The position
Only a fraction of the genome codes for the proteins in standard reference catalogs. Many small open reading frames (smORFs) are translated into microproteins that those catalogs miss, but which of these recently evolved microproteins actually carry out a biological function remains largely unknown. Evolutionary signatures, such as how strongly a sequence is conserved or constrained across species and within human populations, offer one of the few ways to tell a functional microprotein from a spurious translation product.
This project will build and validate computational models that predict the functionality of recently evolved microproteins from evolutionary features, integrating ribosome profiling data, phylostratigraphy (evolutionary age), and genetic variant data from public resources such as gnomAD and UK Biobank. It sits within ORFeus Work Package 2, which moves from discovery to function, and provides an evolutionary framework for the wider network: shared variant and DepMap data from partner projects help measure sequence constraints,



the resulting constraint data feeds back into the network's AI prediction models for validation, and top candidates are tested in CRISPR-Cas9 screens in cancer cell lines, with phenotypic hits connecting to partner work on cancer.
Main tasks
● Develop computational models that predict microprotein functionality by integrating ribosome profiling data, phylostratigraphy (evolutionary age estimates), and genetic constraint data from public resources such as gnomAD and UK Biobank, drawing on shared variant and DepMap datasets from another doctoral candidate (DC) in the network, here DC12, to measure sequence constraints.
● Prioritize candidate microproteins for functional validation, with the resulting evolutionary constraint data contributing to the AI model validation carried out in DC1.
● Validate model predictions using CRISPR-Cas9 functional screens in cancer cell lines, assessing effects on cell growth, drug res

📌 Project 8: Predicting microprotein functionality through... (España)
🏢 ORFeus doctoral network
📍 España