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A comprehensive map of evolutionary constraints across the enterovirus A genome

Bakhache, William1; Dolan, Patrick1

Research facility: National Institute of Allergy and Infectious Diseases
Published Jun 19, 2024; Updated Aug 16, 2024 on Dryad. https://doi.org/10.5061/dryad.866t1g1xm

Data files

Jun 19, 2024 version files 238.78 MB
Aug 16, 2024 version files 332.64 MB

Abstract

Insertions and deletions (InDels) are essential sources of novelty in protein evolution. In RNA viruses, InDels cause dramatic phenotypic changes that contribute to the emergence of viruses with altered immune profiles and host engagement. This work aims to comprehensively quantify the mutational tolerance of an RNA virus to insertion, deletion, and substitution. Using Enterovirus A71 (EV-A71) as a prototype for the Enterovirus A species (EV-A) of picornaviruses, we engineered approximately 45,000 insertions, 6,000 deletions, and 41,000 AA substitutions across the nearly 2,200 coding positions of the EV-A71 proteome, quantifying their effects on viral fitness. In contrast with AA changes, the vast majority of InDels are lethal to virus growth. Those that are tolerated primarily reside in a few hotspot regions. These tolerant sites highlight structurally flexible and mutationally plastic regions of EV-A71 proteins that avoid core structural and functional elements but often overlap with key sites of host- and immune recognition, suggesting a complex evolutionary role for InDels and substitutions at these sites. Phylogenetic analysis examining EV-A species isolated from diverse mammalian hosts reveals that many of the experimentally identified hotspots also correspond to sites of natural InDel diversity, suggesting these hotspots of mutational tolerance in EV-A genomes may have contributed to past phenotypic diversification of EV-A. Insights from this and future mutational scanning studies mapping viral evolutionary potential will inform better epidemiological monitoring and Enterovirus vaccine development.