C->U transition biases in SARS-CoV-2 - still rampant four years from the start of the COVID-19 pandemic

Abstract

The evolution of SARS-CoV2 in the pandemic and post-pandemic periods has been characterised by rapid adaptive changes that confer immune escape and enhanced human-to-human transmissibility. Sequence change is additionally marked by an excess number of C->U transitions suggested as being due to host-mediated genome editing. To investigate how therse influence the evolutionary trajectory of SARS-CoV-2, 2000 high quality, coding complete genome sequences of SARS-CoV-2 variants collected pre-September, 2020, and from each subsequently appearing alpha, delta, BA.1, BA.2, BA.5, XBB, EG, HK and JN.1 lineages were downloaded from NCBI Virus in April, 2024. C->U transitions were the most common substitution during diversification of SARS-CoV-2 lineages over the 4-year observation period. A net loss of C bases and accumulation of Us occurred at a constant rate of approximately 0.2%-0.25% / decade. C->U transitions occurred in over a quarter of all sites with a C (26.5%; range 20.0%-37.2%), around 5 times more than observed for the other transitions (5.3%-6.8%). In contrast to an approximately random distribution of other transitions across the genome, most C->U substitutions occurred at statistically preferred sites in each lineage. However, only the most C->U polymorphic sites showed evidence for a preferred 5U context previously associated with APOBEC 3A editing. There was a similarly weak preference for unpaired bases suggesting much less stringent targeting of RNA than mediated by A3 deaminases in DNA editing. Future functional studies are required to determine editing preferences, impacts on replication fitness in vivo of SARS-CoV-2 and other RNA viruses and impact on host tropism.