Ongoing shuffling of protein fragments diversifies core viral functions to tackle bacterial resistance mechanisms

Abstract Phages are known for their genetic modularity. Their genomes are built of independent functional modules that evolve separately and combine in various ways, making them astoundingly diverse. Multiple studies have demonstrated how genome mosaicism emerges in phage populations and facilitates adaptation to their hosts, bacteria. However, less is known about the extent of (within-)protein modularity and its impact on viral evolution. To fill this knowledge gap, here we quantified such modularity by detecting instances of protein mosaicism, defined as a homologous fragment between two otherwise unrelated proteins. We used highly sensitive homology detection to quantify protein mosaicism between pairs of 133,574 representative phage proteins and to understand its relationship with functional diversity in phage genomes. We found that diverse functional classes often shared homologous domains. This phenomenon was often linked to protein modularity, particularly in receptor-binding proteins, endolysins and DNA polymerases. We also identified multiple instances of recent diversification via exchange and gain/loss of domains in receptor-binding proteins, neck passage structures, endolysins and some members of the core replication machinery. We argue that the ongoing diversification via shuffling of protein domains associated with those functions is reflective of co-evolutionary arms race and the resulting diversifying selection to overcome multiple bacterial resistance mechanisms.