Expanding the human proteome with microproteins and peptideins

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 Heesch

doi:10.1038/s41586-026-10459-x

Expanding the human proteome with microproteins and peptideins

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 (Lead / Corresponding author), John R Prensner (Lead / Corresponding author), Sebastiaan van Heesch (Lead / Corresponding author)

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

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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 states1-3, 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 language	English
Journal	Nature
Early online date	6 May 2026
DOIs	https://doi.org/10.1038/s41586-026-10459-x
Publication status	E-pub ahead of print - 6 May 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Cite this

Deutsch, 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., ... van Heesch, S. (2026). Expanding the human proteome with microproteins and peptideins. Nature. Advance online publication. https://doi.org/10.1038/s41586-026-10459-x

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title = "Expanding the human proteome with microproteins and peptideins",

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 states1-3, 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.",

author = "Deutsch, \{Eric W\} and Kok, \{Leron W\} and Mudge, \{Jonathan M\} and Valls, \{Cristian F\} and Irwin Jungreis and Jorge Ruiz-Orera and Zhi Sun and Ulrike Kusebauch and Ivo Fierro-Monti and Abelin, \{Jennifer G\} and Alba, \{M Mar\} and Aspden, \{Julie L\} and Sreejan Bandyopadhyay and Kaushik Banerjee and Baranov, \{Pavel V\} and Bazzini, \{Ariel A\} and Francis Bourassa and Bruford, \{Elspeth A\} and Lorenzo Calviello and Carr, \{Steven A\} and Anne-Ruxandra Carvunis and Sonia Chothani and Jim Clauwaert and Kellie Dean and Pouya Faridi and Adam Frankish and Amy Goodale and Thomas Green and Norbert Hubner and Ingolia, \{Nicholas T\} and Manolis Kellis and Michele Magrane and Martin, \{Maria Jesus\} and Martinez, \{Thomas F\} and Gerben Menschaert and Uwe Ohler and Sandra Orchard and Alisa Potter and Rackham, \{Owen J L\} and Rees, \{Matthew G\} and Root, \{David E\} and Roth, \{Jennifer A\} and Xavier Roucou and Sialana, \{Fernando J\} and Slavoff, \{Sarah A\} and {\'S}wirski, \{Micha{\l} I\} and Tierney, \{Jack A S\} and F{\'e}lix-Antoine Trifiro and Eivind Valen and Valeriia Vasylieva and Aaron Wacholder and Shengbo Wang and Li Wang and Weissman, \{Jonathan S\} and Wei Wu and Zhi Xie and Choudhary, \{Jyoti S\} and Michal Bassani-Sternberg and Vizca{\'i}no, \{Juan Antonio\} and Nicola Ternette and Brunet, \{Marie A\} and Moritz, \{Robert L\} and Prensner, \{John R\} and \{van Heesch\}, Sebastiaan",

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doi = "10.1038/s41586-026-10459-x",

language = "English",

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Deutsch, EW, Kok, LW, Mudge, JM, Valls, CF, Jungreis, I, Ruiz-Orera, J, Sun, Z, Kusebauch, U, Fierro-Monti, I, Abelin, JG, Alba, MM, Aspden, JL, Bandyopadhyay, S, Banerjee, K, Baranov, PV, Bazzini, AA, Bourassa, F, Bruford, EA, Calviello, L, Carr, SA, Carvunis, A-R, Chothani, S, Clauwaert, J, Dean, K, Faridi, P, Frankish, A, Goodale, A, Green, T, Hubner, N, Ingolia, NT, Kellis, M, Magrane, M, Martin, MJ, Martinez, TF, Menschaert, G, Ohler, U, Orchard, S, Potter, A, Rackham, OJL, Rees, MG, Root, DE, Roth, JA, Roucou, X, Sialana, FJ, Slavoff, SA, Świrski, MI, Tierney, JAS, Trifiro, F-A, Valen, E, Vasylieva, V, Wacholder, A, Wang, S, Wang, L, Weissman, JS, Wu, W, Xie, Z, Choudhary, JS, Bassani-Sternberg, M, Vizcaíno, JA, Ternette, N, Brunet, MA, Moritz, RL, Prensner, JR & van Heesch, S 2026, 'Expanding the human proteome with microproteins and peptideins', Nature. https://doi.org/10.1038/s41586-026-10459-x

TY - JOUR

T1 - Expanding the human proteome with microproteins and peptideins

AU - Deutsch, Eric W

AU - Kok, Leron W

AU - Mudge, Jonathan M

AU - Valls, Cristian F

AU - Jungreis, Irwin

AU - Ruiz-Orera, Jorge

AU - Sun, Zhi

AU - Kusebauch, Ulrike

AU - Fierro-Monti, Ivo

AU - Abelin, Jennifer G

AU - Alba, M Mar

AU - Aspden, Julie L

AU - Bandyopadhyay, Sreejan

AU - Banerjee, Kaushik

AU - Baranov, Pavel V

AU - Bazzini, Ariel A

AU - Bourassa, Francis

AU - Bruford, Elspeth A

AU - Calviello, Lorenzo

AU - Carr, Steven A

AU - Carvunis, Anne-Ruxandra

AU - Chothani, Sonia

AU - Clauwaert, Jim

AU - Dean, Kellie

AU - Faridi, Pouya

AU - Frankish, Adam

AU - Goodale, Amy

AU - Green, Thomas

AU - Hubner, Norbert

AU - Ingolia, Nicholas T

AU - Kellis, Manolis

AU - Magrane, Michele

AU - Martin, Maria Jesus

AU - Martinez, Thomas F

AU - Menschaert, Gerben

AU - Ohler, Uwe

AU - Orchard, Sandra

AU - Potter, Alisa

AU - Rackham, Owen J L

AU - Rees, Matthew G

AU - Root, David E

AU - Roth, Jennifer A

AU - Roucou, Xavier

AU - Sialana, Fernando J

AU - Slavoff, Sarah A

AU - Świrski, Michał I

AU - Tierney, Jack A S

AU - Trifiro, Félix-Antoine

AU - Valen, Eivind

AU - Vasylieva, Valeriia

AU - Wacholder, Aaron

AU - Wang, Shengbo

AU - Wang, Li

AU - Weissman, Jonathan S

AU - Wu, Wei

AU - Xie, Zhi

AU - Choudhary, Jyoti S

AU - Bassani-Sternberg, Michal

AU - Vizcaíno, Juan Antonio

AU - Ternette, Nicola

AU - Brunet, Marie A

AU - Moritz, Robert L

AU - Prensner, John R

AU - van Heesch, Sebastiaan

PY - 2026/5/6

Y1 - 2026/5/6

N2 - 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 states1-3, 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.

AB - 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 states1-3, 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.

U2 - 10.1038/s41586-026-10459-x

DO - 10.1038/s41586-026-10459-x

M3 - Article

C2 - 42092140

SN - 0028-0836

JO - Nature

JF - Nature

ER -

Expanding the human proteome with microproteins and peptideins

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