Virus attenuation by genome-scale changes in codon pair bias
Open accessAbstract
As a result of the redundancy of the genetic code, adjacent pairs of amino acids can be encoded by as many as 36 different pairs of synonymous codons. A species-specific "codon pair bias" provides that some synonymous codon pairs are used more or less frequently than statistically predicted. We synthesized de novo large DNA molecules using hundreds of over-or underrepresented synonymous codon pairs to encode the poliovirus capsid protein. Underrepresented codon pairs caused decreased rates of protein translation, and polioviruses containing such amino acid-independent changes were attenuated in mice. Polioviruses thus customized were used to immunize mice and provided protective immunity after challenge. This "death by a thousand cuts" strategy could be generally applicable to attenuating many kinds of viruses.
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The molecular mechanisms that underlie the attenuation by CPD have remained unknown.
“Despite its great potential, the molecular mechanisms that underlie the attenuation by CPD have remained unknown (Broadbent et al., 2016;Coleman et al., 2008;Futcher et al., 2015;Le Noue ¨n et al., 2014;Shen et al., 2015;Simmonds et al., 2015;Yang et al., 2013).”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Coleman et al., 2008
In the passage describing the translation assay (section labeled Abstract; no page given), Coleman et al. report that underrepresented codon pairs reduced translation and say this is probably sufficient to explain the attenuated phenotype. They leave open why particular codon pairs are underrepresented, but do not present the mechanism of attenuation as wholly unknown. (LLM, conf=0.85)
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Experimental — accuracy not yet measuredReduction of protein production is not the sum of small negative effects exerted by individual underrepresented, non-optimal codon pairs.
“The identification of a clear premature translation termination point in different recoded genes (Figure 5G; Figure S6) suggests that reduction of protein production is not the sum of small negative effects exerted by individual underrepresented, non-optimal codon pairs (Coleman et al., 2008).”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Coleman et al., 2008
The cited paper reports that underrepresented codon pairs reduce translation, but it does not attribute that reduction to a clear premature termination point. Its discussion of PV-Min attenuation instead says that many mutations are consistent with causing “small, additive defects”—the opposite of the sentence’s proposed account. The latter finding concerns attenuation rather than a direct measurement of each pair’s effect on protein production. (LLM, conf=0.83)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn mammals, many disfavored codon pairs have UpA or CpG at their junctions.
“In mammals, many disfavored codon pairs have UpA or CpG at their junctions (4).”
From Reply to Simmonds et al.: Codon pair and dinucleotide bias have not been functionally distinguished (2015) · cites this paper as [4]
The passage labeled Abstract gives a human example of an underrepresented codon pair, GCC|GAA, which has CpG at the codon junction. It does not say that many disfavored pairs have CpG junctions or mention UpA junctions, so it supports only the narrower example. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe prevailing hypothesis is that the large number of underrepresented codon pairs interferes with efficient protein production or processing.
“While different mechanisms have been proposed, the prevailing hypothesis is that the large number of underrepresented codon pairs interferes with efficient protein production or processing (Coleman et al., 2008;Shen et al., 2015).”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Coleman et al., 2008
The paper reports that hundreds of underrepresented codon pairs reduced protein translation in recoded poliovirus, supporting the protein-production mechanism (Abstract; page not supplied). It does not establish that this is the prevailing hypothesis across settings or address impaired protein processing. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCodon pair bias can be quantified using the codon pair score (CPS) statistics, where statistically underrepresented codon pairs have negative and overrepresented codon pairs have positive CPS values.
“Codon pair bias can be quantified using the codon pair score (CPS) statistics (Coleman et al., 2008), where statistically underrepresented codon pairs have negative and overrepresented codon pairs have positive CPS values.”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Coleman et al., 2008
The passage labeled Abstract says codon pairs can be under- or overrepresented relative to statistical expectations, and describes a codon pair bias (CPB) score for a recoded virus. It does not define a codon pair score (CPS) or state that negative CPS values indicate underrepresentation and positive values indicate overrepresentation. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Codon pair deoptimization (CPD) is a highly efficient virus attenuation strategy that utilizes suboptimal codon pairs to achieve attenuation of recoded viruses.
“Codon pair deoptimization (CPD) is a highly efficient virus attenuation strategy that utilizes suboptimal codon pairs to achieve attenuation of recoded viruses.”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Coleman et al., 2008
CPD rearranges the positions of existing synonymous codons in a viral gene, without changing the codon bias or amino acid composition of the encoded protein.
“CPD rearranges the positions of existing synonymous codons in a viral gene, without changing the codon bias or amino acid composition of the encoded protein (Coleman et al., 2008;Mueller et al., 2010).”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Coleman et al., 2008
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“It is also calculated to be independent of codon bias and amino acid frequency (Coleman et al., 2008 when they started with an ATG codon, ended with an in-frame stop codon, and had no internal stop codons or undetermined nucleotides.”
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Self-citation
- Authors
- Coleman, J. R., Papamichail, D., Skiena, S., Futcher, B., Wimmer, E., & Mueller, S.
- Affiliations
- Stony Brook University (US)
- Corresponding author
- Papamichail, Dimitris
- Wimmer, Eckard
- ORCID
- Venue
- Science
- Published
- 2008-06-27
- Volume
- 320
- Issue
- 5884
- Pages
- 1784-1787
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2754401
- OpenAlex
- W2001674944
- Cited by
- 715
- References
- 5
- Citations by year
- 2026: 27 · 2025: 27 · 2024: 50 · 2023: 39 · 2022: 29 · 2021: 75 · 2020: 44 · 2019: 41 · 2018: 35 · 2017: 50 · 2016: 32 · 2015: 43 · 2014: 42 · 2013: 42 · 2012: 44
- FWCI
- 13.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI-15122, R37AI015122, R01AI075219, AI075219)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
- Keywords
- viral attenuation, codon pair bias, synonymous codons, poliovirus, capsid protein, genetic code redundancy, translation efficiency, de novo DNA synthesis, protective immunity
- MeSH terms
- Algorithms, Animals, Antibodies, Viral, Cloning, Molecular, Codon, Cytopathogenic Effect, Viral, Hot Temperature, HeLa Cells, Humans, Mice, Transgenic, Mutation, Viral Plaque Assay, Poliomyelitis, Protein Biosynthesis, Vaccination, Vaccines, Attenuated, Virulence, Genome, Viral, Poliovirus, Poliovirus Vaccines, Capsid Proteins, Mice
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