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Still watching the emerging lineages of SARS-CoV2 I noticed that the amino acid mutation from threonine to isoleucine seems to be particularly frequent. Counting mutations in a lineage with a lot of mutation (I choose BA.4) kind of confirmed my anecdotal impression: Indeed, T-to-I mutations were the most frequent ones.

They are more frequent than alanine to valine mutations, and the difference in frequency is not explained by a difference in the frequency of the amino acids in the virus proteines (Threonine is somewhat more frequent than alanine, but not that much).

In part this phenomenon can be explained that a T-to-I mutation involves a nucleotide change from C to T which is the most frequent nucleotide mutation of Coronaviruses in humans. However, in order to be fixated in a lineage, the T-to-I mutation needs also to provide some evolutionary advantage. It seems to be a generic advantage of that kind of mutation.

So my question is: What are evolutionary advantages of T-to-I mutations of SARS-CoV2 in humans?

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    $\begingroup$ To elucidate an evolutionary advantage, you'd need to consider the structural context each mutation site along with other nearby mutations. The T->I mutation changes the position from polar to non-polar, which can change how that region of the protein folds (if it folds). Thr is also a site for post-translational modifications like phosphorylation or O-linked glycosylation, either of which could be relevant to just about any aspect of infection like receptor binding, cellular entry, regulation of cellular processes, structural stability of the capsid, or immune system evasion. $\endgroup$
    – MikeyC
    Commented Apr 12, 2022 at 15:24

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The change from C to T (or U in the case of RNA) can happen via the oxidation and deamination of the Cytosine (see reference 1 for the explanation of the mechanism).

The mechanisms looks like the following figure (from the reference 1):

enter image description here

The changes the genetic of the codon from AC* to AU* the first coding for Threonine (T) the later for Isoleucine (I) (image from the Wikipedia):

enter image description here

This does not mean that there is any driving mechanism for this mutation or any particular advantage. As the article states there are quite a few oxidative events per day, since a viral infection causes the generation of a lot of viral particles, this reaction will simply happen by chance.

Besides this mutation happening by chance there seems to be a mechanism called the "APOBEC-mediated RNA editing" which seems to edit the RNA of viruses. According the reference 2 this can be observed on other RNA viruses as well, leading to a higher prevalence of this mutation as it should occur naturally. The author speculate about this as a potent driver for diversification and evolution.

In DNA this error is not so problematic since there are two strands and error correction mechanisms but for a single stranded RNA genome every mutation will persist.

Reference:

  1. Oxidized, deaminated cytosines are a source of C → T transitions in vivo
  2. Extensive C->U transition biases in the genomes of a wide range of mammalian RNA viruses; potential associations with transcriptional mutations, damage- or host-mediated editing of viral RNA
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  • $\begingroup$ This is a great answer (+1) exhibing the mechanism behind the mutations, but it does not explain the prevalence of T-to-I mutations over A-to-V mutations. $\endgroup$
    – Sir Cornflakes
    Commented Apr 12, 2022 at 9:29
  • $\begingroup$ @jk-ReinstateMonica I think the prevalence of this mutation comes from the APOBEC-mediated mechanism. Why this is in place is unknown I think. I will try to see if I find some further information on it. $\endgroup$
    – Chris ♦
    Commented Apr 12, 2022 at 10:05

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