Plotkin, J. B. & Kudla, G. Synonymous but not the same: the causes and consequences of codon bias. Nat. Rev. Genet. 12, 32–42 (2011).
Hanson, G. & Coller, J. Codon optimality, bias and usage in translation and mRNA decay. Nat. Rev. Mol. Cell Biol. 19, 20–30 (2018).
Liu, Y., Yang, Q. & Zhao, F. Synonymous but not silent: the codon usage code for gene expression and protein folding. Annu. Rev. Biochem. 90, 375–401 (2021).
Chaney, J. L. & Clark, P. L. Roles for synonymous codon usage in protein biogenesis. Annu. Rev. Biophys. 44, 143–166 (2015).
Yu, C. H. et al. Codon usage influences the local rate of translation elongation to regulate co-translational protein folding. Mol. Cell 59, 744–754 (2015).
Zhou, M. et al. Non-optimal codon usage affects expression, structure and function of clock protein FRQ. Nature 495, 111–115 (2013).
Chu, D. et al. Translation elongation can control translation initiation on eukaryotic mRNAs. EMBO J. 33, 21–34 (2014).
Lyu, X., Yang, Q., Zhao, F. & Liu, Y. Codon usage and protein length-dependent feedback from translation elongation regulates translation initiation and elongation speed. Nucleic Acids Res. 49, 9404–9423 (2021).
Barrington, C. L. et al. Synonymous codon usage regulates translation initiation. Cell Rep. 42, 113413 (2023).
Zhou, Z. et al. Codon usage is an important determinant of gene expression levels largely through its effects on transcription. Proc. Natl Acad. Sci. USA 113, E6117–E6125 (2016).
Yang, Q., Lyu, X., Zhao, F. & Liu, Y. Effects of codon usage on gene expression are promoter context dependent. Nucleic Acids Res. 49, 818–831 (2021).
Mordstein, C. et al. Codon usage and splicing jointly influence mRNA localization. Cell Syst. 10, 351–362 (2020).
Palazzo, A. F. & Kang, Y. M. GC-content biases in protein-coding genes act as an “mRNA identity” feature for nuclear export. Bioessays 43, e2000197 (2021).
Mordstein, C. et al. Transcription, mRNA export, and immune evasion shape the codon usage of viruses. Genome Biol. Evol. 13, evab106 (2021).
Bahir, I., Fromer, M., Prat, Y. & Linial, M. Viral adaptation to host: a proteome-based analysis of codon usage and amino acid preferences. Mol. Syst. Biol. 5, 311 (2009).
Jenkins, G. M. & Holmes, E. C. The extent of codon usage bias in human RNA viruses and its evolutionary origin. Virus Res. 92, 1–7 (2003).
Hernandez-Alias, X., Benisty, H., Schaefer, M. H. & Serrano, L. Translational adaptation of human viruses to the tissues they infect. Cell Rep. 34, 108872 (2021).
Plotkin, J. B. & Dushoff, J. Codon bias and frequency-dependent selection on the hemagglutinin epitopes of influenza A virus. Proc. Natl Acad. Sci. USA 100, 7152–7157 (2003).
Wang, Y., Li, Z., Wang, X., Jiang, W. & Jiang, W. SARS-CoV-2 continuously optimizes its codon usage to adapt to human lung environment. J. Appl. Genet. 64, 831–837 (2023).
Sharp, P. M. & Li, W. H. The codon adaptation index—a measure of directional synonymous codon usage bias, and its potential applications. Nucleic Acids Res. 15, 1281–1295 (1987).
Chen, F. et al. Dissimilation of synonymous codon usage bias in virus-host coevolution due to translational selection. Nat. Ecol. Evol. 4, 589–600 (2020).
Iyaniwura, S. A. et al. The kinetics of SARS-CoV-2 infection based on a human challenge study. Proc. Natl Acad. Sci. USA 121, e2406303121 (2024).
Dos Santos, F. M. et al. Dynamic cellular proteome remodeling during SARS-CoV-2 infection. Identification of plasma protein readouts. J. Proteome Res. 24, 171–188 (2025).
Weingarten-Gabbay, S. et al. Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs. Cell 184, 3962–3980 (2021).
Skowronski, D. M. & De Serres, G. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 384, 1576–1577 (2021).
Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).
Wu, X. et al. Optimization and deoptimization of codons in SARS-CoV-2 and related implications for vaccine development. Adv. Sci. 10, e2205445 (2023).
Castello, A., Alvarez, E. & Carrasco, L. The multifaceted poliovirus 2A protease: regulation of gene expression by picornavirus proteases. J. Biomed. Biotechnol. 2011, 369648 (2011).
Gaikwad, S. et al. Reprogramming of translation in yeast cells impaired for ribosome recycling favors short, efficiently translated mRNAs. eLife 10, e64283 (2021).
Fan, W. et al. TRIM7 inhibits enterovirus replication and promotes emergence of a viral variant with increased pathogenicity. Cell 184, 3410–3425 (2021).
Sorokin, I. I. et al. Non-canonical translation initiation mechanisms employed by eukaryotic viral mRNAs. Biochemistry 86, 1060–1094 (2021).
Park, G. J. et al. The mechanism of RNA capping by SARS-CoV-2. Nature 609, 793–800 (2022).
