Using protein-per-mRNA differences among human tissues in codon optimization

Genome Biology

Research

Leandro G. Radusky¹  Hannah Benisty¹  Xavier Hernandez-Alias¹  Luis Serrano²  Martin H. Schaefer³ 

[1] Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003, Barcelona, Spain;Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003, Barcelona, Spain;Universitat Pompeu Fabra (UPF), 08002, Barcelona, Spain;ICREA, Pg. Lluís Companys 23, 08010, Barcelona, Spain;IEO European Institute of Oncology IRCCS, Department of Experimental Oncology, Via Adamello 16, 20139, Milan, Italy;

关键词: Tissue;    Codon optimization;    Gene design;    Translation;    Proteomics;    Transcriptomics;   

DOI  :  10.1186/s13059-023-02868-2

 received in 2022-04-26, accepted in 2023-02-07,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundCodon usage and nucleotide composition of coding sequences have profound effects on protein expression. However, while it is recognized that different tissues have distinct tRNA profiles and codon usages in their transcriptomes, the effect of tissue-specific codon optimality on protein synthesis remains elusive.ResultsWe leverage existing state-of-the-art transcriptomics and proteomics datasets from the GTEx project and the Human Protein Atlas to compute the protein-to-mRNA ratios of 36 human tissues. Using this as a proxy of translational efficiency, we build a machine learning model that identifies codons enriched or depleted in specific tissues. We detect two clusters of tissues with an opposite pattern of codon preferences. We then use these identified patterns for the development of CUSTOM, a codon optimizer algorithm which suggests a synonymous codon design in order to optimize protein production in a tissue-specific manner. In human cell-line models, we provide evidence that codon optimization should take into account particularities of the translational machinery of the tissues in which the target proteins are expressed and that our approach can design genes with tissue-optimized expression profiles.ConclusionsWe provide proof-of-concept evidence that codon preferences exist in tissue-specific protein synthesis and demonstrate its application to synthetic gene design. We show that CUSTOM can be of benefit in biological and biotechnological applications, such as in the design of tissue-targeted therapies and vaccines.

【 授权许可】

CC BY   
© The Author(s) 2023

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