Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Adaptation in protein fitness landscapes is facilitated by indirect paths

Nicholas C. Wu, Lei Dai, C. Anders Olson, James O. Lloyd-Smith, Ren Sun
doi: https://doi.org/10.1101/045096
Nicholas C. Wu
1Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA
2Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: RSun@mednet.ucla.edu
Lei Dai
1Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA
3Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: RSun@mednet.ucla.edu
C. Anders Olson
1Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James O. Lloyd-Smith
3Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ren Sun
1Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA
2Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: RSun@mednet.ucla.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

The structure of fitness landscapes is critical for understanding adaptive protein evolution (e.g. antimicrobial resistance, affinity maturation, etc.). Due to limited throughput in fitness measurements, 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, however, the dimensionality of protein sequence space is higher (20L, L being the length of the relevant sequence) and there may be higher-order interactions among more than two sites. To study how these features impact the course of protein evolution, we experimentally characterized the fitness landscape of four sites in the IgG-binding domain of protein G, containing 204 = 160,000 variants. We found that the fitness landscape was rugged and direct paths of adaptation were often constrained by pairwise epistasis. However, while direct paths were blocked by reciprocal sign epistasis, we found systematic evidence that such evolutionary traps could be circumvented by “extra-dimensional bypass”. Extra dimensions in sequence space – with a different amino acid at the site of interest or an additional interacting site – open up indirect paths of adaptation via gain and subsequent loss of mutations. These indirect paths alleviate the constraint on reaching high fitness genotypes via selectively accessible trajectories, suggesting that the heretofore neglected dimensions of sequence space may completely change our views on how proteins evolve.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
Back to top
PreviousNext
Posted March 22, 2016.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Adaptation in protein fitness landscapes is facilitated by indirect paths
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Adaptation in protein fitness landscapes is facilitated by indirect paths
Nicholas C. Wu, Lei Dai, C. Anders Olson, James O. Lloyd-Smith, Ren Sun
bioRxiv 045096; doi: https://doi.org/10.1101/045096
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Adaptation in protein fitness landscapes is facilitated by indirect paths
Nicholas C. Wu, Lei Dai, C. Anders Olson, James O. Lloyd-Smith, Ren Sun
bioRxiv 045096; doi: https://doi.org/10.1101/045096

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Evolutionary Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4383)
  • Biochemistry (9602)
  • Bioengineering (7097)
  • Bioinformatics (24869)
  • Biophysics (12622)
  • Cancer Biology (9959)
  • Cell Biology (14358)
  • Clinical Trials (138)
  • Developmental Biology (7955)
  • Ecology (12111)
  • Epidemiology (2067)
  • Evolutionary Biology (15990)
  • Genetics (10929)
  • Genomics (14745)
  • Immunology (9871)
  • Microbiology (23680)
  • Molecular Biology (9486)
  • Neuroscience (50886)
  • Paleontology (369)
  • Pathology (1540)
  • Pharmacology and Toxicology (2683)
  • Physiology (4019)
  • Plant Biology (8657)
  • Scientific Communication and Education (1510)
  • Synthetic Biology (2397)
  • Systems Biology (6440)
  • Zoology (1346)