Adaptive substitutions underlying cardiac glycoside insensitivity in insects exhibit epistasis in vivo

  1. Andrew M Taverner
  2. Lu Yang
  3. Zachary J Barile
  4. Becky Lin
  5. Julie Peng  Is a corresponding author
  6. Ana P Pinharanda
  7. Arya S Rao
  8. Bartholomew P Roland
  9. Aaron D Talsma
  10. Daniel Wei
  11. Georg Petschenka
  12. Michael J Palladino  Is a corresponding author
  13. Peter Andolfatto  Is a corresponding author
  1. Princeton University, United States
  2. University of Pittsburgh, United States
  3. Columbia University, United States
  4. Justus-Liebig-Universität Gießen, Germany

Abstract

Predicting how species will respond to selection pressures requires understanding the factors that constrain their evolution. We use genome engineering of Drosophila to investigate constraints on the repeated evolution of unrelated herbivorous insects to toxic cardiac glycosides, which primarily occurs via a small subset of possible functionally-relevant substitutions to Na+,K+-ATPase. Surprisingly, we find that frequently observed adaptive substitutions at two sites, 111 and 122, are lethal when homozygous and adult heterozygotes exhibit dominant neural dysfunction. We identify a phylogenetically correlated substitution, A119S, that partially ameliorates the deleterious effects of substitutions at 111 and 122. Despite contributing little to cardiac glycoside-insensitivity in vitro, A119S, like substitutions at 111 and 122, substantially increases adult survivorship upon cardiac glycoside exposure. Our results demonstrate the importance of epistasis in constraining adaptive paths. Moreover, by revealing distinct effects of substitutions in vitro and in vivo, our results underscore the importance of evaluating the fitness of adaptive substitutions and their interactions in whole organisms.

Data availability

Sequence data as been deposited in Genbank and the details of all accession numbers of this and previously published data are tabulated in Supplementary Table S1.

The following data sets were generated

Article and author information

Author details

  1. Andrew M Taverner

    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8265-6836
  2. Lu Yang

    Department of Ecology and Evolutionary Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Zachary J Barile

    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Becky Lin

    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Julie Peng

    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States
    For correspondence
    jzpeng@Princeton.edu
    Competing interests
    The authors declare that no competing interests exist.
  6. Ana P Pinharanda

    Department of Biological Sciences, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Arya S Rao

    Department of Biological Sciences, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3007-4812
  8. Bartholomew P Roland

    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Aaron D Talsma

    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Daniel Wei

    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Georg Petschenka

    Institute for Insect Biotechnology, Justus-Liebig-Universität Gießen, Hesse, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Michael J Palladino

    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsbugh, United States
    For correspondence
    mjp44@pitt.edu
    Competing interests
    The authors declare that no competing interests exist.
  13. Peter Andolfatto

    Department of Biological Sciences, Columbia University, New York, United States
    For correspondence
    pa2543@columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3393-4574

Funding

National Institutes of Health (R01 GM115523)

  • Peter Andolfatto

National Institutes of Health (T32 GM008424)

  • Bartholomew P Roland

National Institutes of Health (R01 GM108073)

  • Michael J Palladino

National Institutes of Health (R01 AG027453)

  • Michael J Palladino

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

Reviewing Editor

  1. Lauren A O'Connell, Stanford University, United States

Version history

  1. Received: May 6, 2019
  2. Accepted: August 24, 2019
  3. Accepted Manuscript published: August 27, 2019 (version 1)
  4. Accepted Manuscript updated: August 29, 2019 (version 2)
  5. Version of Record published: September 9, 2019 (version 3)
  6. Version of Record updated: September 30, 2019 (version 4)

Copyright

© 2019, Taverner 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. Andrew M Taverner
  2. Lu Yang
  3. Zachary J Barile
  4. Becky Lin
  5. Julie Peng
  6. Ana P Pinharanda
  7. Arya S Rao
  8. Bartholomew P Roland
  9. Aaron D Talsma
  10. Daniel Wei
  11. Georg Petschenka
  12. Michael J Palladino
  13. Peter Andolfatto
(2019)
Adaptive substitutions underlying cardiac glycoside insensitivity in insects exhibit epistasis in vivo
eLife 8:e48224.
https://doi.org/10.7554/eLife.48224

Share this article

https://doi.org/10.7554/eLife.48224

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