Agashe, D. in Single Nucleotide Polymorphisms (eds Sauna, Z. E. & Kimchi-Sarfaty, C.) 15–36 (Springer, 2022).

Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge Univ. Press, 1983).

Zhang, J. in Evolution Since Darwin: The First 150 Years (eds Bell, M. A. et al.) 87–118 (Sinauer, 2010).

Fiers, W. et al. A-protein gene of bacteriophage MS2. Nature 256, 273–278 (1975).

Article  CAS  PubMed  Google Scholar 

Air, G. M. et al. Gene F of bacteriophage X174. Correlation of nucleotide sequences from the DNA and amino acid sequences from the gene product. J. Mol. Biol. 107, 445–458 (1976).

Article  CAS  PubMed  Google Scholar 

Efstratiadis, A., Kafatos, F. C. & Maniatis, T. The primary structure of rabbit β-globin mRNA as determined from cloned DNA. Cell 10, 571–585 (1977).

Article  CAS  PubMed  Google Scholar 

Grantham, R., Gautier, C., Gouy, M., Mercier, R. & Pavé, A. Codon catalog usage and the genome hypothesis. Nucleic Acids Res. 8, r49–r62 (1980).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ikemura, T. Correlation between the abundance of Escherichia coli transfer RNAs and the occurrence of the respective codons in its protein genes: a proposal for a synonymous codon choice that is optimal for the E. coli translational system. J. Mol. Biol. 151, 389–409 (1981).

Article  CAS  PubMed  Google Scholar 

Gouy, M. & Gautier, C. Codon usage in bacteria: correlation with gene expressivity. Nucleic Acids Res. 10, 7055–7074 (1982).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hanson, G. & Coller, J. Codon optimality, bias and usage in translation and mRNA decay. Nat. Rev. Mol. Cell Biol. 19, 20–30 (2018).

Article  CAS  PubMed  Google Scholar 

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).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Stergachis, A. B. et al. Exonic transcription factor binding directs codon choice and affects protein evolution. Science 342, 1367–1372 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Birnbaum, R. Y. et al. Coding exons function as tissue-specific enhancers of nearby genes. Genome Res. 22, 1059–1068 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Doolittle, W. F., Brunet, T. D., Linquist, S. & Gregory, T. R. Distinguishing between “function” and “effect” in genome biology. Genome Biol. Evol. 6, 1234–1237 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Agoglia, R. M. & Fraser, H. B. Disentangling sources of selection on exonic transcriptional enhancers. Mol. Biol. Evol. 33, 585–590 (2016).

Article  CAS  PubMed  Google Scholar 

Xing, K. & He, X. Reassessing the “duon” hypothesis of protein evolution. Mol. Biol. Evol. 32, 1056–1062 (2015).

Article  CAS  PubMed  Google Scholar 

Chen, J. et al. Prevalent uses and evolution of exonic regulatory sequences in the human genome. Nat. Sci. 3, e20220058 (2023).

Article  CAS  Google Scholar 

Shen, X., Song, S., Li, C. & Zhang, J. Synonymous mutations in representative yeast genes are mostly strongly non-neutral. Nature 606, 725–731 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rodriguez, A. et al. Synonymous codon substitutions modulate transcription and translation of a divergent upstream gene by modulating antisense RNA production. Proc. Natl Acad. Sci. USA 121, e2405510121 (2024).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sekinger, E. A., Moqtaderi, Z. & Struhl, K. Intrinsic histone-DNA interactions and low nucleosome density are important for preferential accessibility of promoter regions in yeast. Mol. Cell 18, 735–748 (2005).

Article  CAS  PubMed  Google Scholar 

Tillo, D. & Hughes, T. R. G+C content dominates intrinsic nucleosome occupancy. BMC Bioinform. 10, 442 (2009).

Article  Google Scholar 

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).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhao, F. et al. Genome-wide role of codon usage on transcription and identification of potential regulators. Proc. Natl Acad. Sci. USA 118, e2022590118 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Qian, W. & Zhang, J. Codon usage bias and nuclear mRNA concentration: correlation vs. causation. Proc. Natl Acad. Sci. USA 118, e2104714118 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhou, Z., Dang, Y., Zhou, M., Yuan, H. & Liu, Y. Codon usage biases co-evolve with transcription termination machinery to suppress premature cleavage and polyadenylation. eLife 7, e33569 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Savisaar, R. & Hurst, L. D. Exonic splice regulation imposes strong selection at synonymous sites. Genome Res. 28, 1442–1454 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chamary, J. V., Parmley, J. L. & Hurst, L. D. Hearing silence: non-neutral evolution at synonymous sites in mammals. Nat. Rev. Genet. 7, 98–108 (2006).

Article  CAS  PubMed  Google Scholar 

Lan, Y. et al. Synonymous mutations promote tumorigenesis by disrupting m6A-dependent mRNA metabolism. Cell 188, 1828–1841.e15 (2025).

Article  CAS  PubMed  Google Scholar 

Courel, M. et al. GC content shapes mRNA storage and decay in human cells. eLife 8, e49708 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Mordstein, C. et al. Codon usage and splicing jointly influence mRNA localization. Cell Syst. 10, 351–362.e8 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zuckerman, B., Ron, M., Mikl, M., Segal, E. & Ulitsky, I. Gene architecture and sequence composition underpin selective dependency of nuclear export of long RNAs on NXF1 and the TREX complex. Mol. Cell 79, 251–267.e6 (2020).

Article  CAS  PubMed  Google Scholar 

Savisaar, R. & Hurst, L. D. Both maintenance and avoidance of RNA-binding protein interactions constrain coding sequence evolution. Mol. Biol. Evol. 34, 1110–1126 (2017).

CAS  PubMed  PubMed Central  Google Scholar 

Yang, J. R., Chen, X. & Zhang, J. Codon-by-codon modulation of translational speed and accuracy via mRNA folding. PLoS Biol. 12, e1001910 (2014).

Article  PubMed  PubMed Central  Google Scholar