Speaker
Description
Over the course of the SARS-CoV-2 pandemic, several divergent variants emerged which carried insertion-deletion mutations (indels), suggesting indels may be crucial in enabling the virus to adapt to changing host environments. However, indels are challenging to study, especially at the within-host level, as the process of sequencing and alignment generation can introduce artefacts. We developed a realignment method that accurately determines the genomic location and within-host frequency of indels, which we applied to the 120,000 high-quality sequenced samples collected as part of the UK Office for National Statistics’ Covid Infection Survey (ONS-CIS). We found that a high proportion of samples had within-host polymorphisms for deletions in the N-terminal domain of non-structural protein 1 (NSP1), which is the host translation shut-off factor. Recurrent deletions in this region were also observed during persistent infections captured in the ONS-CIS. Deletions in this region have been previously linked to reduced interferon response and lower viral load. The deletions observed within-host in this region were almost always in-frame, suggesting they are genuine and not artefacts. At the consensus level, these deletions occur sporadically across many different lineages, are rarely clustered on the phylogeny, and appear at markedly different frequencies among samples depending on variant. Using the linked data of the ONS-CIS including household outbreaks, we will present evidence that the deletions generated at a high rate in this region in SARS-CoV-2 are transmitted, and that this region is subject to conflicting within-host and between-host evolutionary pressures shaped by the role of NSP1 in suppressing the interferon response. The role of indels in driving genetic diversity in RNA viruses is often overlooked, and this analysis provides new insight into this important but underappreciated evolutionary dynamic.
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