The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication
Open accessAbstract
Most RNA viruses infecting mammals and other vertebrates show profound suppression of CpG and UpA dinucleotide frequencies. To investigate this functionally, mutants of the picornavirus, echovirus 7 (E7), were constructed with altered CpG and UpA compositions in two 1.1–1.3 Kbase regions. Those with increased frequencies of CpG and UpA showed impaired replication kinetics and higher RNA/infectivity ratios compared with wild-type virus. Remarkably, mutants with CpGs and UpAs removed showed enhanced replication, larger plaques and rapidly outcompeted wild-type virus on co-infections. Luciferase-expressing E7 sub-genomic replicons with CpGs and UpAs removed from the reporter gene showed 100-fold greater luminescence. E7 and mutants were equivalently sensitive to exogenously added interferon-β, showed no evidence for differential recognition by ADAR1 or pattern recognition receptors RIG-I, MDA5 or PKR. However, kinase inhibitors roscovitine and C16 partially or entirely reversed the attenuated phenotype of high CpG and UpA mutants, potentially through inhibition of currently uncharacterized pattern recognition receptors that respond to RNA composition. Generating viruses with enhanced replication kinetics has applications in vaccine production and reporter gene construction. More fundamentally, the findings introduce a new evolutionary paradigm where dinucleotide composition of viral genomes is subjected to selection pressures independently of coding capacity and profoundly influences host–pathogen interactions.
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SAVE increases the number of codon pairs that are underrepresented in coding sequences of the target host.
“Previous studies have shown that SAVE not only increases the number of codon pairs that are underrepresented in coding sequences of the target host”
From Codon Pair Bias Is a Direct Consequence of Dinucleotide Bias (2016) · cites this paper as Atkinson et al., 2014
The Discussion (page unavailable) reports that earlier mutants increased bias toward unfavourable codon pairs, supporting the core point about increasing disfavoured pairs. It does not identify those pairs as underrepresented in the target host’s coding sequences or name the approach SAVE. (LLM, conf=0.78)
Experimental — accuracy not yet measuredWhen SAVE is done using vertebrate CPSs, it inadvertently increases the number of CpG and, to a lesser degree, TpA dinucleotides in recoded sequences.
“when done using vertebrate CPSs, inadvertently increases the number of CpG and, to lesser degree, also TpA dinucleotides in recoded sequences”
From Codon Pair Bias Is a Direct Consequence of Dinucleotide Bias (2016) · cites this paper as Atkinson et al., 2014
The Discussion (Relationship between virus replication and CpG and UpA frequencies; page unavailable) reports that earlier codon de-optimization increased CpG and UpA frequencies. It does not establish that SAVE using vertebrate codon-pair scores causes those increases, or that the increase in UpA (TpA in DNA notation) is smaller than the increase in CpG. (LLM, conf=0.76)
Experimental — accuracy not yet measuredCodon pairs that contain CpG and TpA dinucleotides at codon position P3-A1 are among the most underrepresented codon pairs.
“codon pairs that contain CpG and TpA dinucleotides at codon position P3-A1 are among the most underrepresented codon pairs”
From Codon Pair Bias Is a Direct Consequence of Dinucleotide Bias (2016) · cites this paper as Atkinson et al., 2014
The Introduction (page unavailable) reports that CpG and UpA dinucleotides are underrepresented in RNA-virus genomes, including poliovirus coding regions. The Methods (page unavailable) describe calculating codon-pair bias, but the passages do not establish that pairs with CpG or TpA specifically at the P3–A1 boundary are among the most underrepresented codon pairs. (LLM, conf=0.78)
Experimental — accuracy not yet measuredIncreasing the frequency of CpG dinucleotides in RNA virus genomes reduces virus fitness.
“Several studies have shown that increasing the frequency of CpG dinucleotides in the RNA virus genome reduces the virus fitness (Atkinson et al., 2014;Burns et al., 2009;Tulloch et al., 2014).”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Atkinson et al., 2014
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- Authors
- Atkinson, N. J., Witteveldt, J., Evans, D. J., & Simmonds, P.
- Affiliations
- Roslin Institute (GB)
- 1 Infection and Immunity Division, Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK and 2School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-01-25
- Volume
- 42
- Issue
- 7
- Pages
- 4527-4545
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC3985648
- OpenAlex
- W2057088297
- Cited by
- 192
- References
- 57
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 9 · 2023: 8 · 2022: 11 · 2021: 36 · 2020: 26 · 2019: 17 · 2018: 11 · 2017: 20 · 2016: 10 · 2015: 13 · 2014: 3
- FWCI
- 7.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nucleic Acids Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- St Andrews Research Repository (St Andrews Research Repository) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (095831, WT087628MA)
- University of St Andrews
- Medical Research Council
- Biotechnology and Biological Sciences Research Council (BBS/E/D/20241864)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- CpG, RNA virus replication, echovirus 7, picornavirus, viral genome evolution, RNA composition, innate immune recognition, pattern recognition receptors, interferon-beta, roscovitine, RNA replicon, vaccine production, host-pathogen interaction
- MeSH terms
- Base Composition, Cell Line, Mutation, RNA, Viral, Virus Replication, Dinucleoside Phosphates, GC Rich Sequence, Enterovirus B, Human
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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