How domain mimicry shapes genetic conflicts between hosts and viruses

Viral mimicry is a prevalent evolutionary mechanism for the acquisition of host-protein domains in order to hijack cellular pathways.

By leveraging the similarity between the original host and the mimicked domain, the viral mimic forms interactions with host proteins.

This introduces genetic conflict since these interactions are advantageous for the virus and deleterious for the host.The host is limited in its capacity to avoid mimics because evolving to escape them can disrupt the host interactome.

Elucidating the way in which hosts evolve in the face of mimicry, and the constraints placed on viral mimics, are central to understanding the evolution of genetic conflicts.To address these questions, we will uniquely combine advanced structural modelling, comparative interactomics, evolutionary analyses and functional validations to map the functions, interactions and constraints of viral mimics and their host-interacting proteins.

Specifically, we will: (1) Map the landscape of mimicry occurrence in viral proteomes to find which domains are mimicked and which viral families tend to acquire such domains, (2) Characterize the cellular interactomes of both mimics and host-mimicked domains to identify shared targets between host and mimic, and to find mimic-specific interactions, pointing to neo-functionalization, (3) Study the sequence evolution of interface residues between mimics and their host targets, and (4) Characterize evolutionary mechanisms, such as gene duplication, that may be adaptive for the host or the virus.

Using these novel techniques and integrative analyses, we will unravel the factors shaping the evolution of mimics and their resulting genetic conflicts with the host.

These principles are important for understanding the evolution of mechanisms by which viruses acquire new functions, and ultimately for predicting zoonotic potential and viral emergence.