{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Institute for Systems Biology (ISB), Seattle, WA, USA",
    "Oncode Institute, Utrecht, The Netherlands",
    "Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands",
    "European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK",
    "Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA",
    "Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA",
    "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA",
    "Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany",
    "Biozentrum, University of Basel, Basel, Switzerland",
    "Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, Spain",
    "Hospital del Mar Research Institute, Barcelona, Spain",
    "School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK",
    "Functional Proteomics Group, Institute of Cancer Research, Chester Beatty Labs, London, UK",
    "School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland",
    "Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA",
    "Stowers Institute for Medical Research, Kansas City, MO, USA",
    "Pediatrics Department, University of Sherbrooke, Sherbrooke, Quebec, Canada",
    "HUGO Gene Nomenclature Committee (HGNC), Department of Haematology, University of Cambridge School of Clinical Medicine, Cambridge, UK",
    "Human Technopole, Milan, Italy",
    "Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland",
    "Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA",
    "Pittsburgh Center for Evolutionary Biology and Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA",
    "Centre for Computational Biology and Program in Cardiovascular and Metabolic Disorders, Duke-NUS (National University of Singapore) Medical School, Singapore, Singapore",
    "Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore",
    "Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia",
    "Monash Proteomics & Metabolomics Platform, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia",
    "Charité-Universitätsmedizin Berlin, Berlin, Germany",
    "DZHK (German Center for Cardiovascular Research)-Partner Site Berlin, Berlin, Germany",
    "Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) at Heidelberg University, Heidelberg, Germany",
    "Department of Molecular and Cell Biology, Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA",
    "Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA",
    "Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA",
    "Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA",
    "Biobix, Lab of Bioinformatics and Computational Genomics, Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium",
    "Berlin Institute of Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany",
    "Department of Biology, Humboldt University Berlin, Berlin, Germany",
    "Biomolecular Mass Spectrometry and Proteomics, Bijvoet Centre for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands",
    "School of Biological Sciences, University of Southampton, Southampton, UK",
    "Department of Biochemistry and Functional Genomics, University of Sherbrooke, Sherbrooke, Quebec, Canada"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 64,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Eric W. Deutsch",
      "orcid": "0000-0001-8732-0928"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Leron W. Kok",
      "orcid": "0009-0008-0841-2313"
    },
    {
      "affs": [
        3
      ],
      "name": "Jonathan M. Mudge",
      "orcid": "0000-0003-4789-7495"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Cristian Valls",
      "orcid": "0009-0000-0517-1069"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Irwin Jungreis",
      "orcid": "0000-0002-3197-5367"
    },
    {
      "affs": [
        8
      ],
      "name": "Jorge Ruiz‐Orera",
      "orcid": "0000-0002-8317-0034"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhi Sun",
      "orcid": "0000-0003-3324-6851"
    },
    {
      "affs": [
        0
      ],
      "name": "Ulrike Kusebauch",
      "orcid": "0000-0001-6162-7577"
    },
    {
      "affs": [
        9,
        3
      ],
      "name": "Ivo Fierro-Monti",
      "orcid": "0000-0002-5460-2117"
    },
    {
      "affs": [
        6
      ],
      "name": "Jennifer G. Abelin",
      "orcid": "0000-0001-5262-7241"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "M. Mar Albà",
      "orcid": "0000-0002-7963-7375"
    },
    {
      "affs": [
        12
      ],
      "name": "Julie L. Aspden",
      "orcid": "0000-0002-8537-6204"
    },
    {
      "affs": [
        13
      ],
      "name": "Sreejan Bandyopadhyay"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Kaushik Banerjee",
      "orcid": "0000-0002-9903-4192"
    },
    {
      "affs": [
        14
      ],
      "name": "Pavel V. Baranov",
      "orcid": "0000-0001-9017-0270"
    },
    {
      "affs": [
        15,
        16
      ],
      "name": "Ariel Bazzini",
      "orcid": "0000-0002-2251-5174"
    },
    {
      "affs": [
        17
      ],
      "name": "Francis Bourassa",
      "orcid": "0009-0001-9012-7245"
    },
    {
      "affs": [
        18
      ],
      "name": "Elspeth A. Bruford",
      "orcid": "0000-0002-8380-5247"
    },
    {
      "affs": [
        19
      ],
      "name": "Lorenzo Calviello",
      "orcid": "0000-0002-5600-0988"
    },
    {
      "affs": [
        6
      ],
      "name": "Steven A. Carr",
      "orcid": "0000-0002-7203-4299"
    },
    {
      "affs": [
        20,
        21,
        22
      ],
      "name": "Anne‐Ruxandra Carvunis",
      "orcid": "0000-0002-6474-6413"
    },
    {
      "affs": [
        23,
