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Peer-reviewedCC BY-NC-NDNature

Expanding the human proteome with microproteins and peptideins

  • Eric W. Deutsch1
  • Leron W. Kok2,3
  • Jonathan M. Mudge4
  • Cristian Valls5,6
  • Irwin Jungreis7,8
  • Jorge Ruiz‐Orera9
  • Zhi Sun1
  • Ulrike Kusebauch1
  • Ivo Fierro-Monti10,4
  • Jennifer G. Abelin7
  • M. Mar Albà11,12
  • Julie L. Aspden13
52 more authors
  • Sreejan Bandyopadhyay14
  • Kaushik Banerjee5,6
  • Pavel V. Baranov15
  • Ariel Bazzini16,17
  • Francis Bourassa18
  • Elspeth A. Bruford19
  • Lorenzo Calviello20
  • Steven A. Carr7
  • Anne‐Ruxandra Carvunis21,22,23
  • Sonia Pankaj Chothani24,25
  • Jim Clauwaert6
  • Kellie A. Dean15
  • Pouya Faridi26,27
  • Adam Frankish4
  • Amy B. Goodale7
  • Thomas Green7
  • Norbert Hubner9,28,29,30
  • Nicholas T. Ingolia31
  • M Kellis7,8
  • Michele Magrane4
  • Maria Jesus Martin4
  • Thomas F. Martinez32,33,34
  • Gerben Menschaert35
  • Uwe Ohler36,37
  • Sandra E. Orchard4
  • Alisa Potter38,2,3
  • Owen J. L. Rackham39
  • Matthew G. Rees7
  • David E. Root7
  • Jennifer A. Roth7
  • Xavier Roucou40
  • Fernando J. Sialana14
  • Sarah A. Slavoff
  • Michał I. Świrski
  • Jack A. S. Tierney4
  • Félix-Antoine Trifiro18
  • Eivind Valen
  • Valeriia Vasylieva18
  • Aaron C. Wacholder21,22,23
  • Shengbo Wang4
  • Li Wang7
  • Jonathan S. Weissman
  • Wei Wu
  • Zhi Xie
  • Jyoti S. Choudhary14
  • Michal Bassani-Sternberg
  • Juan Antonio Vizcaíno4
  • Nicola Ternette

60 listed; 64 in total.

40 affiliations
  1. 1Institute for Systems Biology (ISB), Seattle, WA, USA
  2. 2Oncode Institute, Utrecht, The Netherlands
  3. 3Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
  4. 4European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK
  5. 5Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA
  6. 6Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA
  7. 7Broad Institute of MIT and Harvard, Cambridge, MA, USA
  8. 8Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA
  9. 9Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
  10. 10Biozentrum, University of Basel, Basel, Switzerland
  11. 11Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, Spain
  12. 12Hospital del Mar Research Institute, Barcelona, Spain
  13. 13School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
  14. 14Functional Proteomics Group, Institute of Cancer Research, Chester Beatty Labs, London, UK
  15. 15School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
  16. 16Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA
  17. 17Stowers Institute for Medical Research, Kansas City, MO, USA
  18. 18Pediatrics Department, University of Sherbrooke, Sherbrooke, Quebec, Canada
  19. 19HUGO Gene Nomenclature Committee (HGNC), Department of Haematology, University of Cambridge School of Clinical Medicine, Cambridge, UK
  20. 20Human Technopole, Milan, Italy
  21. 21Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
  22. 22Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
  23. 23Pittsburgh Center for Evolutionary Biology and Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
  24. 24Centre for Computational Biology and Program in Cardiovascular and Metabolic Disorders, Duke-NUS (National University of Singapore) Medical School, Singapore, Singapore
  25. 25Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
  26. 26Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  27. 27Monash Proteomics & Metabolomics Platform, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia
  28. 28Charité-Universitätsmedizin Berlin, Berlin, Germany
  29. 29DZHK (German Center for Cardiovascular Research)-Partner Site Berlin, Berlin, Germany
  30. 30Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) at Heidelberg University, Heidelberg, Germany
  31. 31Department of Molecular and Cell Biology, Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA
  32. 32Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA
  33. 33Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
  34. 34Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
  35. 35Biobix, Lab of Bioinformatics and Computational Genomics, Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium
  36. 36Berlin Institute of Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
  37. 37Department of Biology, Humboldt University Berlin, Berlin, Germany
  38. 38Biomolecular Mass Spectrometry and Proteomics, Bijvoet Centre for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
  39. 39School of Biological Sciences, University of Southampton, Southampton, UK
  40. 40Department of Biochemistry and Functional Genomics, University of Sherbrooke, Sherbrooke, Quebec, Canada
Open at sourceDOICite

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. A large-scale proteomics analysis of the dark proteome by the TransCODE Consortium reveals many translated non-canonical open reading frames to encode microproteins and peptideins.

