荷兰乌得勒支Oncode研究所Sebastiaan van Heesch团队发现了用微蛋白和肽扩展人类蛋白质组。相关论文于2026年5月6日发表于国际顶尖学术期刊《自然》杂志上。

在这里，该课题组报告了TransCODE联盟的合作努力，以产生ncORF的蛋白质水平证据的共识景观。在对95,520个蛋白质组学实验的大规模分析中，研究团队发现在一组7,264个ncORF中约有25%产生可检测的肽。课题组开发了一个ncORF编码的微蛋白作为人类蛋白质的注释框架，并编纂了“肽素”作为微蛋白的新概念模型，这些微蛋白作为功能蛋白具有不确定的潜力。

为了探究肽素的生物学意义，研究组创建了一种进化分析方法，称为ORF相对分支长度（ORBL），并确定进化约束是常见的，并与观察ncORF衍生肽有关。然后，研究小组表征了来自OLMALINC长非编码RNA的一种肽素的泛必需细胞表型。总的来说，该课题组人员创造了由GENCODE和PeptideAtlas支持的公共研究工具，并推进了对人类蛋白质组中未被研究的成分的生物医学发现。

据悉，一个主要的科学驱动力是表征蛋白质编码基因组，这是研究人类健康的主要基础。但最根本的问题仍然是，在之前的分析中遗漏了什么。在过去的十年中，非规范开放阅读框架（ncORF）的翻译已经在人类细胞类型和疾病状态中被观察到，对生物医学科学具有重大意义。然而，一个关键的知识缺口是，ncORF产生的小微蛋白或替代蛋白分子对人类蛋白质组有贡献。

附：英文原文

Title: Expanding the human proteome with microproteins and peptideins

Author: Deutsch, Eric W., Kok, Leron W., Mudge, Jonathan M., Valls, Cristian F., Jungreis, Irwin, Ruiz-Orera, Jorge, Sun, Zhi, Kusebauch, Ulrike, Fierro-Monti, Ivo, Abelin, Jennifer G., Alba, M. Mar, Aspden, Julie L., Bandyopadhyay, Sreejan, Banerjee, Kaushik, Baranov, Pavel V., Bazzini, Ariel A., Bourassa, Francis, Bruford, Elspeth A., Calviello, Lorenzo, Carr, Steven A., Carvunis, Anne-Ruxandra, Chothani, Sonia, Clauwaert, Jim, Dean, Kellie, Faridi, Pouya, Frankish, Adam, Goodale, Amy, Green, Thomas, Hubner, Norbert, Ingolia, Nicholas T., Kellis, Manolis, Magrane, Michele, Martin, Maria Jesus, Martinez, Thomas F., Menschaert, Gerben, Ohler, Uwe, Orchard, Sandra, Potter, Alisa, Rackham, Owen J. L., Rees, Matthew G., Root, David E., Roth, Jennifer A., Roucou, Xavier, Sialana, Fernando J., Slavoff, Sarah A., wirski, Micha I., Tierney, Jack A. S., Trifiro, Flix-Antoine, Valen, Eivind, Vasylieva, Valeriia, Wacholder, Aaron, Wang, Shengbo, Wang, Li, Weissman, Jonathan S., Wu, Wei, Xie, Zhi, Choudhary, Jyoti S., Bassani-Sternberg, Michal, Vizcano, Juan Antonio, Ternette, Nicola

Issue&Volume: 2026-05-06

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 states1,2,3, 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 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.

DOI: 10.1038/s41586-026-10459-x

Source: https://www.nature.com/articles/s41586-026-10459-x