
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.26.609665
preprint
1
Article
Alternate RNA decoding results in stable and abundant proteins in mammals
Tsour Shira http://orcid.org/0000-0003-1382-4044

Machne Rainer http://orcid.org/0000-0002-1274-5099

Leduc Andrew http://orcid.org/0000-0001-6234-0623

Widmer Simon
Slavov Nikolai http://orcid.org/0000-0003-2035-1820

26 8 2024
2024.08.26.609665https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.26.609665
nihpp-2024.08.26.609665.pdf
Amino acid substitutions may substantially alter protein stability and function, but the con-tribution of substitutions arising from alternate translation (deviations from the genetic code) is unknown. To explore it, we analyzed deep proteomic and transcriptomic data from over 1,000 human samples, including 6 cancer types and 26 healthy human tissues. This global analysis identified 60,024 high confidence substitutions corresponding to 8,801 unique sites in 1,990 proteins. Some substitutions are shared across samples, while others exhibit strong tissue-type and cancer specificity. Surprisingly, products of alternate translation are more abundant than their canonical counterparts for hundreds of proteins, suggesting sense codon recoding. Recoded proteins include transcription factors, proteases, signaling proteins, and proteins associated with neurodegeneration. Mechanisms contributing to substitution abun-dance include protein stability, codon frequency, codon-anticodon mismatches, and RNA modifications. We characterize sequence motifs around alternatively translated amino acids and how substitution ratios vary across protein domains, tissue types and cancers. Both the sequence and the tissue-specificity of alternatively translated proteins are conserved between human and mouse. These results demonstrate the contribution of alternate translation to diversifying mammalian proteomes, and its association with protein stability, tissue-specific proteomes, and diseases.
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pmc
