The impact of a virus's dual obligations - to maintain high inter-host transmissibility while also effectively adapting within hosts - on viral genetic diversity remains largely unexplored. We posit that these demands could induce uncorrelated selection pressure even antagonistic pleiotropy, a scenario where mutations enhance certain fitness aspects at others' expense, and contribute to the maintenance of genetic variation and promote adaptation. The vast wealth of SARS-CoV-2 genetic data gathered from within and across hosts offers an unparalleled opportunity to test above hypothesis. By analyzing a large set of SARS-CoV-2 sequences (~ 2 million) collected from early 2020 to mid-2021, we found that high frequency mutations within hosts are usually detrimental during inter-host transmission. This highlights potential inverse selection pressures within versus between hosts. We also identified a group of nonsynonymous changes, which are probably maintained by antagonistic pleiotropy, as their frequencies are significantly higher than four-fold degenerate sites but never experienced clonal expansion. Analyzing one such mutation, spike M1237I, reveals that spike I1237 boosts viral assembly but reduces in vitro transmission, highlighting its antagonistic effect. Though they make up about 2% of total changes, they represent 37% of genetic diversity. These mutations are notably prevalent in the Omicron variant from late 2021, hinting that antagonistic pleiotropy may promote positive epistasis and new adaptive variants. As many viral dynamics assumptions rest on mutations being selectively neutral, these fitness-effect mutations might skew estimates like transmission bottleneck and effective population sizes.
Antagonist pleiotropy caused by the dual demand of the viral life cycle shapes genetic diversity and adaptive changes in SARS-CoV-2
Abstract ID: 123
Event: The 3rd AsiaEvo Conference
Topic: Virus evolution: from basic research to public health applications
Presenter Name: Jui-Hung, Tai