The codon adaptation index-a measure of directional synonymous codon usage bias, and its potential applications
Open accessAbstract
A simple, effective measure of synonymous codon usage bias, the Codon Adaptation Index, is detailed. The index uses a reference set of highly expressed genes from a species to assess the relative merits of each codon, and a score for a gene is calculated from the frequency of use of all codons in that gene. The index assesses the extent to which selection has been effective in moulding the pattern of codon usage. In that respect it is useful for predicting the level of expression of a gene, for assessing the adaptation of viral genes to their hosts, and for making comparisons of codon usage in different organisms. The index may also give an approximate indication of the likely success of heterologous gene expression.
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The codon optimization applied to BNT-162b2 and mRNA-1273 leads to a much increased CAI and ITE for the two vaccine mRNAs.
“The codon optimization applied to BNT-162b2 and mRNA-1273 leads to a much increased codon adaptation index (CAI) [21,22] and index of translation efficiency (ITE) [11,36] for the two vaccine mRNAs.”
From Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines (2021) · cites this paper as [21]
The 'Comparison of CAI with other indices' section defines CAI as a measure of synonymous codon usage bias, and 'Predicting levels of heterologous gene expression' discusses using it to assess whether a gene might benefit from more appropriate codons. The paper does not report CAI values for BNT-162b2 or mRNA-1273, so it cannot substantiate the claimed increase in those vaccine mRNAs. The ITE claim has separate citations and is not attributed to this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe frequencies of the peptides displayed on phages are not even in the library.
“Usually, the frequencies of the peptides displayed on phages are not even in the library. There were some reasons for the heterogenous phage amount, such as biases in library construction, variance in the use of cryptography,45,46 the different growth rates of phages and peptide degradation by protease.47”
From Identification of heptapeptides targeting a lethal bacterial strain in septic mice through an integrative approach (2022) · cites this paper as [45]
The Introduction discusses uneven synonymous codon usage, and ‘Predicting levels of heterologous gene expression’ discusses codon usage in phage genes. Neither addresses whether peptides displayed in a phage library occur at uneven frequencies; searches for phage-display libraries and peptide frequencies found no such passage. (LLM, conf=0.76)
Experimental — accuracy not yet measuredCodon preference varies extensively in different organisms; adjusting the balance between codon usage frequency and host tRNA availability can significantly improve translation efficiency and in vivo expression of the target antigen.
“Codon preference varies extensively in different organisms,249 therefore adjusting the balance between codon usage frequency and host tRNA availability can significantly improve translation efficiency and in vivo expression of the target antigen.250,251”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [249]
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- Authors
- Sharp, P. M., & Li, W.-H.
- Affiliations
- The University of Texas System (US)
- Corresponding author
- Sharp, Paul M.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 1987
- Volume
- 15
- Issue
- 3
- Pages
- 1281-1295
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC340524
- OpenAlex
- W2018590530
- Cited by
- 3,992
- References
- 30
- Citations by year
- 2026: 223 · 2025: 203 · 2024: 205 · 2023: 177 · 2022: 198 · 2021: 239 · 2020: 212 · 2019: 147 · 2018: 155 · 2017: 120 · 2016: 133 · 2015: 112 · 2014: 147 · 2013: 145 · 2012: 137
- FWCI
- 7.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nucleic Acids Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM30998)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- codon adaptation index, codon usage bias, codon usage, gene expression prediction, heterologous expression, highly expressed genes, natural selection
- MeSH terms
- Animals, Base Sequence, Cattle, Codon, Escherichia coli, Biological Evolution, Genes, Genes, Bacterial, Genes, Fungal, Humans, Mathematics, Models, Genetic, RNA, Messenger, Saccharomyces cerevisiae
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