Rangan, R. et al. RNA genome conservation and secondary structure in SARS-CoV-2 and SARS-related viruses: a first look. RNA 26, 937–959 (2020).
Li, H. C., Yang, C. H. & Lo, S. Y. Strategies of influenza A virus to ensure the translation of viral mRNAs. Pathogens 11, 1521 (2022).
Sikora, D., Rocheleau, L., Brown, E. G. & Pelchat, M. Influenza A virus cap-snatches host RNAs based on their abundance early after infection. Virology 509, 167–177 (2017).
Sonenberg, N. & Hinnebusch, A. G. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136, 731–745 (2009).
Hinnebusch, A. G. The scanning mechanism of eukaryotic translation initiation. Annu. Rev. Biochem. 83, 779–812 (2014).
Yang, Q. et al. eRF1 mediates codon usage effects on mRNA translation efficiency through premature termination at rare codons. Nucleic Acids Res. 47, 9243–9258 (2019).
Garg, R., Xie, P., Duan, J., Liu, H. & Liu, Y. Nuclear effects play an important role in determining codon usage-dependent human gene expression. Nat. Commun. https://doi.org/10.1038/s41467-025-65907-5 (2025).
Kahvejian, A., Roy, G. & Sonenberg, N. The mRNA closed-loop model: the function of PABP and PABP-interacting proteins in mRNA translation. Cold Spring Harb. Symp. Quant. Biol. 66, 293–300 (2001).
Wakiyama, M., Imataka, H. & Sonenberg, N. Interaction of eIF4G with poly(A)-binding protein stimulates translation and is critical for Xenopus oocyte maturation. Curr. Biol. 10, 1147–1150 (2000).
Wells, S. E., Hillner, P. E., Vale, R. D. & Sachs, A. B. Circularization of mRNA by eukaryotic translation initiation factors. Mol. Cell 2, 135–140 (1998).
Kim, B., Seol, J., Kim, Y. K. & Lee, J. B. Single-molecule visualization of mRNA circularization during translation. Exp. Mol. Med. 55, 283–289 (2023).
Khong, A. & Parker, R. mRNP architecture in translating and stress conditions reveals an ordered pathway of mRNP compaction. J. Cell Biol. 217, 4124–4140 (2018).
Adivarahan, S. et al. Spatial organization of single mRNPs at different stages of the gene expression pathway. Mol. Cell 72, 727–738 (2018).
Alekhina, O. M., Terenin, I. M., Dmitriev, S. E. & Vassilenko, K. S. Functional cyclization of eukaryotic mRNAs. Int. J. Mol. Sci. 21, 1677 (2020).
Rice, A. M. et al. Evidence for strong mutation bias toward, and selection against, U content in SARS-CoV-2: implications for vaccine design. Mol. Biol. Evol. 38, 67–83 (2021).
Christofi, T. & Zaravinos, A. RNA editing in the forefront of epitranscriptomics and human health. J. Transl. Med. 17, 319 (2019).
Presnyak, V. et al. Codon optimality is a major determinant of mRNA stability. Cell 160, 1111–1124 (2015).
Castellano, L. A. et al. Dengue virus preferentially uses human and mosquito non-optimal codons. Mol. Syst. Biol. 20, 1085–1108 (2024).
Villordo, S. M., Alvarez, D. E. & Gamarnik, A. V. A balance between circular and linear forms of the dengue virus genome is crucial for viral replication. RNA 16, 2325–2335 (2010).
Gebhard, L. G., Filomatori, C. V. & Gamarnik, A. V. Functional RNA elements in the dengue virus genome. Viruses 3, 1739–1756 (2011).
Sanford, T. J., Mears, H. V., Fajardo, T., Locker, N. & Sweeney, T. R. Circularization of flavivirus genomic RNA inhibits de novo translation initiation. Nucleic Acids Res. 47, 9789–9802 (2019).
Ikeuchi, K. et al. Molecular basis for recognition and deubiquitination of 40S ribosomes by Otu2. Nat. Commun. 14, 2730 (2023).
Villa, S. et al. OTUD6 deubiquitination of RPS7/eS7 on the free 40 S ribosome regulates global protein translation and stress. Nat. Commun. 15, 6873 (2024).
Frøkjær-Jensen, C. et al. Single-copy insertion of transgenes in Caenorhabditis elegans. Nat. Genet. 40, 1375–1383 (2008).
Peterson, J., Li, S., Kaltenbrun, E., Erdogan, O. & Counter, C. M. Expression of transgenes enriched in rare codons is enhanced by the MAPK pathway. Sci. Rep. 10, 22166 (2020).
Chen, R. et al. Engineering circular RNA for enhanced protein production. Nat. Biotechnol. 41, 262–272 (2023).
Gagnon, K. T., Li, L., Janowski, B. A. & Corey, D. R. Analysis of nuclear RNA interference in human cells by subcellular fractionation and Argonaute loading. Nat. Protoc. 9, 2045–2060 (2014).
Fu, J., Dang, Y., Counter, C. & Liu, Y. Codon usage regulates human KRAS expression at both transcriptional and translational levels. J. Biol. Chem. 293, 17929–17940 (2018).
Zhao, F., Yu, C. H. & Liu, Y. Codon usage regulates protein structure and function by affecting translation elongation speed in Drosophila cells. Nucleic Acids Res. 45, 8484–8492 (2017).

