate more indirect paths, where mutations are adaptively gained and later adaptively lost or changed. This enhanced accessibility allows evolution to proceed through many adaptive steps while delaying commitment to genotypic fate, hindering our ability to predict or control evolutionary outcomes.

Suggested Citation

  • Adam C. Palmer & Erdal Toprak & Michael Baym & Seungsoo Kim & Adrian Veres & Shimon Bershtein & Roy Kishony, 2015. "Delayed commitment to evolutionary fate in antibiotic resistance fitness landscapes," Nature Communications, Nature, vol. 6(1), pages 1-8, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8385
    DOI: 10.1038/ncomms8385
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    Cited by:

    1. Solip Park & Fran Supek & Ben Lehner, 2021. "Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    2. Karol Buda & Charlotte M. Miton & Nobuhiko Tokuriki, 2023. "Pervasive epistasis exposes intramolecular networks in adaptive enzyme evolution," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Yeonwoo Park & Brian P. H. Metzger & Joseph W. Thornton, 2024. "The simplicity of protein sequence-function relationships," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Andreas Wagner, 2023. "Evolvability-enhancing mutations in the fitness landscapes of an RNA and a protein," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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