Scientists shed light on the human “dark proteome”

14 05 2026

For many years, it was assumed that the human genome contains around 19,500 canonical, well-described protein-coding genes. However, a growing body of research suggests that this picture may be more complex. Beyond the classical set of genes, there are poorly understood regions of the genome that can also be read by the cell. Products arising from such previously overlooked regions are sometimes described as part of the so-called dark proteome.

In a study published in Nature, the international TransCODE consortium, with the participation of Michał Świrski from the Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, analysed 7,264 non-canonical open reading frames, or ncORFs. These are pieces of genetic information that had not previously been treated as classical protein-coding genes, but that may give rise to short protein products, so-called microproteins.

The discovery may be relevant, among other areas, to cancer research and immunotherapy. The study showed that many peptides derived from newly described translation products are presented on the surface of cells by HLA class I molecules. This is one of the ways in which the immune system can monitor what is happening inside cells.

The researchers also provided evidence for around 1,700 peptideins, i.e. microproteins derived from non-canonical open reading frames whose production can be experimentally confirmed, but whose function and status require further investigation.

Peptideins may be important for cell survival. One product arising from OLMALINC RNA, previously classified as non-coding, stood out in particular. Disrupting the open reading frame responsible for its production impaired the viability of most of the analysed cancer cell lines. The role of this molecule in normal cells, however, remains unknown.

The study shows that the human proteome may be more complex than previously thought and proposes a cautious evaluation of poorly understood translation products. The results have been linked to public databases used by researchers, including GENCODE, UniProt and PeptideAtlas.

The article “Expanding the human proteome with microproteins and peptideins” was published in Nature. The study was conducted by the TransCODE consortium, bringing together more than 60 researchers from over 30 institutions worldwide.

Cover picture: Cancer cell expressing microprotein (colored in red). Credit Ting Luo/Princess Máxima Center for pediatric oncology

The full article is available at: https://doi.org/10.1038/s41586-026-10459-x

Link to Nature news: https://www.nature.com/articles/d41586-026-01492-x

Link to the TransCODE Consortium website: https://transcodeconsortium.org

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