2. Academic Validation
  3. Mechanism of Virus Attenuation by Codon Pair Deoptimization

Mechanism of Virus Attenuation by Codon Pair Deoptimization

  • Cell Rep. 2020 Apr 28;31(4):107586. doi: 10.1016/j.celrep.2020.107586.
Nicole Groenke 1,  Jakob Trimpert 1,  Sophie Merz 2,  Andelé M Conradie 1,  Emanuel Wyler 3,  Hongwei Zhang 4,  Orsalia-Georgia Hazapis 3,  Sebastian Rausch 4,  Markus Landthaler 5,  Nikolaus Osterrieder 6,  Dusan Kunec 7
Affiliations

Affiliations

  • 1 Institut für Virologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163 Berlin, Germany.
  • 2 Institut für Veterinärpathologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 15, 14163 Berlin, Germany.
  • 3 Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str. 28, 10115 Berlin, Germany.
  • 4 Institut für Immunologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163 Berlin, Germany.
  • 5 Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str. 28, 10115 Berlin, Germany; IRI Life Sciences, Institute of Biology, Humboldt-Universität zu Berlin, Philippstraße 13, 10115 Berlin, Germany.
  • 6 Institut für Virologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163 Berlin, Germany. Electronic address: [email protected].
  • 7 Institut für Virologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163 Berlin, Germany. Electronic address: [email protected].
PMID: 32348767 DOI: 10.1016/j.celrep.2020.107586
Abstract

Codon pair deoptimization is an efficient virus attenuation strategy, but the mechanism that leads to attenuation is unknown. The strategy involves synthetic recoding of viral genomes that alters the positions of synonymous codons, thereby increasing the number of suboptimal codon pairs and CpG dinucleotides in recoded genomes. Here we identify the molecular mechanism of codon pair deoptimization-based attenuation by studying recoded influenza A viruses. We show that suboptimal codon pairs cause attenuation, whereas the increase of CpG dinucleotides has no effect. Furthermore, we show that suboptimal codon pairs reduce both mRNA stability and translation efficiency of codon pair-deoptimized genes. Consequently, reduced protein production directly causes virus attenuation. Our study provides evidence that suboptimal codon pairs are major determinants of mRNA stability. Additionally, it demonstrates that codon pair bias can be used to increase mRNA stability and protein production of synthetic genes in many areas of biotechnology.

Keywords

attenuation; codon bias; codon pair bias; codon pair deoptimization; dinucleotide frequencies; influenza A virus; mRNA stability; recoding; synthetic attenuated virus engineering.

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