Weirdness #1. It has 62 new mutations compared to its predecessors. Previous variants (alpha through mu) have between 18 and 29 mutations. So, 62 is a lot. Too many to arise from a natural process? Probably not. It would just take more time to accumulate that many.
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Weirdness #2. There are no intermediate versions of Omicron that have a subset of the 62 mutations. Probably the biggest problem for the natural origin idea. Accumulation takes a long time, and Omicron is more infectious than the measles. How could it hide this long?
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Weirdness #3. Mutations come in 2 flavors, compliments of the redundant genetic code: Silent ("synonymous" or S) mutations do not alter the amino acid they encode Defining ("nonsynonymous" or NS) mutations do change a protein's AA sequence.
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Defining (NS) mutations are subject to evolutionary selection pressure, because they tend to alter protein function. Most will be rejected, a lucky few survive. Omicron was lucky 62 times. With a few exceptions, silent (S) mutations are not selected for or against.
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In the absence of evolutionary pressure, the ratio of NS/S can be estimated. I did this for SARS-like genomes and the average ratio is 3.5 Selection pressure can change this ratio. The spike gene has 30 functional (NS) and 1 silent (S) mutation. Weird: bit.ly/3FzEpGF
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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.
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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.
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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.
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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?
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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.
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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

Jan 13, 2022 · 1:10 AM UTC

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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).
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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 ...
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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.
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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?
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RNA C>U editing generates 4 times more defining than silent mutations (see mutation matrix above). So without evolutionary selection, we expect much more than 63% C>T mutations. Instead we see 17%. So selection pressure has removed a very large number of C>U mutations?
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