PXD073135

PXD073135 is an original dataset announced via ProteomeXchange.

Title	Encoded and non-genetic alternative protein variants expand human functional proteome
Description	Each stage of the Central Dogma contributes to proteome diversity through mechanisms such as heterozygosity, somatic mutations, transcriptional errors, and translational errors. As a result, a diverse array of protein variants can coexist within a single proteome, such as that of humans. However, until now, methods to detect, quantify, and evaluate the functional consequences of these variants have been lacking. Here we examined a large-scale proteogenomic dataset from 29 healthy human tissues and uncovered 13,910 confidently localized variants representing 7,215 unique single amino acid substitutions co-existing alongside their corresponding reference proteoforms. We found that the abundance of both genetic (SNP’s, somatic mutations) and mistranslated protein variants mirrors their allele frequencies in the human population. Moreover, we show that non-genetic substitutions may provide a distinct route for exploring protein sequence space, circumventing the mutational constraints imposed by the genetic code. In addition, we provide experimental validation of non-genetic substitution on selected purified proteins. We demonstrate specific and recurring non-genetic variation patterns upon amino acid starvation in proteome-wide analyses of cancer-derived cell lines and identify hundreds of substituted non-genetic proteoforms that recur consistently in multiple healthy individuals or map to annotated protein functional sites. We propose that these substitutions constitute a novel class of functional protein phenotypic variants. Finally, we highlight potential non-genetic routes of immunoglobulin diversification. Collectively, our findings indicate that non-genetic amino acid substitutions in human proteins provide an abundant source to expanding the functional proteome.
HostingRepository	PRIDE
AnnounceDate	2026-01-22
AnnouncementXML	Submission_2026-01-22_11:11:33.854.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Vjaceslav Tretjacenko
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2026-01-15 17:42:33	ID requested
⏵ 1	2026-01-22 11:11:34	announced

Dataset with its publication pending

submitter keyword: None

Yitzhak Pilpel
contact affiliation	Weizmann Institute of Science
contact email	pilpel@weizmann.ac.il
lab head
Vjaceslav Tretjacenko
contact affiliation	Weizmann Institute of Science
contact email	tretyacv@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/01/PXD073135

PRIDE project URI

• PRIDE
  1. PXD073135
     1. Label: PRIDE project
     2. Name: Encoded and non-genetic alternative protein variants expand human functional proteome