Rp3: Ribosome profiling-assisted proteogenomics improves coverage and confidence during microprotein discovery

Eduardo Vieira de Souza, Angie L. Bookout, Christopher A. Barnes, Brendan Miller, Pablo Machado, Luiz A. Basso, Cristiano V. Bizarro () and Alan Saghatelian ()
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Eduardo Vieira de Souza: Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)
Angie L. Bookout: Novo Nordisk Research Center Seattle Inc.
Christopher A. Barnes: Novo Nordisk Research Center Seattle Inc.
Brendan Miller: Salk Institute for Biological Studies
Pablo Machado: Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)
Luiz A. Basso: Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)
Cristiano V. Bizarro: Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)
Alan Saghatelian: Salk Institute for Biological Studies

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract There has been a dramatic increase in the identification of non-canonical translation and a significant expansion of the protein-coding genome. Among the strategies used to identify unannotated small Open Reading Frames (smORFs) that encode microproteins, Ribosome profiling (Ribo-Seq) is the gold standard for the annotation of novel coding sequences by reporting on smORF translation. In Ribo-Seq, ribosome-protected footprints (RPFs) that map to multiple genomic sites are removed since they cannot be unambiguously assigned to a specific genomic location. Furthermore, RPFs necessarily result in short (25-34 nucleotides) reads, increasing the chance of multi-mapping alignments, such that smORFs residing in these regions cannot be identified by Ribo-Seq. Moreover, it has been challenging to identify protein evidence for Ribo-Seq. To solve this, we developed Rp3, a pipeline that integrates proteogenomics and Ribosome profiling to provide unambiguous evidence for a subset of microproteins missed by current Ribo-Seq pipelines. Here, we show that Rp3 maximizes proteomics detection and confidence of microprotein-encoding smORFs.

Date: 2024
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DOI: 10.1038/s41467-024-50301-4

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