Mechanism of Virus Attenuation by Codon Pair Deoptimization
Summary: 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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720305350 |
| _version_ | 1819267342221180928 |
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| author | Nicole Groenke Jakob Trimpert Sophie Merz Andelé M. Conradie Emanuel Wyler Hongwei Zhang Orsalia-Georgia Hazapis Sebastian Rausch Markus Landthaler Nikolaus Osterrieder Dusan Kunec |
| author_facet | Nicole Groenke Jakob Trimpert Sophie Merz Andelé M. Conradie Emanuel Wyler Hongwei Zhang Orsalia-Georgia Hazapis Sebastian Rausch Markus Landthaler Nikolaus Osterrieder Dusan Kunec |
| author_sort | Nicole Groenke |
| collection | DOAJ |
| description | Summary: 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. : Codon pair deoptimization is a highly efficient virus attenuation strategy. It involves the recoding of viral genomes using underrepresented codon pairs. Groenke et al. show that suboptimal codon pairs are the primary cause of attenuation because they reduce mRNA stability, translation efficiency, and thus also protein production of recoded genes. Keywords: codon bias, codon pair bias, codon pair deoptimization, synthetic attenuated virus engineering, dinucleotide frequencies, recoding, influenza A virus, attenuation, mRNA stability |
| first_indexed | 2024-12-23T21:15:38Z |
| format | Article |
| id | doaj.art-38982959a57c444799b182563cd6310d |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-23T21:15:38Z |
| publishDate | 2020-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-38982959a57c444799b182563cd6310d2022-12-21T17:30:54ZengElsevierCell Reports2211-12472020-04-01314Mechanism of Virus Attenuation by Codon Pair DeoptimizationNicole Groenke0Jakob Trimpert1Sophie Merz2Andelé M. Conradie3Emanuel Wyler4Hongwei Zhang5Orsalia-Georgia Hazapis6Sebastian Rausch7Markus Landthaler8Nikolaus Osterrieder9Dusan Kunec10Institut für Virologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163 Berlin, GermanyInstitut für Virologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163 Berlin, GermanyInstitut für Veterinärpathologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 15, 14163 Berlin, GermanyInstitut für Virologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163 Berlin, GermanyBerlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str. 28, 10115 Berlin, GermanyInstitut für Immunologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163 Berlin, GermanyBerlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Hannoversche Str. 28, 10115 Berlin, GermanyInstitut für Immunologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163 Berlin, GermanyBerlin 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, GermanyInstitut für Virologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163 Berlin, Germany; Corresponding authorInstitut für Virologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163 Berlin, Germany; Corresponding authorSummary: 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. : Codon pair deoptimization is a highly efficient virus attenuation strategy. It involves the recoding of viral genomes using underrepresented codon pairs. Groenke et al. show that suboptimal codon pairs are the primary cause of attenuation because they reduce mRNA stability, translation efficiency, and thus also protein production of recoded genes. Keywords: codon bias, codon pair bias, codon pair deoptimization, synthetic attenuated virus engineering, dinucleotide frequencies, recoding, influenza A virus, attenuation, mRNA stabilityhttp://www.sciencedirect.com/science/article/pii/S2211124720305350 |
| spellingShingle | Nicole Groenke Jakob Trimpert Sophie Merz Andelé M. Conradie Emanuel Wyler Hongwei Zhang Orsalia-Georgia Hazapis Sebastian Rausch Markus Landthaler Nikolaus Osterrieder Dusan Kunec Mechanism of Virus Attenuation by Codon Pair Deoptimization Cell Reports |
| title | Mechanism of Virus Attenuation by Codon Pair Deoptimization |
| title_full | Mechanism of Virus Attenuation by Codon Pair Deoptimization |
| title_fullStr | Mechanism of Virus Attenuation by Codon Pair Deoptimization |
| title_full_unstemmed | Mechanism of Virus Attenuation by Codon Pair Deoptimization |
| title_short | Mechanism of Virus Attenuation by Codon Pair Deoptimization |
| title_sort | mechanism of virus attenuation by codon pair deoptimization |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720305350 |
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