预印本 / 版本 1

Rare Codons as Passive Byproducts of Genomic Constraints, Not Translational Regulators in Mammals

本文是预印本，尚未经过同行评审认证。

作者

    Xiao-Yan Fan， 
    Xiao-Yan Fan
    • The Affiliated Guangdong Second Provincial General Hospital of Jinan University
    • Inner Mongolia University image/svg+xml
    Tie-Gang Meng， 
    Tie-Gang Meng
    • The Affiliated Guangdong Second Provincial General Hospital of Jinan University
    Teng Zhang， 
    Teng Zhang
    Yu-Feng Wang， 
    Yu-Feng Wang
    • The Affiliated Guangdong Second Provincial General Hospital of Jinan University
    Si-Tong Zhou， 
    Si-Tong Zhou
    • The Affiliated Guangdong Second Provincial General Hospital of Jinan University
    Gui Zhang，  Zhen Tang，  Shi-Min Wang，  Tao Jing，  Lei Guo，  Lei-Ning Chen，  Sen Li，  Juan Chen，  Rui-Bao Su，  Meng-Wen Hu，  Jun-Yu Ma，  Li-Zhang Zeng， 
    Li-Zhang Zeng
    Qing-Yuan Sun， 
    Qing-Yuan Sun
    • The Affiliated Guangdong Second Provincial General Hospital of Jinan University
    Xiang-Hong Ou， 
    Xiang-Hong Ou
    • The Affiliated Guangdong Second Provincial General Hospital of Jinan University
    Shi-Ming Luo
    Shi-Ming Luo
    • Guangdong Provincial People's Hospital image/svg+xml
    • The Affiliated Guangdong Second Provincial General Hospital of Jinan University
分类
细胞生物学
关键词
Rare codons; codon optimization; translation kinetics; synonymous mutations; mRNA therapeutics; genomic constraints; tRNA abundance

摘要

The prevailing view holds that rare codons function as evolutionarily conserved modulators of translation kinetics, a concept that has provided a critical framework for interpreting synonymous mutations in disease and guiding coding sequence optimization in gene therapy. Our findings, however, challenge this premise by demonstrating that rare codons are primarily passive byproducts of genome stability constraints, rather than adaptive regulators of translation. Supporting this, genomic analyses reveal that rare codons, which are predominantly CpG- or TpA-ending, are genomically scarce; for more than half of them, the corresponding nucleotide triplet appears in the genome at a frequency that is approximately half of its occurrence in coding sequences, indicating that codon rarity reflects genome-wide sequence constraints rather than adaptive pressures for translational control. Furthermore, interrogation of tRNA abundance, via both genomic copy number and direct cellular quantification, shows no consistent correlation between codon rarity and cognate tRNA scarcity. Crucially, direct experimental assessment via cytoplasmic microinjection of engineered mRNAs into mouse embryos demonstrates that even a substantial artificial increase in rare codon load has a negligible impact on protein synthesis kinetics. Consequently, we conclude that rare codons cannot be regarded as an independent factor limiting translation rates in mammalian cells. This insight demands a reassessment of the role of synonymous mutations in disease and expands the design principles for mRNA-based therapeutics by alleviating the presumed constraint of rare codon avoidance.

指标

收藏: 2
查看次数: 220
下载次数: 106

DOI：

https://doi.org/10.65215/LTSpreprints.2026.03.10.000139

Submission ID：

139

下载次数

附加文件

补充文件

已发布

2026-03-11

如何引用

Fan, X.-Y., Meng, T.-G., Zhang, T., Wang, Y.-F., Zhou, S.-T., Zhang, G., Tang, Z., Wang, S.-M., Jing, T., Guo, L., Chen, L.-N., Li, S., Chen, J., Su, R.-B., Hu, M.-W., Ma, J.-Y., Zeng, L.-Z., Sun, Q.-Y., Ou, X.-H., & Luo, S.-M. (2026). Rare Codons as Passive Byproducts of Genomic Constraints, Not Translational Regulators in Mammals. 浪淘沙预印本平台. https://doi.org/10.65215/LTSpreprints.2026.03.10.000139

利益冲突声明

作者声明无任何需要披露的利益冲突。

Copyright

本预印本的版权持有者为作者/资助方。

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.