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Background <p>Since its emergence in 2019, SARS-CoV-2 has undergone continuous evolution, raising questions about codon usage and adaptation to the human host. Because viral fitness depends on rapid replication and efficient protein production, evolutionary processes that optimize translation speed and accuracy may be favoured. The aim of this study was to investigate temporal and gene-specific changes in synonymous codon usage in this coronavirus to assess whether its evolution reflects adaptation to the human translational machinery. To address this question, we analyzed 84,324 genomes collected between January 2020 and October 2024.</p> Results <p>Codons were recoded into six groups based on their synonymous usage in human protein-coding genes, enabling detection of temporal shifts in viral codon preferences. This analysis revealed pronounced changes in codon class composition occurring around 2021–2022, early 2023, and late 2023–2024, periods that coincide with major viral variant replacements. Distinct evolutionary trends were observed among functional gene groups. Structural genes exhibited codon usage biased toward less optimal (frequent) human codon classes. In contrast, non-structural genes (ORF1a and ORF1ab) showed a progressive increase in the use of more optimal (frequent) codon classes, whereas accessory genes exhibited variable patterns.</p> Discussion <p>Greater codon adaptation in ORF1a and ORF1ab likely enhances translation efficiency, supporting genome replication and transcription. Conversely, suboptimal codon usage in structural and accessory genes may favour immune evasion or regulate translation to prevent overuse of host resources. Codon shifts correlated strongly with nucleotide composition, indicating combined effects of mutational pressure and selection. Notably, codon usage dynamics aligned with vaccination campaigns and infection surges, suggesting that intense selective pressure and high replication rates promoted new mutations shaping codon preferences.</p> Conclusions <p>SARS-CoV-2 codon adaptation varies by time, gene type, and function, balancing replication efficiency with immune evasion. These insights may guide codon (de)optimization strategies in mRNA and DNA vaccines against emerging variants, e.g. by replacing more optimal with less optimal codons.</p>

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Temporal and gene-specific dynamics of codon usage evolution in SARS-CoV-2 genomes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月24日

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  • Paweł Błażej,
  • Dorota Mackiewicz,
  • Paweł Mackiewicz

摘要

Background

Since its emergence in 2019, SARS-CoV-2 has undergone continuous evolution, raising questions about codon usage and adaptation to the human host. Because viral fitness depends on rapid replication and efficient protein production, evolutionary processes that optimize translation speed and accuracy may be favoured. The aim of this study was to investigate temporal and gene-specific changes in synonymous codon usage in this coronavirus to assess whether its evolution reflects adaptation to the human translational machinery. To address this question, we analyzed 84,324 genomes collected between January 2020 and October 2024.

Results

Codons were recoded into six groups based on their synonymous usage in human protein-coding genes, enabling detection of temporal shifts in viral codon preferences. This analysis revealed pronounced changes in codon class composition occurring around 2021–2022, early 2023, and late 2023–2024, periods that coincide with major viral variant replacements. Distinct evolutionary trends were observed among functional gene groups. Structural genes exhibited codon usage biased toward less optimal (frequent) human codon classes. In contrast, non-structural genes (ORF1a and ORF1ab) showed a progressive increase in the use of more optimal (frequent) codon classes, whereas accessory genes exhibited variable patterns.

Discussion

Greater codon adaptation in ORF1a and ORF1ab likely enhances translation efficiency, supporting genome replication and transcription. Conversely, suboptimal codon usage in structural and accessory genes may favour immune evasion or regulate translation to prevent overuse of host resources. Codon shifts correlated strongly with nucleotide composition, indicating combined effects of mutational pressure and selection. Notably, codon usage dynamics aligned with vaccination campaigns and infection surges, suggesting that intense selective pressure and high replication rates promoted new mutations shaping codon preferences.

Conclusions

SARS-CoV-2 codon adaptation varies by time, gene type, and function, balancing replication efficiency with immune evasion. These insights may guide codon (de)optimization strategies in mRNA and DNA vaccines against emerging variants, e.g. by replacing more optimal with less optimal codons.