Expanding the human proteome with microproteins and peptideins
Name
Deutsch-Expanding the human proteome with microproteins and peptideins-2026-Nature_supplement_1.pdf
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Supplementary information
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Author(s)
Deutsch, Eric
Kok, Leron
Mudge, Jonathan
Valls, Cristian
Jungreis, Irwin
Ruiz-Orera, Jorge
Sun, Zhi
Kusebauch, Ulrike
Fierro-Monti, Ivo
Abelin, Jennifer
Date Issued
May 6, 2026
Journal
Nature
Publisher
Nature
Citation
Deutsch, E.W., Kok, L.W., Mudge, J.M. et al. Expanding the human proteome with microproteins and peptideins. Nature 654, 813–825 (2026).
Version
Final published version
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 states [1,2,3], 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 Consortium [4] 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.
Subjects
GENCODE
Ribo-seq
Human Proteome Project
mass spectrometry
immunopeptidomics
proteomics
microproteins
non-canonical ORFs
translation
peptidein
ORBL
ncORFs
translon
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivatives
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DOI of Published Version
https://doi.org/10.1038/s41586-026-10459-x
