Ongoing shuffling of protein fragments diversifies core viral functions linked to interactions with bacterial hosts

Abstract

Biological modularity enhances evolutionary adaptability by allowing rearrangement of functional components. One striking example are bacterial viruses (phages). They exhibit extensive genomic modularity by being built of independent functional modules that evolve separately and combine in various ways, making them astoundingly diverse. While multiple studies have investigated genomic modularity in phages, less attention has been given to protein modularity--proteins having distinct building blocks or domains that can evolve and recombine, enhancing functional and genetic diversity. To better understand the impact of protein modularity on viral evolution, we quantified it by detecting instances of domain mosaicism, defined as a homologous fragment sharing between two otherwise unrelated proteins. We used highly sensitive homology detection to quantify domain 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. Diversification via protein fragment exchange often transcended distant taxonomic and ecological borders. 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 mechanisms of bacterial resistance against phages.