Reply to Simmonds et al.: Codon pair and dinucleotide bias have not been functionally distinguished

Futcher, Bruce; Gorbatsevych, Oleksandr; Shen, Sam H.; Stauft, Charles B.; Song, Yinglin; Wang, Bingyin; Leatherwood, Janet; Gardin, Justin; Yurovsky, Alisa; Mueller, Steffen; Wimmer, Eckard

doi:10.1073/pnas.1507710112

Cited by 24 publications

(21 citation statements)

References 4 publications

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“…Indeed, RNA viruses have, in general, a low dinucleotide frequency (50,51), and an increase in CpG or UpA dinucleotide content in the genomes of picornaviruses results in variants that are debilitated in growth (17,23) or nonviable (16). Comparative analysis of the viruses used in our studies showed that the A12P1 deopt virus had an increased dinucleotide frequency, and this might be one possible reason for the observed attenuation; however, at this point, codon pair and dinucleotide biases have not been functionally distinguished, and the topic remains highly controversial (52,53).…”

Section: Discussionmentioning

confidence: 73%

Synonymous Deoptimization of Foot-and-Mouth Disease Virus Causes Attenuation In Vivo while Inducing a Strong Neutralizing Antibody Response

Segundo

Medina

Ramírez-Medina

et al. 2016

J Virol

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Codon bias deoptimization has been previously used to successfully attenuate human pathogens, including poliovirus, respiratory syncytial virus, and influenza virus. We have applied a similar technology to deoptimize the capsid-coding region (P1) of foot-andmouth disease virus (FMDV). Despite the introduction of 489 nucleotide changes (19%), synonymous deoptimization of the P1 region rendered a viable FMDV progeny. The resulting strain was stable and reached cell culture titers similar to those obtained for wild-type (WT) virus, but at reduced specific infectivity. Studies in mice showed that 100% of animals inoculated with the FMDV A12 P1 deoptimized mutant (A12-P1 deopt) survived, even when the animals were infected at doses 100 times higher than the dose required to cause death by WT virus. All mice inoculated with the A12-P1 deopt mutant developed a strong antibody response and were protected against subsequent lethal challenge with WT virus at 21 days postinoculation. Remarkably, the vaccine safety margin was at least 1,000-fold higher for A12-P1 deopt than for WT virus. Similar patterns of attenuation were observed in swine, in which animals inoculated with A12-P1 deopt virus did not develop clinical disease until doses reached 1,000 to 10,000 times the dose required to cause severe disease in 2 days with WT A12. Consistently, high levels of antibody titers were induced, even at the lowest dose tested. These results highlight the potential use of synonymous codon pair deoptimization as a strategy to safely attenuate FMDV and further develop live attenuated vaccine candidates to control such a feared livestock disease. Our work demonstrates that newly developed codon pair bias deoptimization technologies can be applied to FMD virus to obtain attenuated strains with potential for further development as novel live attenuated vaccine candidates that may rapidly control disease without reverting to virulence.

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Section: Discussionmentioning

confidence: 73%

Synonymous Deoptimization of Foot-and-Mouth Disease Virus Causes Attenuation In Vivo while Inducing a Strong Neutralizing Antibody Response

Segundo

Medina

Ramírez-Medina

et al. 2016

J Virol

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“…However, the process of choosing how many codons to change and what type of synonymous changes to implement is currently done without guiding principles. If fact, which synonymous features most strongly affect recoded viruses is debated (79,114,115,115) . Of the dozens of viruses that have been deoptimized, a minority of them measure compositional features different from the one being directly targeted for deoptimization.…”

Section: Synonymous Virus Genome Recoding For Vaccinesmentioning

confidence: 99%

ΦX174 Attenuation by Whole Genome Codon Deoptimization

Leuven

Ederer

Burleigh

et al. 2020

Preprint

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Natural selection acting on synonymous mutations in protein-coding genes influences genome composition and evolution. In viruses, introducing synonymous mutations in genes encoding structural proteins can drastically reduce viral growth, providing a means to generate potent, live attenuated vaccine candidates. However, an improved understanding of what compositional features are under selection and how combinations of synonymous mutations affect viral growth is needed to predictably attenuate viruses and make them resistant to reversion. We systematically recoded all non-overlapping genes of the bacteriophage ΦX174 with codons rarely used in its E. coli host. The fitness of recombinant viruses decreases as additional deoptimizing mutations are made to the genome, although not always linearly, and not consistently across genes. Combining deoptimizing mutations may reduce viral fitness more or less than expected from the effect size of the constituent mutations and we point out difficulties in untangling correlated compositional features. We test our model by optimizing the same genes and find that the relationship between codon usage and fitness does not hold for optimization, suggesting that wild-type ΦX174 is at a fitness optimum. This work highlights the need to better understand how selection acts on patterns of synonymous codon usage across the genome and provides a convenient system to investigate the genetic determinants of virulence.

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“…Codon pair bias exists in many organisms in all three kingdoms [81, 82], but its role in expression was not clear [81], since some codon pairs are avoided in all three kingdoms (for instance nnUAnn codon pairs to decrease the likelihood of forming an out-of-frame stop codon) [82]. The observation that recoding viral genes with underrepresented codon pairs resulted in virus attenuation in mice [83] suggests that use of such pairs is deleterious to expression although the nature of their effects remains to be deciphered [84, 85]. In general, considerably less work has focused on the possibility that codon combinations or codon contexts are key to regulating translation elongation.…”

Section: Specific Codon Pairs Modulate the Rate And Efficiency Of Tramentioning

confidence: 99%

Synonymous Codons: Choose Wisely for Expression

2017

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The genetic code, which defines the amino acid sequence of a protein, also contains information that influences the rate and efficiency of translation. Neither the mechanisms nor functions of codon-mediated regulation were understood. The prevailing model was that slow translation of codons decoded by rare tRNAs reduces efficiency. Recent genome-wide analyses have clarified three issues. Specific codons and codon combinations do modulate ribosome speed and facilitate protein folding. However, tRNA availability is not the sole determinant of rate, rather interactions between adjacent codons and wobble base pairing are key. One mechanism linking translation efficiency and codon use is that slower decoding is coupled to reduced mRNA stability. tRNA supply mediates biological regulation: changes in tRNA amounts facilitate cancer metastasis.

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Reply to Simmonds et al.: Codon pair and dinucleotide bias have not been functionally distinguished

Cited by 24 publications

References 4 publications

Synonymous Deoptimization of Foot-and-Mouth Disease Virus Causes Attenuation In Vivo while Inducing a Strong Neutralizing Antibody Response

Synonymous Deoptimization of Foot-and-Mouth Disease Virus Causes Attenuation In Vivo while Inducing a Strong Neutralizing Antibody Response

ΦX174 Attenuation by Whole Genome Codon Deoptimization

Synonymous Codons: Choose Wisely for Expression

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