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Richard Neher
@neher.io

Building on the UShER tree of millions of SARS-CoV-2 genomes maintained by Angie Hinrichs, Hugh Haddox and Georg Angehrn (and others in @matsen.bsky.social lab and @jbloomlab.bsky.social) have looked into how the neutral mutation rate varies along the genome: [1/N] www.biorxiv.org/content/10.1...

biorxiv.orgThe mutation rate of SARS-CoV-2 is highly variable between sites and is influenced by sequence context, genomic region, and RNA structureRNA viruses like SARS-CoV-2 have a high mutation rate, which contributes to their rapid evolution. The rate of mutations depends on the mutation type (e.g., A→C, A→G, etc.) and can vary between sites ...

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Richard Neher
@neher.io

Some rates, like C>T(U), are much higher than others. But even for the same mutation type, rates vary dramatically from site to site, sometimes in striking patterns: A>T mutations are 2-3 fold more common after the start of Spike. C>T drops almost two-fold at the ORF1a/b boundary. [2/N]

Richard Neher
@neher.io

The underlying mechanism is a mystery to us (we speculate a bit in the preprint). Rates also depend on neighboring bases, sometimes by more than 10-fold. These neighbor-dependence is very strand symmetric for some mutations (e.g. T>G and A>C), but not others. [3/N]

Richard Neher
@neher.io

A symmetry between strands would be expected for mutations associated with replication (the genome is copied from + to - and back to +), while processes like deamination would depend mostly on the accessibility of the base to mutagens. [4/N]

Richard Neher
@neher.io

Base accessibility is likely also the underlying reason for the dependence of mutation rates on RNA secondary structure, as described by Zach Hensel last year. www.biorxiv.org/content/10.1... [5/N]

biorxiv.orgSecondary structure of the SARS-CoV-2 genome is predictive of nucleotide substitution frequencyAccurate estimation of the effects of mutations on SARS-CoV-2 viral fitness can inform public-health responses such as vaccine development and predicting the impact of a new variant; it can also illum...