Expanding the human proteome with microproteins and peptideins

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dc.contributor.authorDeutsch, Eric W.
dc.contributor.authorKok, Leron W.
dc.contributor.authorMudge, Jonathan M.
dc.contributor.authorValls, Cristian F.
dc.contributor.authorJungreis, Irwin
dc.contributor.authorRuiz-Orera, Jorge
dc.contributor.authorSun, Zhi
dc.contributor.authorKusebauch, Ulrike
dc.contributor.authorFierro-Monti, Ivo
dc.contributor.authorAbelin, Jennifer G.
dc.contributor.authorAlba, M. Mar
dc.contributor.authorAspden, Julie L.
dc.contributor.authorBandyopadhyay, Sreejan
dc.contributor.authorBanerjee, Kaushik
dc.contributor.authorBaranov, Pavel V.
dc.contributor.authorBazzini, Ariel A.
dc.contributor.authorBourassa, Francis
dc.contributor.authorBruford, Elspeth A.
dc.contributor.authorCalviello, Lorenzo
dc.contributor.authorCarr, Steven A.
dc.contributor.authorCarvunis, Anne Ruxandra
dc.contributor.authorChothani, Sonia
dc.contributor.authorClauwaert, Jim
dc.contributor.authorDean, Kellie
dc.contributor.authorFaridi, Pouya
dc.contributor.authorFrankish, Adam
dc.contributor.authorGoodale, Amy
dc.contributor.authorGreen, Thomas
dc.contributor.authorHubner, Norbert
dc.contributor.authorIngolia, Nicholas T.
dc.contributor.authorKellis, Manolis
dc.contributor.authorMagrane, Michele
dc.contributor.authorMartin, Maria Jesus
dc.contributor.authorMartinez, Thomas F.
dc.contributor.authorMenschaert, Gerben
dc.contributor.authorOhler, Uwe
dc.contributor.authorOrchard, Sandra
dc.contributor.authorPotter, Alisa
dc.contributor.authorRackham, Owen J.L.
dc.contributor.authorRees, Matthew G.
dc.contributor.authorRoot, David E.
dc.contributor.authorRoth, Jennifer A.
dc.contributor.authorRoucou, Xavier
dc.contributor.authorSialana, Fernando J.
dc.contributor.authorSlavoff, Sarah A.
dc.contributor.authorŚwirski, Michał I.
dc.contributor.authorTierney, Jack A.S.
dc.contributor.authorTrifiro, Félix Antoine
dc.contributor.authorValen, Eivind
dc.contributor.authorVasylieva, Valeriia
dc.contributor.authorWacholder, Aaron
dc.contributor.authorWang, Shengbo
dc.contributor.authorWang, Li
dc.contributor.authorWeissman, Jonathan S.
dc.contributor.authorWu, Wei
dc.contributor.authorXie, Zhi
dc.contributor.authorChoudhary, Jyoti S.
dc.contributor.authorBassani-Sternberg, Michal
dc.contributor.authorVizcaíno, Juan Antonio
dc.contributor.authorTernette, Nicola
dc.contributor.authorBrunet, Marie A.
dc.contributor.authorMoritz, Robert L.
dc.contributor.authorPrensner, John R.
dc.contributor.authorvan Heesch, Sebastiaan
dc.contributor.funderNational Institutes of Health
dc.contributor.funderNational Science Foundation
dc.date.accessioned2026-06-30T13:50:08Z
dc.date.available2026-06-30T13:50:08Z
dc.date.issued2026
dc.description.abstractA 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.en
dc.description.sponsorshipNational Institutes of Health (grants R01 GM087221
dc.description.sponsorshipR24 GM148372
dc.description.sponsorshipS10 OD026936)
dc.description.sponsorshipNational Science Foundation (grants DBI-1933311
dc.description.sponsorshipMRI-1920268)
dc.description.versionPublished Version
dc.format.extent13
dc.format.mimetypeapplication/pdfen
dc.identifier.authororcidDeutsch, Eric W.
dc.identifier.authororcidKok, Leron W.
dc.identifier.authororcidMudge, Jonathan M.
dc.identifier.authororcidValls, Cristian F.
dc.identifier.authororcidJungreis, Irwin
dc.identifier.authororcidRuiz-Orera, Jorge
dc.identifier.authororcidSun, Zhi
dc.identifier.authororcidKusebauch, Ulrike
dc.identifier.authororcidFierro-Monti, Ivo
dc.identifier.authororcidAbelin, Jennifer G.
dc.identifier.authororcidAlba, M. Mar
dc.identifier.authororcidAspden, Julie L.
dc.identifier.authororcidBandyopadhyay, Sreejan
dc.identifier.authororcidBanerjee, Kaushik
dc.identifier.authororcidBaranov, Pavel V.
dc.identifier.authororcidBazzini, Ariel A.
dc.identifier.authororcidBourassa, Francis
dc.identifier.authororcidBruford, Elspeth A.
