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

Evidence for strong mutation bias towards, and selection against, T/U content in SARS-CoV2: implications for attenuated vaccine design

View ORCID ProfileAlan M. Rice, View ORCID ProfileAtahualpa Castillo Morales, Alexander T. Ho, View ORCID ProfileChristine Mordstein, View ORCID ProfileStefanie Mühlhausen, View ORCID ProfileSamir Watson, Laura Cano, Bethan Young, View ORCID ProfileGrzegorz Kudla, View ORCID ProfileLaurence D. Hurst
doi: https://doi.org/10.1101/2020.05.11.088112
Alan M. Rice
1The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Alan M. Rice
Atahualpa Castillo Morales
1The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Atahualpa Castillo Morales
Alexander T. Ho
1The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christine Mordstein
1The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK
2MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Christine Mordstein
Stefanie Mühlhausen
1The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Stefanie Mühlhausen
Samir Watson
3Aarhus University, Department of Molecular Biology and Genetics, C F MøllersAllé 3, 8000 Aarhus, Denmark
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Samir Watson
Laura Cano
2MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bethan Young
1The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK
2MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Grzegorz Kudla
2MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Grzegorz Kudla
Laurence D. Hurst
1The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Laurence D. Hurst
  • For correspondence: l.d.hurst@bath.ac.uk
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

ABSTRACT

Large-scale re-engineering of synonymous sites is a promising strategy to generate attenuated viruses for vaccines. Attenuation typically relies on de-optimisation of codon pairs and maximization of CpG dinculeotide frequencies. So as to formulate evolutionarily-informed attenuation strategies, that aim to force nucleotide usage against the estimated direction favoured by selection, here we examine available whole-genome sequences of SARS-CoV2 to infer patterns of mutation and selection on synonymous sites. Analysis of mutational profiles indicates a strong mutation bias towards T with concomitant selection against T. Accounting for dinucleotide effects reinforces this conclusion, observed TT content being a quarter of that expected under neutrality. A significantly different mutational profile at CDS sites that are not 4-fold degenerate is consistent with contemporaneous selection against T mutations more widely. Although selection against CpG dinucleotides is expected to drive synonymous site G+C content below mutational equilibrium, observed G+C content is slightly above equilibrium, possibly because of selection for higher expression. Consistent with gene-specific selection against CpG dinucleotides, we observe systematic differences of CpG content between SARS-CoV2 genes. We propose an evolutionarily informed gene-bespoke approach to attenuation that, unusually, seeks to increase usage of the already most common synonymous codons. Comparable analysis of H1N1 and Ebola finds that GC3 deviated from neutral equilibrium is not a universal feature, cautioning against generalization of results.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵§ Co-senior authors

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 May 11, 2020.
Download PDF

Supplementary Material

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.
Evidence for strong mutation bias towards, and selection against, T/U content in SARS-CoV2: implications for attenuated vaccine design
(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
Evidence for strong mutation bias towards, and selection against, T/U content in SARS-CoV2: implications for attenuated vaccine design
Alan M. Rice, Atahualpa Castillo Morales, Alexander T. Ho, Christine Mordstein, Stefanie Mühlhausen, Samir Watson, Laura Cano, Bethan Young, Grzegorz Kudla, Laurence D. Hurst
bioRxiv 2020.05.11.088112; doi: https://doi.org/10.1101/2020.05.11.088112
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Evidence for strong mutation bias towards, and selection against, T/U content in SARS-CoV2: implications for attenuated vaccine design
Alan M. Rice, Atahualpa Castillo Morales, Alexander T. Ho, Christine Mordstein, Stefanie Mühlhausen, Samir Watson, Laura Cano, Bethan Young, Grzegorz Kudla, Laurence D. Hurst
bioRxiv 2020.05.11.088112; doi: https://doi.org/10.1101/2020.05.11.088112

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 (4672)
  • Biochemistry (10340)
  • Bioengineering (7658)
  • Bioinformatics (26300)
  • Biophysics (13501)
  • Cancer Biology (10672)
  • Cell Biology (15413)
  • Clinical Trials (138)
  • Developmental Biology (8487)
  • Ecology (12806)
  • Epidemiology (2067)
  • Evolutionary Biology (16831)
  • Genetics (11382)
  • Genomics (15469)
  • Immunology (10603)
  • Microbiology (25182)
  • Molecular Biology (10210)
  • Neuroscience (54383)
  • Paleontology (399)
  • Pathology (1667)
  • Pharmacology and Toxicology (2889)
  • Physiology (4334)
  • Plant Biology (9235)
  • Scientific Communication and Education (1586)
  • Synthetic Biology (2555)
  • Systems Biology (6773)
  • Zoology (1461)