Thread by @jeremydratcliff

How might the sequence space available to SARS-CoV-2 shift? In this review, @Simmonds_Lab and I explore the overabundance of C>U transitions as SARS-CoV-2 has adapted to humans and speculate on the role of mammalian APOBEC proteins in this process (1/8)
doi.org/10.1016/j.viro…

Lots of information is covered in this article, broadly looking at APOBEC evolution and how they may be involved in driven evolution in structured RNA viruses, but here I'll just focus on the bits relevant to SARS-CoV-2 (2/8)

As noted by many authors, C>U transitions are represented well above their expected frequencies in SARS-CoV-2 and have accumulated over time as the virus has adapted to circulating in humans. Much of the viral amino acid diversity has been due to these transitions (3/8)

This phenotype is similar in direction and structure and sequence preference as those of APOBECs, wherein certain locations in the genome are target motifs for the protein's action. This phenomenon is most thoroughly studied in the context of HIV cDNA (4/8)

Antiviral driven evolution has the interesting effect wherein these specific mutations are not a mechanism through which SARS-CoV-2 is exploring a fitness landscape and more just an inevitable consequence of replication in human cells. (5/8)

@firefoxx66 and @macroliter are spot on when they note that convergent, non-synonymous mutations that are NOT C>U transitions deserve special attention (6/8)

doi.org/10.1101/2021.0…

In the long term, the slightly deleterious, neutral, and beneficial target motifs will be depleted and we will likely see a decrease in C>U transitions over time and effective mutation rate (as well as a general depletion of cytosine from the genome) (7/8)

Lots of experimental work to be done to verify this hypothesis but certainly an interesting item to keep an eye on (8/8)