1. Microbiology and Infectious Disease

RNA virus attenuation by codon pair deoptimisation is an artefact of increases in CpG/UpA dinucleotide frequencies

  1. Fiona Tulloch
  2. Nicky J Atkinson
  3. David J Evans
  4. Martin D Ryan
  5. Peter Simmonds  Is a corresponding author
  1. University of St Andrews, United Kingdom
  2. University of Edinburgh, United Kingdom
  3. University of Warwick, United Kingdom
https://doi.org/10.7554/eLife.04531
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  1. Fiona Tulloch
  2. Nicky J Atkinson
  3. David J Evans
  4. Martin D Ryan
  5. Peter Simmonds
(2014)
RNA virus attenuation by codon pair deoptimisation is an artefact of increases in CpG/UpA dinucleotide frequencies
eLife 3:e04531.
https://doi.org/10.7554/eLife.04531
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Abstract

Mutating RNA virus genomes to alter codon pair (CP) frequencies and reduce translation efficiency has been advocated as a method to generate safe, attenuated virus vaccines. However, selection for disfavoured CPs leads to unintended increases in CpG and UpA dinucleotide frequencies that also attenuate replication. We designed and phenotypically characterised mutants of the picornavirus, echovirus 7, in which these parameters were independently varied to determine which most influenced virus replication. CpG and UpA dinucleotide frequencies primarily influenced virus replication ability while no fitness differences were observed between mutants with different CP usage where dinucleotide frequencies were kept constant. Contrastingly, translation efficiency was unaffected by either CP usage or dinucleotide frequencies. This mechanistic insight is critical for future rational design of live virus vaccines and their safety evaluation; attenuation is mediated through enhanced innate immune responses to viruses with elevated CpG/UpA dinucleotide frequencies rather the viruses themselves being intrinsically defective.

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Author details

  1. Fiona Tulloch

    School of Biology, University of St Andrews, St Andrews, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Nicky J Atkinson

    Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. David J Evans

    School of Life Sciences, University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Martin D Ryan

    School of Biology, University of St Andrews, St Andrews, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Peter Simmonds

    Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    Peter.Simmonds@ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Stephen P Goff, Howard Hughes Medical Institute, Columbia University, United States

Version history

  1. Received: August 28, 2014
  2. Accepted: December 8, 2014
  3. Accepted Manuscript published: December 9, 2014 (version 1)
  4. Version of Record published: January 9, 2015 (version 2)

Copyright

© 2014, Tulloch 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. Fiona Tulloch
  2. Nicky J Atkinson
  3. David J Evans
  4. Martin D Ryan
  5. Peter Simmonds
(2014)
RNA virus attenuation by codon pair deoptimisation is an artefact of increases in CpG/UpA dinucleotide frequencies
eLife 3:e04531.
https://doi.org/10.7554/eLife.04531

Share this article

https://doi.org/10.7554/eLife.04531

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