IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v10y2019i1d10.1038_s41467-019-12130-8.html
   My bibliography  Save this article

Learning the pattern of epistasis linking genotype and phenotype in a protein

Author

Listed:
  • Frank J. Poelwijk

    (Dana-Farber Cancer Institute)

  • Michael Socolich

    (University of Chicago)

  • Rama Ranganathan

    (University of Chicago)

Abstract

Understanding the pattern of epistasis—the non-independence of mutations—is critical for relating genotype and phenotype. However, the combinatorial complexity of potential epistatic interactions has severely limited the analysis of this problem. Using new mutational approaches, we report a comprehensive experimental study of all 213 mutants that link two phenotypically distinct variants of the Entacmaea quadricolor fluorescent protein—an opportunity to examine epistasis up to the 13th order. The data show the existence of many high-order epistatic interactions between mutations, but also reveal extraordinary sparsity, enabling novel experimental and computational strategies for learning the relevant epistasis. We demonstrate that such information, in turn, can be used to accurately predict phenotypes in practical situations where the number of measurements is limited. Finally, we show how the observed epistasis shapes the solution space of single-mutation trajectories between the parental fluorescent proteins, informative about the protein’s evolutionary potential. This work provides conceptual and experimental strategies to profoundly characterize epistasis in a protein, relevant to both natural and laboratory evolution.

Suggested Citation

  • Frank J. Poelwijk & Michael Socolich & Rama Ranganathan, 2019. "Learning the pattern of epistasis linking genotype and phenotype in a protein," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12130-8
    DOI: 10.1038/s41467-019-12130-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-019-12130-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-019-12130-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Remkes A. Scheele & Laurens H. Lindenburg & Maya Petek & Markus Schober & Kevin N. Dalby & Florian Hollfelder, 2022. "Droplet-based screening of phosphate transfer catalysis reveals how epistasis shapes MAP kinase interactions with substrates," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Rachapun Rotrattanadumrong & Yohei Yokobayashi, 2022. "Experimental exploration of a ribozyme neutral network using evolutionary algorithm and deep learning," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. 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.
    4. Federica Luppino & Ivan A. Adzhubei & Christopher A. Cassa & Agnes Toth-Petroczy, 2023. "DeMAG predicts the effects of variants in clinically actionable genes by integrating structural and evolutionary epistatic features," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Brian M. Petersen & Monica B. Kirby & Karson M. Chrispens & Olivia M. Irvin & Isabell K. Strawn & Cyrus M. Haas & Alexis M. Walker & Zachary T. Baumer & Sophia A. Ulmer & Edgardo Ayala & Emily R. Rhod, 2024. "An integrated technology for quantitative wide mutational scanning of human antibody Fab libraries," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. 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.
    7. Jonathan Yaacov Weinstein & Carlos Martí-Gómez & Rosalie Lipsh-Sokolik & Shlomo Yakir Hoch & Demian Liebermann & Reinat Nevo & Haim Weissman & Ekaterina Petrovich-Kopitman & David Margulies & Dmitry I, 2023. "Designed active-site library reveals thousands of functional GFP variants," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    8. 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.
    9. David C. Marciano & Chen Wang & Teng-Kuei Hsu & Thomas Bourquard & Benu Atri & Ralf B. Nehring & Nicholas S. Abel & Elizabeth A. Bowling & Taylor J. Chen & Pamela D. Lurie & Panagiotis Katsonis & Susa, 2022. "Evolutionary action of mutations reveals antimicrobial resistance genes in Escherichia coli," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    10. David Ding & Ada Y. Shaw & Sam Sinai & Nathan Rollins & Noam Prywes & David F. Savage & Michael T. Laub & Debora S. Marks, 2024. "Protein design using structure-based residue preferences," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12130-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.