Discovery of coding regions in the human genome by integrated proteogenomics analysis workflow

Proteogenomics enable the discovery of novel peptides (from unannotated genomic protein-coding loci) and single amino acid variant peptides (derived from single-nucleotide polymorphisms and mutations). Increasing the reliability of these identifications is crucial to ensure their usefulness for geno...

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Veröffentlicht in:Nature communications 2018-03, Vol.9 (1), p.903-14, Article 903
Hauptverfasser: Zhu, Yafeng, Orre, Lukas M., Johansson, Henrik J., Huss, Mikael, Boekel, Jorrit, Vesterlund, Mattias, Fernandez-Woodbridge, Alejandro, Branca, Rui M. M., Lehtiö, Janne
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Sprache:eng
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Zusammenfassung:Proteogenomics enable the discovery of novel peptides (from unannotated genomic protein-coding loci) and single amino acid variant peptides (derived from single-nucleotide polymorphisms and mutations). Increasing the reliability of these identifications is crucial to ensure their usefulness for genome annotation and potential application as neoantigens in cancer immunotherapy. We here present integrated proteogenomics analysis workflow (IPAW), which combines peptide discovery, curation, and validation. IPAW includes the SpectrumAI tool for automated inspection of MS/MS spectra, eliminating false identifications of single-residue substitution peptides. We employ IPAW to analyze two proteomics data sets acquired from A431 cells and five normal human tissues using extended (pH range, 3–10) high-resolution isoelectric focusing (HiRIEF) pre-fractionation and TMT-based peptide quantitation. The IPAW results provide evidence for the translation of pseudogenes, lncRNAs, short ORFs, alternative ORFs, N-terminal extensions, and intronic sequences. Moreover, our quantitative analysis indicates that protein production from certain pseudogenes and lncRNAs is tissue specific. Proteogenomics enables the discovery of protein coding regions and disease-relevant mutations but their verification remains challenging. Here, the authors combine peptide discovery, curation and validation in an integrated proteogenomics workflow, robustly identifying unknown coding regions and mutations.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-018-03311-y