1. Computational and Systems Biology
  2. Evolutionary Biology
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Adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak

  1. João V Rodrigues
  2. Eugene I Shakhnovich  Is a corresponding author
  1. Harvard University, United States
Research Article
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Cite this article as: eLife 2019;8:e50509 doi: 10.7554/eLife.50509

Abstract

The mechanisms of adaptation to inactivation of essential genes remain unknown. Here we inactivate E. coli dihydrofolate reductase (DHFR) by introducing D27G,N,F chromosomal mutations in a key catalytic residue with subsequent adaptation by an automated serial transfer protocol. The partial reversal G27->C occurred in three evolutionary trajectories. Conversely, in one trajectory for D27G and in all trajectories for D27F,N strains adapted to grow at very low metabolic supplement (folAmix) concentrations but did not escape entirely from supplement auxotrophy. Major global shifts in metabolome and proteome occurred upon DHFR inactivation, which were partially reversed in adapted strains. Loss-of-function mutations in two genes, thyA and deoB, ensured adaptation to low folAmix by rerouting the 2-Deoxy-D-ribose-phosphate metabolism from glycolysis towards synthesis of dTMP. Multiple evolutionary pathways of adaptation converged to a suboptimal solution due to the high accessibility to loss-of-function mutations that block the path to the highest, yet least accessible, fitness peak.

Article and author information

Author details

  1. João V Rodrigues

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Eugene I Shakhnovich

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    For correspondence
    shakhnovich@chemistry.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4769-2265

Funding

National Institute of General Medical Sciences (068670)

  • João V Rodrigues

National Institute of General Medical Sciences (068670)

  • Eugene I Shakhnovich

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

Reviewing Editor

  1. Antonis Rokas, Vanderbilt University, United States

Publication history

  1. Received: July 24, 2019
  2. Accepted: September 30, 2019
  3. Accepted Manuscript published: October 1, 2019 (version 1)

Copyright

© 2019, Rodrigues & Shakhnovich

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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