dc.identifier.authororcidCalviello, Lorenzo
dc.identifier.authororcidCarr, Steven A.
dc.identifier.authororcidCarvunis, Anne Ruxandra
dc.identifier.authororcidChothani, Sonia
dc.identifier.authororcidClauwaert, Jim
dc.identifier.authororcidDean, Kellie§0000-0002-3213-8181
dc.identifier.authororcidFaridi, Pouya
dc.identifier.authororcidFrankish, Adam
dc.identifier.authororcidGoodale, Amy
dc.identifier.authororcidGreen, Thomas
dc.identifier.authororcidHubner, Norbert
dc.identifier.authororcidIngolia, Nicholas T.
dc.identifier.authororcidKellis, Manolis
dc.identifier.authororcidMagrane, Michele
dc.identifier.authororcidMartin, Maria Jesus
dc.identifier.authororcidMartinez, Thomas F.
dc.identifier.authororcidMenschaert, Gerben
dc.identifier.authororcidOhler, Uwe
dc.identifier.authororcidOrchard, Sandra
dc.identifier.authororcidPotter, Alisa
dc.identifier.authororcidRackham, Owen J.L.
dc.identifier.authororcidRees, Matthew G.
dc.identifier.authororcidRoot, David E.
dc.identifier.authororcidRoth, Jennifer A.
dc.identifier.authororcidRoucou, Xavier
dc.identifier.authororcidSialana, Fernando J.
dc.identifier.authororcidSlavoff, Sarah A.
dc.identifier.authororcidŚwirski, Michał I.
dc.identifier.authororcidTierney, Jack A.S.
dc.identifier.authororcidTrifiro, Félix Antoine
dc.identifier.authororcidValen, Eivind
dc.identifier.authororcidVasylieva, Valeriia
dc.identifier.authororcidWacholder, Aaron
dc.identifier.authororcidWang, Shengbo
dc.identifier.authororcidWang, Li
dc.identifier.authororcidWeissman, Jonathan S.
dc.identifier.authororcidWu, Wei
dc.identifier.authororcidXie, Zhi
dc.identifier.authororcidChoudhary, Jyoti S.
dc.identifier.authororcidBassani-Sternberg, Michal
dc.identifier.authororcidVizcaíno, Juan Antonio
dc.identifier.authororcidTernette, Nicola
dc.identifier.authororcidBrunet, Marie A.
dc.identifier.authororcidMoritz, Robert L.
dc.identifier.authororcidPrensner, John R.
dc.identifier.authororcidvan Heesch, Sebastiaan
dc.identifier.citationDeutsch, E W, Kok, L W, Mudge, J M, Valls, C F, Jungreis, I, Ruiz-Orera, J, Sun, Z, Kusebauch, U, Fierro-Monti, I, Abelin, J G, Alba, M M, Aspden, J L, Bandyopadhyay, S, Banerjee, K, Baranov, P V, Bazzini, A A, Bourassa, F, Bruford, E A, Calviello, L, Carr, S A, Carvunis, A R, Chothani, S, Clauwaert, J, Dean, K, Faridi, P, Frankish, A, Goodale, A, Green, T, Hubner, N, Ingolia, N T, Kellis, M, Magrane, M, Martin, M J, Martinez, T F, Menschaert, G, Ohler, U, Orchard, S, Potter, A, Rackham, O J L, Rees, M G, Root, D E, Roth, J A, Roucou, X, Sialana, F J, Slavoff, S A, Świrski, M I, Tierney, J A S, Trifiro, F A, Valen, E, Vasylieva, V, Wacholder, A, Wang, S, Wang, L, Weissman, J S, Wu, W, Xie, Z, Choudhary, J S, Bassani-Sternberg, M, Vizcaíno, J A, Ternette, N, Brunet, M A, Moritz, R L, Prensner, J R & van Heesch, S 2026, 'Expanding the human proteome with microproteins and peptideins', Nature, vol. 654, no. 8119, pp. 813-825. https://doi.org/10.1038/s41586-026-10459-x
dc.identifier.doi10.1038/s41586-026-10459-x
dc.identifier.endpage825
dc.identifier.issn0028-0836
dc.identifier.issued8119
dc.identifier.journaltitleNature
dc.identifier.startpage813
dc.identifier.urihttps://hdl.handle.net/10468/18982
dc.identifier.volume654
dc.language.isoen
dc.publisherNature Research
dc.relation.urihttps://www.scopus.com/pages/publications/105038148448
dc.rights© The Author(s) 2026. Open Access. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, 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 you modified the licensed material.
dc.rights.accessrightsopen access
dc.rights.licensenameAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.statusPeer reviewed
dc.subjectHuman proteome
dc.subject[BiochemistryCellBiology]
dc.subjectMicroproteins
dc.subjectPeptideins
dc.titleExpanding the human proteome with microproteins and peptideinsen
dc.typeArticle (peer-reviewed)
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