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Cite

BibTeXRIS
BibTeX
@article{deutsch2026expanding,
  title = {{Expanding the human proteome with microproteins and peptideins}},
  author = {Eric W. Deutsch and Leron W. Kok and Jonathan M. Mudge and Cristian Valls and Irwin Jungreis and Jorge Ruiz‐Orera and Zhi Sun and Ulrike Kusebauch and Ivo Fierro-Monti and Jennifer G. Abelin and M. Mar Albà and Julie L. Aspden and Sreejan Bandyopadhyay and Kaushik Banerjee and Pavel V. Baranov and Ariel Bazzini and Francis Bourassa and Elspeth A. Bruford and Lorenzo Calviello and Steven A. Carr and Anne‐Ruxandra Carvunis and Sonia Pankaj Chothani and Jim Clauwaert and Kellie A. Dean and Pouya Faridi and Adam Frankish and Amy B. Goodale and Thomas Green and Norbert Hubner and Nicholas T. Ingolia and M Kellis and Michele Magrane and Maria Jesus Martin and Thomas F. Martinez and Gerben Menschaert and Uwe Ohler and Sandra E. Orchard and Alisa Potter and Owen J. L. Rackham and Matthew G. Rees and David E. Root and Jennifer A. Roth and Xavier Roucou and Fernando J. Sialana and Sarah A. Slavoff and Michał I. Świrski and Jack A. S. Tierney and Félix-Antoine Trifiro and Eivind Valen and Valeriia Vasylieva and Aaron C. Wacholder and Shengbo Wang and Li Wang and Jonathan S. Weissman and Wei Wu and Zhi Xie and Jyoti S. Choudhary and Michal Bassani-Sternberg and Juan Antonio Vizcaíno and Nicola Ternette},
  journal = {Nature},
  year = {2026},
  month = may,
  doi = {10.1038/s41586-026-10459-x},
  url = {https://doi.org/10.1038/s41586-026-10459-x},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Expanding the human proteome with microproteins and peptideins
AU  - Eric W. Deutsch
AU  - Leron W. Kok
AU  - Jonathan M. Mudge
AU  - Cristian Valls
AU  - Irwin Jungreis
AU  - Jorge Ruiz‐Orera
AU  - Zhi Sun
AU  - Ulrike Kusebauch
AU  - Ivo Fierro-Monti
AU  - Jennifer G. Abelin
AU  - M. Mar Albà
AU  - Julie L. Aspden
AU  - Sreejan Bandyopadhyay
AU  - Kaushik Banerjee
AU  - Pavel V. Baranov
AU  - Ariel Bazzini
AU  - Francis Bourassa
AU  - Elspeth A. Bruford
AU  - Lorenzo Calviello
AU  - Steven A. Carr
AU  - Anne‐Ruxandra Carvunis
AU  - Sonia Pankaj Chothani
AU  - Jim Clauwaert
AU  - Kellie A. Dean
AU  - Pouya Faridi
AU  - Adam Frankish
AU  - Amy B. Goodale
AU  - Thomas Green
AU  - Norbert Hubner
AU  - Nicholas T. Ingolia
AU  - M Kellis
AU  - Michele Magrane
AU  - Maria Jesus Martin
AU  - Thomas F. Martinez
AU  - Gerben Menschaert
AU  - Uwe Ohler
AU  - Sandra E. Orchard
AU  - Alisa Potter
AU  - Owen J. L. Rackham
AU  - Matthew G. Rees
AU  - David E. Root
AU  - Jennifer A. Roth
AU  - Xavier Roucou
AU  - Fernando J. Sialana
AU  - Sarah A. Slavoff
AU  - Michał I. Świrski
AU  - Jack A. S. Tierney
AU  - Félix-Antoine Trifiro
AU  - Eivind Valen
AU  - Valeriia Vasylieva
AU  - Aaron C. Wacholder
AU  - Shengbo Wang
AU  - Li Wang
AU  - Jonathan S. Weissman
AU  - Wei Wu
AU  - Zhi Xie
AU  - Jyoti S. Choudhary
AU  - Michal Bassani-Sternberg
AU  - Juan Antonio Vizcaíno
AU  - Nicola Ternette
PY  - 2026
DA  - 2026/05/06
JO  - Nature
DO  - 10.1038/s41586-026-10459-x
UR  - https://doi.org/10.1038/s41586-026-10459-x
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. A large-scale proteomics analysis of the dark proteome by the TransCODE Consortium reveals many translated non-canonical open reading frames to encode microproteins and peptideins.
SN  - 0028-0836
SN  - 1476-4687
ER  -