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

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• dc.contributor.author Hernandez-Alias, Xavier
• dc.contributor.author Benisty, Hannah, 1986-
• dc.contributor.author Radusky, Leandro
• dc.contributor.author Serrano Pubull, Luis, 1982-
• dc.contributor.author Schaefer, Martin H.
• dc.date.accessioned 2023-06-08T06:48:56Z
• dc.date.available 2023-06-08T06:48:56Z
• dc.date.issued 2023
• dc.description.abstract Background: Codon 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. Results: We 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. Conclusions: We 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.
• dc.description.sponsorship We acknowledge the support of the Spanish Ministry of Science and Innovation (MICINN) (PGC2018-101271-B-I00 Plan Estatal), ‘Centro de Excelencia Severo Ochoa’, and the CERCA Programme/Generalitat de Catalunya. The work of X.H. has been supported by a PhD fellowship from the Fundación Ramón Areces. The work leading to this manuscript was supported by Fondazione AIRC, grant reference number MFAG 21791, and partially supported by the Italian Ministry of Health with Ricerca Corrente and 5x1000 funds.
• dc.format.mimetype application/pdf
• dc.identifier.citation Hernandez-Alias X, Benisty H, Radusky LG, Serrano L, Schaefer MH. Using protein-per-mRNA differences among human tissues in codon optimization. Genome Biol. 2023 Feb 24;24(1):34. DOI: 10.1186/s13059-023-02868-2
• dc.identifier.doi http://dx.doi.org/10.1186/s13059-023-02868-2
• dc.identifier.issn 1474-760X
• dc.identifier.uri http://hdl.handle.net/10230/57110
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Genome Biol. 2023 Feb 24;24(1):34
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-101271-B-I00
• dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Codon optimization
• dc.subject.keyword Gene design
• dc.subject.keyword Proteomics
• dc.subject.keyword Tissue
• dc.subject.keyword Transcriptomics
• dc.subject.keyword Translation
• dc.title Using protein-per-mRNA differences among human tissues in codon optimization
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion