Stunning news! How is this possible!
"One of the biggest surprises to emerge when the human genome was first sequenced more than 20 years ago was how few genes it contained, with that number now hovering around 20,000. But a new systematic analysis of what some call the “dark proteome” suggests scientists have missed thousands of non-traditional genes that make smaller-than-average proteins.
Genes typically consist of a long protein-coding DNA sequence known as an open reading frame or ORF; this is preceded by a snippet of DNA that attracts the proteins needed for the gene to be read. But biologists studying everything from yeast to snakes to humans have recently unearthed a plethora of so-called non-canonical ORFs, which lack these snippets and can code for just a few amino acids. Initially dismissed as “noise,” [or artifacts?] studies have demonstrated that many do make proteins and at least a few of these proteins matter.
So, after a multidisciplinary, international consortium tracked down 7264 of these non-canonical ORFs in 2022, they teamed up with the Human Proteome Organization and PeptideAtlas to see which ones make proteins—and they found at least 25% of those ORFs do. The newly discovered miniproteins “help provide a more complete picture of the coding portion of the genome,” ..."
"... Where does all this leave the tally of human genes? The dark proteome has clearly boosted the total, but no one knows the true number.
“My gut feeling it is probably not as high as 100,000,” Martinez says, “but 50,000 is in the realm of possibility.”"
About 43 authors affiliated with 24 different organisations contributed to this research paper.
From the abstract:
"A major scientific drive is to characterize the protein-coding genome as it provides the primary basis for the study of human health. But the fundamental question remains: what has been missed in prior genomic analyses? Over the past decade, the translation of non-canonical open reading frames (ncORFs) has been observed across human cell types and disease states, with major implications for proteomics, genomics, and clinical science. However, the impact of ncORFs has been limited by the absence of a large-scale understanding of their contribution to the human proteome. Here, we report the collaborative efforts of stakeholders in proteomics, immunopeptidomics, Ribo-seq ORF discovery, and gene annotation, to produce a consensus landscape of protein-level evidence for ncORFs. We show that at least 25% of a set of 7,264 ncORFs give rise to translated gene products, yielding over 3,000 peptides in a pan-proteome analysis encompassing 3.8 billion mass spectra from 95,520 experiments. With these data, we developed an annotation framework for ncORFs and created public tools for researchers through GENCODE and PeptideAtlas. This work will provide a platform to advance ncORF-derived proteins in biomedical discovery and, beyond humans, diverse animals and plants where ncORFs are similarly observed."
‘Dark proteome’ survey reveals thousands of new human genes "Database confirms that overlooked segments of the genome code for a multitude of tiny proteins"
High-quality peptide evidence for annotating non-canonical open reading frames as human proteins (open access)
What a gigantic, global effort!
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