1. Evolutionary Biology

Adaptation in protein fitness landscapes is facilitated by indirect paths

  1. Nicholas C Wu
  2. Lei Dai
  3. C Anders Olson
  4. James O Lloyd-Smith
  5. Ren Sun  Is a corresponding author
  1. The Scripps Research Institute, United States
  2. University of California, Los Angeles, United States
https://doi.org/10.7554/eLife.16965
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  1. Nicholas C Wu
  2. Lei Dai
  3. C Anders Olson
  4. James O Lloyd-Smith
  5. Ren Sun
(2016)
Adaptation in protein fitness landscapes is facilitated by indirect paths
eLife 5:e16965.
https://doi.org/10.7554/eLife.16965
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Abstract

The structure of fitness landscapes is critical for understanding adaptive protein evolution. Previous empirical studies on fitness landscapes were confined to either the neighborhood around the wild type sequence, involving mostly single and double mutants, or a combinatorially complete subgraph involving only two amino acids at each site. In reality, the dimensionality of protein sequence space is higher (20L) and there may be higher-order interactions among more than two sites. Here we experimentally characterized the fitness landscape of four sites in protein GB1, containing 204 = 160,000 variants. We found that while reciprocal sign epistasis blocked many direct paths of adaptation, such evolutionary traps could be circumvented by indirect paths through genotype space involving gain and subsequent loss of mutations. These indirect paths alleviate the constraint on adaptive protein evolution, suggesting that the heretofore neglected dimensions of sequence space may change our views on how proteins evolve.

Data availability

The following data sets were generated
    1. NC Wu
    2. L Dai
    3. CA Olson
    4. JO Lloyd-Smith
    5. R Sun
    (2015) Streptococcus dysgalactiae strain:GB1_AO
    Publicly available at the NCBI Gene Expression Omnibus (Accession no: PRJNA278685).
    https://www.ncbi.nlm.nih.gov/bioproject/PRJNA278685/

Article and author information

Author details

  1. Nicholas C Wu

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Lei Dai

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. C Anders Olson

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. James O Lloyd-Smith

    Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7941-502X

  5. Ren Sun

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    rsun@mednet.ucla.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Richard A Neher, Max Planck Institute for Developmental Biology, Germany

Version history

  1. Received: April 18, 2016
  2. Accepted: July 7, 2016
  3. Accepted Manuscript published: July 8, 2016 (version 1)
  4. Accepted Manuscript updated: July 11, 2016 (version 2)
  5. Version of Record published: August 15, 2016 (version 3)
  6. Version of Record updated: August 15, 2016 (version 4)

Copyright

© 2016, Wu 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. Nicholas C Wu
  2. Lei Dai
  3. C Anders Olson
  4. James O Lloyd-Smith
  5. Ren Sun
(2016)
Adaptation in protein fitness landscapes is facilitated by indirect paths
eLife 5:e16965.
https://doi.org/10.7554/eLife.16965

Share this article

https://doi.org/10.7554/eLife.16965

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