V- and VL-scores unveil viral signatures and origins of protein families

Abstract

Abstract Viruses are key drivers of microbial ecology and evolution, yet their study is hindered due to challenges in culturing. Traditional gene-centric methods, which focus on a few hallmark genes like for capsids, miss much of the viral genome, leaving key viral proteins and functions undiscovered. Here, we introduce two powerful annotation-free metrics, V-score and V L -score, designed to quantify the “virus-likeness” of protein families and genomes and create an open-access searchable database, ‘V-Score-Search’. By applying V- and V L -scores to public protein databases, we link 19 − 59% of protein families with viruses representing a 5 − 8x increase over current estimates. These metrics outperform existing approaches, enabling high efficiency in detection of viral genomes, prophages, and host-derived auxiliary viral genes (AVGs) from fragmented sequences. Remarkably, we identify up to 17 times more AVGs dominated by non-metabolic proteins of unknown function. This innovation unlocks new insights into virus signatures and host interactions, with wide-ranging implications from genomics to biotechnology.