Growth for the proteome: The human genome apparently not only encodes proteins – it also produces a completely new class of molecules: peptides. These protein-like biomolecules are made of amino acids but are much shorter than common proteins. An international research project has now identified a good 1,700 of these peptides for the first time. It is still unclear what biological function these molecules have. But they could play a role in the immune system and in diseases, as the researchers report in “Nature”.
Only two percent of our genome consists of protein-coding genes. These sections contain the building instructions for the approximately 19,500 proteins that are essential for our cell functions. But what does the rest of our DNA do? For a long time, these sequences of unknown function were considered mere gene copies or functionless relics. But it is now clear that many of these non-coding DNA sections have important functions, for example in gene regulation. Some of these DNA sequences are also read by the cell machinery and possibly “translated” into molecules.
Searching for clues in the “dark proteome”
But so far it has remained unclear to what extent the “non-canonical open reading frames” (ncORF) of our genome that lie outside the genes produce molecules and which ones. However, there were initial indications that peptide chains made up of amino acids could be among them. “These ncORFs and the polypeptides they encode are therefore also considered part of the ‘dark proteome’,” explain Eric Deutsch from the Institute for Systems Biology in Seattle and his colleagues.
To shed more light on this “dark proteome,” Deutsch and his colleagues examined 7,264 of these non-canonical open reading frames in human DNA in more detail. As part of the international TransCODE consortium, they sequenced the DNA sections, analyzed the molecules read and produced from them in cell cultures and looked for possible biological functions.
1,785 previously unknown microproteins
The result: “Around 25 percent of the non-canonical open reading frames we examined produce detectable peptides,” report the researchers. The DNA sections, which were previously considered largely functionless, contain the building instructions for 1,785 previously unknown microproteins – molecules made of amino acids strung together. However, most of these peptide chains are significantly shorter than normal proteins – two thirds of them contain fewer than 50 amino acids.
“We already knew that the known proteins did not show us the full picture,” says co-author Sebastiaan van Heesch from the Princess Máxima Center for Pediatric Oncology in Utrecht. “Now our study reveals that thousands of previously overlooked DNA sequences contribute to our proteome: creating a whole new class of protein-like molecules that were previously overlooked.”
New, third category of human DNA
The team has named the newly discovered class of molecules “peptideins.” They expand the common classification of the human genome to include a third category: In addition to protein-coding genes and non-coding DNA sections, the peptide-producing sequences form another category. Deutsch and his colleagues suspect that there are far more sections of the human genome with previously unknown products than are known.
“The exciting thing about it is not only that these molecules exist, but also what this means: The peptides indicate that there is a whole, barely understood layer of molecular players beneath the level of the genome we are familiar with,” says co-author Robert Moritz from the Institute for Systems Biology. “We are just beginning to understand their functional role in gene regulation, signaling pathways and cell survival.”
Biological function is largely still unclear
For most peptides, it is still unclear what their purpose is: “For most newly discovered molecules, we don’t yet know exactly what they do,” says van Heesch. In tests with cell cultures, however, at least some of these microproteins appear to play a role in cell division and DNA repair: If they are switched off, cell growth suffers. Others are presented on the cell surface and could be recognized by the immune system, the team reports.
“We are just beginning to understand what the ‘dark proteome’ does,” says co-author John Prensner from the University of Michigan. “It’s like the trailer for a feature film. So far we can only imagine that we have a real game-changer for our view of human biology.” The researchers hope that their discovery and classification of the peptides will now encourage colleagues around the world to research these new molecules in more detail.
“This is not the end of a search, but the door opener to a broad and fruitful new field of research for the entire scientific community,” said Prensner. “I believe that peptideins could be among the most versatile and consequential regulatory molecules we have yet encountered in human biology.”
Source: Eric Deutsch (Institute for Systems Biology, Seattle) et al., Nature, 2026; doi: 10.1038/s41586-026-10459-x