Expanding the human proteome with microproteins and peptideins.

“Expanding the human proteome with microproteins and peptideins. Deutsch EW(#)(1), Kok LW(#)(2)(3), Mudge JM(#)(4), Valls CF(#)(5)(6), Jungreis I(#)(7)(8), Ruiz-Orera J(9), Sun Z(1), Kusebauch U(1), Fierro-Monti I(4)(10), Abelin JG(8), Alba MM(11)(12), Aspden JL(13), Bandyopadhyay S(14), Banerjee K(5)(6), Baranov PV(15), Bazzini AA(16)(17), Bourassa F(18), Bruford EA(19), Calviello L(20), Carr SA(8), Carvunis AR(21)(22)(23), Chothani S(24)(25), Clauwaert J(5), Dean K(15), Faridi P(26)(27), Frankish A(4), Goodale A(8), Green T(8), Hubner N(9)(28)(29)(30), Ingolia NT(31), Kellis M(7)(8), Magrane M(4), Martin MJ(4), Martinez TF(32)(33)(34), Menschaert G(35), Ohler U(36)(37), Orchard S(4), Potter A(2)(3)(38), Rackham OJL(39), Rees MG(8), Root DE(8), Roth JA(8), Roucou X(40), Sialana FJ(14), Slavoff SA(41)(42)(43), Świrski MI(44), Tierney JAS(4), Trifiro FA(18), Valen E(45), Vasylieva V(18), Wacholder A(21)(22)(23), Wang S(4), Wang L(8), Weissman JS(46)(47)(48)(49), Wu W(50)(51), Xie Z(52), Choudhary JS(14), Bassani-Sternberg M(53)(54)(55), Vizcaíno JA(4), Ternette N(56)(57), Brunet MA(18)(58)(59), Moritz RL(60), Prensner JR(61)(62), van Heesch S(63)(64). Author information: (1)Institute for Systems Biology (ISB), Seattle, WA, USA. (2)Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. (3)Oncode Institute, Utrecht, The Netherlands. (4)European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK. (5)Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA. (6)Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA. (7)Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (8)Broad Institute of MIT and Harvard, Cambridge, MA, USA. (9)Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. (10)Biozentrum, University of Basel, Basel, Switzerland. (11)Hospital del Mar Research Institute, Barcelona, Spain. (12)Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, Spain. (13)School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK. (14)Functional Proteomics Group, Institute of Cancer Research, Chester Beatty Labs, London, UK. (15)School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland. (16)Stowers Institute for Medical Research, Kansas City, MO, USA. (17)Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA. (18)Pediatrics Department, University of Sherbrooke, Sherbrooke, Quebec, Canada. (19)HUGO Gene Nomenclature Committee (HGNC), Department of Haematology, University of Cambridge School of Clinical Medicine, Cambridge, UK. (20)Human Technopole, Milan, Italy. (21)Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. (22)Pittsburgh Center for Evolutionary Biology and Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. (23)Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland. (24)Centre for Computational Biology and Program in Cardiovascular and Metabolic Disorders, Duke-NUS (National University of Singapore) Medical School, Singapore, Singapore. (25)Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. (26)Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia. (27)Monash Proteomics & Metabolomics Platform, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia. (28)Charité-Universitätsmedizin Berlin, Berlin, Germany. (29)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. (30)DZHK (German Center for Cardiovascular Research)-Partner Site Berlin, Berlin, Germany. (31)Department of Molecular and Cell Biology, Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA. (32)Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA. (33)Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA. (34)Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA. (35)Biobix, Lab of Bioinformatics and Computational Genomics, Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium. (36)Department of Biology, Humboldt University Berlin, Berlin, Germany. (37)Berlin Institute of Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. (38)Biomolecular Mass Spectrometry and Proteomics, Bijvoet Centre for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. (39)School of Biological Sciences, University of Southampton, Southampton, UK. (40)Department of Biochemistry and Functional Genomics, University of Sherbrooke, Sherbrooke, Quebec, Canada. (41)Department of Chemistry, Yale University, New Haven, CT, USA. (42)Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA. (43)Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT, USA. (44)Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland. (45)Department of Biosciences, University of Oslo, Oslo, Norway. (46)Whitehead Institute for Biomedical Research, Cambridge, MA, USA. (47)Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. (48)Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA, USA. (49)David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. (50)Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. (51)Department of Pharmacy & Pharmaceutical sciences, National University of Singapore (NUS), Singapore, Singapore. (52)State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. (53)Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. (54)Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. (55)Agora Cancer Research Centre, Lausanne, Switzerland. (56)School of Life Sciences, Division Cell Signalling and Immunology, University of Dundee, Dundee, UK. (57)Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (58)Centre de Recherche du Centre hospitalier universitaire de Sherbrooke (CRCHUS), Sherbrooke, Quebec, Canada. (59)Cancer Research Institute, University of Sherbrooke (IRCUS), Sherbrooke, Quebec, Canada. (60)Institute for Systems Biology (ISB), Seattle, WA, USA. rmoritz@systemsbiology.org. (61)Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA. prensner@umich.edu. (62)Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA. prensner@umich.edu. (63)Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. s.a.a.vanheesch@prinsesmaximacentrum.nl. (64)Oncode Institute, Utrecht, The Netherlands. s.a.a.vanheesch@prinsesmaximacentrum.nl. (#)Contributed equally 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. © 2026. The Author(s). Conflict of interest statement: Competing interests: J.R.P. has received research honoraria from Novartis Biosciences and Quantum-Si, and is on the scientific advisory board for, and receives research funding from, ProFound Therapeutics. J.G.A. is a paid consultant for Enara Bio and Moderna. J.L.A. is an advisor to Microneedle Solutions. G.M. is co-founder and CSO of OHMX.bio. S.A.C. is a member of the scientific advisory boards of Kymera, PTM BioLabs, MOBILion Systems and PrognomIQ. N.T.I. holds equity and serves as a scientific advisor to Tevard Biosciences. P.F. is a member of the scientific advisory board of Infinitopes. A.-R.C. is a member of the advisory board of ProFound Therapeutics. P.V.B. is a cofounder and shareholder of Eirnabio. D.E.R. receives research funding from members of the Functional Genomics Consortium (Abbvie, BMS, Jannsen, Merck) and is a director of Addgene. J.S.W. declares the following outside interests, which are unrelated to this work: 5 AM Venture, Amgen, nChroma Bio, KSQ Therapeutics, Maze Therapeutics, Tenaya Therapeutics, Tessera Therapeutics, Thermo Fisher Scientific, Third Rock Ventures and Xaira. The other authors declare no competing interests.”