Abstract
Recent advances in proteogenomics have revealed a previously uncharted layer of the proteome composed of alternative proteins (AltProts), challenging the classical one-gene-one-protein paradigm. AltProts, often derived from small open reading frames (sORFs) or non-canonical translation events, expand our understanding of eukaryotic genome plasticity. Some AltProts exhibit strong evolutionary conservation, suggesting ancestral biological functions, while others appear to emerge de novo from previously non-coding regions, highlighting the genome’s potential for innovation.This dual nature: conserved regulatory elements versus lineage-specific novelties, mirrors observations in model organisms, where proteomic diversity often reflects unique evolutionary adaptations. In glioblastoma, for example, AltProts have been identified as potential prognostic markers, some arising from non-coding RNAs with recent evolutionary origins. These findings align with emerging evidence that de novo gene birth contributes to functional innovation across species, including humans. The mechanisms enabling such rapid integration into cellular networks remain poorly understood, yet they bear striking resemblance to alternative translation strategies observed in viruses.
Understanding how these proteins contribute to fundamental biological processes will not only refine our knowledge of eukaryotic genome evolution but also open new avenues for biomarker discovery and therapeutic innovation.