Synonymous but Not Silent: The Codon Usage Code for Gene Expression and Protein Folding

Yi Liu, Qian Yang, Fangzhou Zhao

Research output: Contribution to journalReview articlepeer-review

54 Scopus citations


Codon usage bias, the preference for certain synonymous codons, is found in all genomes. Although synonymous mutations were previously thought to be silent, a large body of evidence has demonstrated that codon usage can play major roles in determining gene expression levels and protein structures. Codon usage influences translation elongation speed and regulates translation efficiency and accuracy. Adaptation of codon usage to tRNA expression determines the proteome landscape. In addition, codon usage biases result in nonuniform ribosome decoding rates on mRNAs, which in turn influence the cotranslational protein folding process that is critical for protein function in diverse biological processes. Conserved genome-wide correlations have also been found between codon usage and protein structures. Furthermore, codon usage is a major determinant of mRNA levels through translation-dependent effects on mRNA decay and translation-independent effects on transcriptional and posttranscriptional processes. Here, we discuss the multifaceted roles and mechanisms of codon usage in different gene regulatory processes.

Original languageEnglish (US)
Pages (from-to)375-401
Number of pages27
JournalAnnual review of biochemistry
StatePublished - Jun 20 2021


  • Chromatin structure
  • Codon usage
  • Cotranslational protein folding
  • Transcription
  • Translation efficiency
  • Translation elongation
  • mRNA decay

ASJC Scopus subject areas

  • Biochemistry


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