Peptidein

A peptidein is a small molecule made up of amino acids similar in appearance and biomechanical role to proteins. More than 1,700 types of peptideins have been identified, most of which are of unknown functions, but some are implicated with genetic diseases and cancer. Popularly called the "dark proteome" or "dark proteins" due to their elusive identity, they are a type of microproteins, and were identified by an international team of scientists led by Sebastiaan van Heesch of the Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands, in 2026.

Discovery

In 2022, Sonia Chothani at the Duke-NUS Medical School and Genome Institute of Singapore and Jorge Ruiz-Orera at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany, initiated an international project called TransCODE Consortium. The project aimed at identifying all the proteins produced (encoded) from a small open reading frame (sORF or smORF) in the human genome. Hundreds to thousands of sORFs were estimated to exist in different organisms, and were named as such by Munira A. Basrai, Philip Hieter and Jef D. Boeke of the Johns Hopkins University School of Medicine, in 1997. Some sORF are so small, usually shorter than 100 codons, that they were believed to have no protein-coding genes to make functional peptides. However, were different some genetic diseases and cancers in humans were found to be associated with these short DNA sequences. Association with diseases indicated that they must produce some kind of proteins, hundreds of them, but impossible to detect them directly. For their elusive nature, they were known as the "dark proteome" or "dark proteins".

In 2026, the TransCODE Consortium announced the first complete identification of microproteins and published it in the journal Nature, from a research led by Sebastiaan van Heesch of the Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands, and co-led by John Prensner (University of Michigan Medical School) and Robert Moritz (Institute for Systems Biology). The scientists gave the name "peptidein" for the protein-like molecules. By definition, they are too small to be named proteins, as they explained:

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 bring formal reference gene annotation status to less-well-characterized microproteins, we introduce 'peptidein' as a classification scheme, recognized by our consortia, to exist alongside conventional proteins. To illustrate that further characterization of a peptidein may elevate its classification, we use functional genomics and evolutionary constraint to pinpoint examples that exhibit a signature consistent with a protein-coding gene.

The TransCODE Consortium identified 1,785 peptideins. The human genome contain about 19,500 functional proteins, thus peptideins adds 10% more of functional genes. The number is still preliminary, as Moritz explained that there may be thousand more peptideins to be identified and could double the human proteome.