However, the genome replicates as a single unit, so NS muts in the spike can be compensated by S muts elsewhere. Better to look at the entire genome. For O NS=62 and S=10. Ratio is 2.6 standard deviations away from the mean: 1% chance to belong to this group. Not impossible.

Weirdness #4. 24 of the 30 mutations in the spike of O are published: bit.ly/34L0Tro Is it therefore designed? That info could certainly help a designer. But if a mutation has a clear effect (immune escape, ACE2 binding), evolution can find them as well. Neutral.

Weirdness #5. 9 Variants of Concern (alpha-mu) predated Omicron. Of the 30 mutations in Omicron's spike protein, 8 are defining mutations for 7 of its predecessors. Omicron summarizes everything that came before. Except it was in hiding all this time.

That may be a bit more worrisome for the natural hypothesis. SARS-like viruses can copy gene segments between viruses that co-exist in a person using 'template switching'. But that would imply that Omicron co-existed with 7 of its predecessors at some time during its evolution?

Alternatively, the 8 mutations that O shares with its predecessors are "must have" changes, which increase fitness to such a great extent that evolution will find them, given enough time. An example of such a mutation is D614G, which is seen in all VoCs.

Weirdness #6. There are 12 possible random mutations: from 4 bases (ATGC or AUGC) to the remaining 3. If all have an equal chance, each would happen 8.33% of the time. But take a look at the list of silent mutations in the SARS2 variants: 63% are C-to-T

Because these are silent mutations, they are not highly selected. And all variants show the same enrichment for C>T. What gives? Mutations can arise by 2 mechanisms: 1. Transcription errors 2. RNA editing APOBECs can convert a Cytidine base to Uracil (C>U or C>T in DNA).

So it appears both mutation mechanisms are at work here, with RNA editing responsible for 63-8.3 = 54.7% of the changes. And because these are silent mutations, they report unbiased about the underlying processes. So what about defining (NS) mutations? Glad you asked ...

First of all, C>U editing can only account for a very limited number of amino acid changes. See C>U mutation matrix below. Silent mutations in blue. Only 12 NS mutations are possible. Obviously, transcription errors will have to make up for this limited repertoire of RNA editing.

From the silent mutations we know that more than 1/2 of all mutations are generated by RNA editing and result in C>U. Lets take a look at Omicron below. Of the 30 defining mutations, 5 are C>T (1 is silent in S271L). 17% is much smaller than 53%. What does that mean?