Expanding the human proteome with microproteins and peptideins

Expanding the human proteome with microproteins and peptideins - Discover Research at University College Cork

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Eric W. Deutsch , Leron W. Kok , Jonathan M. Mudge , Cristian F. Valls , Irwin Jungreis , Jorge Ruiz-Orera , Zhi Sun , Ulrike Kusebauch , Ivo Fierro-Monti , Jennifer G. Abelin , M. Mar Alba , Julie L. Aspden , Sreejan Bandyopadhyay , Kaushik Banerjee , Pavel V. Baranov , Ariel A. Bazzini , Francis Bourassa , Elspeth A. Bruford , Lorenzo Calviello , Steven A. Carr Anne Ruxandra Carvunis, Sonia Chothani, Jim Clauwaert, Kellie Dean, Pouya Faridi, Adam Frankish, Amy Goodale, Thomas Green, Norbert Hubner, Nicholas T. Ingolia, Manolis Kellis, Michele Magrane, Maria Jesus Martin, Thomas F. Martinez, Gerben Menschaert, Uwe Ohler, Sandra Orchard, Alisa Potter, Owen J.L. Rackham, Matthew G. Rees, David E. Root, Jennifer A. Roth, Xavier Roucou, Fernando J. Sialana, Sarah A. Slavoff, Michał I. Świrski, Jack A.S. Tierney, Félix Antoine Trifiro, Eivind Valen, Valeriia Vasylieva, Aaron Wacholder, Shengbo Wang, Li Wang, Jonathan S. Weissman, Wei Wu, Zhi Xie, Jyoti S. Choudhary, Michal Bassani-Sternberg, Juan Antonio Vizcaíno, Nicola Ternette, Marie A. Brunet, Robert L. Moritz, John R. Prensner, Sebastiaan van HeeschShow 44 moreShow less

School of Biochemistry and Cell Biology

Institute for Systems Biology Princess Máxima Center for Pediatric Oncology Oncode Institute European Molecular Biology Laboratory University of Michigan, Ann Arbor Massachusetts Institute of Technology Broad Institute Max Delbrück Center for Molecular Medicine in the Helmholtz Association University of Basel Hospital del Mar ICREA University of Leeds The Institute of Cancer Research Stowers Institute for Medical Research University of Kansas Université de Sherbrooke University of Cambridge Human Technopole University of Pittsburgh Swiss Federal Institute of Technology Zurich National University of Singapore Agency for Science, Technology and Research, Singapore Hudson Institute of Medical Research Monash University Charité – Universitätsmedizin Berlin German Centre for Cardiovascular Research University of California at Berkeley University of California at Irvine Ghent University Humboldt University of Berlin Utrecht University University of Southampton Yale University University of Warsaw University of Oslo Whitehead Institute Howard Hughes Medical Institute Sun Yat-Sen University University of Lausanne Agora Cancer Research Centre University of Dundee University of Oxford Centre de Recherche du Centre Hospitalier de l'Universite de Sherbrooke

Research output: Contribution to journal › Article › peer-review

Abstract

A major scientific drive is to characterize the protein-coding genome, which is a primary basis for studying human health. But the fundamental question remains of what has been missed in previous analyses. Over the past decade, the translation of non-canonical open reading frames (ncORFs) has been observed across human cell types and disease states1, 2–3, with major implications for biomedical science. However, a key gap in knowledge has been which ncORFs produce small microproteins or alternative protein molecules that contribute to the human proteome. Here we report the collaborative efforts of the TransCODE Consortium4 to produce a consensus landscape of protein-level evidence for ncORFs. We show that about 25% of a set of 7,264 ncORFs gives rise to detectable peptides in a large-scale analysis of 95,520 proteomics experiments. We develop an annotation framework for ncORF-encoded microproteins as human proteins and codify the new conceptual model of ‘peptideins’ as microproteins that have indeterminate potential as functional proteins. To probe the biological implications of peptideins, we create an evolutionary analysis approach, termed ORF relative branch length (ORBL), and determine that evolutionary constraint is common and associates with observation of ncORF-derived peptides. We then characterize a pan-essential cellular phenotype for one peptidein from the OLMALINC long non-coding RNA. Overall, we generate public research tools supported by GENCODE and PeptideAtlas and advance biomedical discovery for understudied components of the human proteome.

Original languageEnglishJournalNatureDOIshttps://doi.org/10.1038/s41586-026-10459-x Publication statusAccepted/In press - 2026

Access to Document

10.1038/s41586-026-10459-xLicence: CC BY-NC-ND

s41586-026-10459-xFinal published version, 17.9 MBLicence: CC BY-NC-ND

Expanding the human proteome with microproteins and peptideins

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