Attenuation of dengue (and other RNA viruses) with codon pair recoding can be explained by increased CpG/UpA dinucleotide frequencies
Open accessAbstract
Shen et al. (1) describe the modification of three regions of the Dengue virus type 2 (DENV-2) genome to match the codon pair use of insect genes rather than those of mammals. We have previously shown that such recoding also modifies frequencies of CpG and UpA dinucleotides and have proposed it is this, rather than codon pair use, that restricts replication in mammalian cells (2). We argue that DENV-2 mutants are attenuated for cell culture and in vivo replication in mice through the same mechanism. Our conclusions are based on the following observations.
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All of the viral constructs in question (from Simmonds et al. and Shen et al.) coordinately alter dinucleotides and codon pairs.
“Accordingly, all of the viral constructs in question (1, 2) coordinately alter dinucleotides and codon pairs (see below)”
From Reply to Simmonds et al.: Codon pair and dinucleotide bias have not been functionally distinguished (2015) · cites this paper as [1]
The paper says Shen et al.’s three recoded dengue regions changed both codon-pair use and CpG/UpA frequencies. But its discussion of the “Min” mutants gives an explicit exception to the claim about all constructs: Min-E incorporated disfavored codon pairs while keeping CpG and UpA frequencies at wild-type levels. (LLM, conf=0.88)
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Mechanism of Virus Attenuation by Codon Pair Deoptimization
Groenke, N., Trimpert, J., Merz, S., Conradie, A. M., Wyler, E., Zhang, H., Hazapis, O.-G., Rausch, S., Landthaler, M., Osterrieder, N., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107586 · Cited by 85 · see citing works
“Hence, uncoupling the effects of the two phenomena is difficult (Broadbent et al., 2016; Futcher et al., 2015; Simmonds et al., 2015).”
BackgroundReply to Simmonds et al.: Codon pair and dinucleotide bias have not been functionally distinguished
Futcher, B., Gorbatsevych, O., Shen, S. H., Stauft, C. B., Song, Y., Wang, B., Leatherwood, J., Gardin, J., Yurovsky, A., Mueller, S., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1507710112 · Cited by 22 · see citing works
- Authors
- Simmonds, P., Tulloch, F., Evans, D. J., & Ryan, M. D.
- Affiliations
- Infection and Immunity Division, Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, United Kingdom;
- University of St Andrews (GB)
- University of Warwick (GB)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-06-12
- Volume
- 112
- Issue
- 28
- Pages
- E3633-4
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4507241
- OpenAlex
- W2161531655
- Cited by
- 28
- References
- 0
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 5 · 2017: 2 · 2016: 1 · 2015: 3
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/K003801/1)
- Wellcome Trust (WT087628MA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- dengue virus, RNA viruses, CpG, nucleotide composition, viral genome evolution, codon usage
- MeSH terms
- Animals, Arboviruses, Humans, Insect Vectors, Mammals, Genome, Viral
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