        24
      ],
      "name": "Sonia Pankaj Chothani",
      "orcid": "0000-0002-1010-7069"
    },
    {
      "affs": [
        5
      ],
      "name": "Jim Clauwaert",
      "orcid": "0000-0002-5876-1406"
    },
    {
      "affs": [
        14
      ],
      "name": "Kellie A. Dean",
      "orcid": "0000-0002-3213-8181"
    },
    {
      "affs": [
        25,
        26
      ],
      "name": "Pouya Faridi",
      "orcid": "0000-0002-2712-3356"
    },
    {
      "affs": [
        3
      ],
      "name": "Adam Frankish",
      "orcid": "0000-0002-4333-628X"
    },
    {
      "affs": [
        6
      ],
      "name": "Amy B. Goodale",
      "orcid": "0000-0003-4294-5777"
    },
    {
      "affs": [
        6
      ],
      "name": "Thomas Green"
    },
    {
      "affs": [
        8,
        27,
        28,
        29
      ],
      "name": "Norbert Hubner",
      "orcid": "0000-0002-1218-6223"
    },
    {
      "affs": [
        30
      ],
      "name": "Nicholas T. Ingolia",
      "orcid": "0000-0002-3395-1545"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "M Kellis",
      "orcid": "0000-0001-7113-9630"
    },
    {
      "affs": [
        3
      ],
      "name": "Michele Magrane",
      "orcid": "0000-0003-3544-996X"
    },
    {
      "affs": [
        3
      ],
      "name": "Maria Jesus Martin",
      "orcid": "0000-0001-5454-2815"
    },
    {
      "affs": [
        31,
        32,
        33
      ],
      "name": "Thomas F. Martinez",
      "orcid": "0000-0002-4011-8164"
    },
    {
      "affs": [
        34
      ],
      "name": "Gerben Menschaert",
      "orcid": "0000-0002-7575-2085"
    },
    {
      "affs": [
        35,
        36
      ],
      "name": "Uwe Ohler",
      "orcid": "0000-0002-0881-3116"
    },
    {
      "affs": [
        3
      ],
      "name": "Sandra E. Orchard",
      "orcid": "0000-0002-8878-3972"
    },
    {
      "affs": [
        37,
        1,
        2
      ],
      "name": "Alisa Potter"
    },
    {
      "affs": [
        38
      ],
      "name": "Owen J. L. Rackham",
      "orcid": "0000-0002-4390-0872"
    },
    {
      "affs": [
        6
      ],
      "name": "Matthew G. Rees",
      "orcid": "0000-0002-2987-7581"
    },
    {
      "affs": [
        6
      ],
      "name": "David E. Root",
      "orcid": "0000-0001-5122-861X"
    },
    {
      "affs": [
        6
      ],
      "name": "Jennifer A. Roth",
      "orcid": "0000-0002-5117-5586"
    },
    {
      "affs": [
        39
      ],
      "name": "Xavier Roucou",
      "orcid": "0000-0001-9370-5584"
    },
    {
      "affs": [
        13
      ],
      "name": "Fernando J. Sialana",
      "orcid": "0000-0001-9083-1657"
    },
    {
      "name": "Sarah A. Slavoff",
      "orcid": "0000-0002-4443-2070"
    },
    {
      "name": "Michał I. Świrski",
      "orcid": "0000-0002-8585-136X"
    },
    {
      "affs": [
        3
      ],
      "name": "Jack A. S. Tierney",
      "orcid": "0000-0002-5331-3604"
    },
    {
      "affs": [
        17
      ],
      "name": "Félix-Antoine Trifiro",
      "orcid": "0009-0003-5912-6812"
    },
    {
      "name": "Eivind Valen",
      "orcid": "0000-0003-1840-6108"
    },
    {
      "affs": [
        17
      ],
      "name": "Valeriia Vasylieva",
      "orcid": "0009-0000-7049-9423"
    },
    {
      "affs": [
        20,
        21,
        22
      ],
      "name": "Aaron C. Wacholder",
      "orcid": "0000-0001-8739-0029"
    },
    {
      "affs": [
        3
      ],
      "name": "Shengbo Wang",
      "orcid": "0000-0001-5034-6374"
    },
    {
      "affs": [
        6
      ],
      "name": "Li Wang",
      "orcid": "0000-0002-4460-8670"
    },
    {
      "name": "Jonathan S. Weissman",
      "orcid": "0000-0003-2445-670X"
    },
    {
      "name": "Wei Wu",
      "orcid": "0000-0002-1092-603X"
    },
    {
      "name": "Zhi Xie",
      "orcid": "0000-0002-5589-4836"
    },
    {
      "affs": [
        13
      ],
      "name": "Jyoti S. Choudhary",
      "orcid": "0000-0003-0881-5477"
    },
    {
      "name": "Michal Bassani-Sternberg",
      "orcid": "0000-0002-1934-954X"
    },
    {
      "affs": [
        3
      ],
      "name": "Juan Antonio Vizcaíno",
      "orcid": "0000-0002-3905-4335"
    },
    {
      "name": "Nicola Ternette",
      "orcid": "0000-0002-9283-0743"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/987wxqfpj8a4e.bib",
  "cited_by": 83,
  "doi": "10.1038/s41586-026-10459-x",
  "fulltext_url": null,
  "id": "987wxqfpj8a4e",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10459-x",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1607|Advanced Proteomics Techniques and Applications"
    ]
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  "openalex": "W7160397057",
  "pdf_url": null,
  "pmcid": "PMC11419116",
  "pmid": "39314370",
  "published": "2026-05-06",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/987wxqfpj8a4e.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:44Z",
      "native_id": "W7160397057",
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      "url": "https://doi.org/10.1038/s41586-026-10459-x"
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  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1607|Advanced Proteomics Techniques and Applications",
      "subfield": "physical"
    }
  ],
  "title": "Expanding the human proteome with microproteins and peptideins",
  "title_text": "Expanding the human proteome with microproteins and peptideins",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T13:20:35Z",
  "url": "https://research.draconitic.com/paper/987wxqfpj8a4e",
  "venue": "Nature",
  "versions": []
}