Evolutionary origins and interactomes of human young microproteins and small peptides translated from short open reading frames

We analyzed the evolutionary origins of 7,264 recently cataloged human sORFs and found that most were evolutionarily young and had emerged de novo. We additionally identified 221 previously missed sORFs potentially translated into peptides of up to 15 amino acids – all of which are smaller than the smallest human microprotein annotated to date.

To investigate the bioactivity of sORF-encoded small peptides and young microproteins, we subjected 266 candidates to a mass spectrometry-based interactome screen with motif-resolution. Based on these interactomes and additional cellular assays, we can associate several candidates with mRNA splicing, translational regulation, and endocytosis. Our work provides insights into the evolutionary origins and interaction potential of young and small proteins and thereby helps to elucidate this underexplored territory of the human proteome.