Hacker News Reader

Comment by tomp | Hacker News Reader

This isn't really anything new, but nicely summarizes the best case (as far as I've read about it) explanation of the lab-leak theory of COVID origin.

Basically, it hinges on:

1. SARS-CoV-19 doesn't have a direct predecessor virus

2. it has a "weird" furin cleavage site on its spike protein, where "weird" means:

2a. it encodes the amino acid arginine by an CGG RNA codon, which is "rare" for SARS-CoV-19's closest relative

2b. the inserted furin cleavage site coding sequence is misaligned, breaking the codon TCA into two parts, which is (citation:) "very odd, clearly pointing to an artificial origin"

Also interesting that the article refers to "T", which is a DNA nucleotide, as opposed to "U", which is the corresponding RNA nucleotide (SARS-CoV-2 is a RNA virus).

View on HN

Furin cleavage sites have evolved and are present in multiple coronaviruses:

- HCoV-OC43 (infects humans)

- HCoV-HKU1 (infects humans)

- MHV-A59

- ChRCoV-HKU24

- BtCoV-ENT

- BtNeCoV-PML-PHE1

- BtCoV-HKU4

- BtCoV-HKU5

- MERS-CoV

- BtHpCoV-Zhejiang2013

- SARS-CoV-2

Phylogenetic analysis suggests that it has evolved independently at least 6 times that we know of.

https://www.sciencedirect.com/science/article/pii/S187350612...

After that article was published a team in Thailand found furin cleavage sites in sarbecoviruses closely related to SARS-CoV-2 called RacCS203 (91.5% similarity to SARS-CoV-2) and RmYN02 (93.3% similarity to SARS-CoV-2)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873279/

Furin cleavage sites are common, nature understands how to utilize that trick very well, and continuously has re-discovered it.

> 2b. the inserted furin cleavage site coding sequence is misaligned, breaking the codon TCA into two parts, which is (citation:) "very odd, clearly pointing to an artificial origin"

But what is odd about this? I don't know of any mechanism for mutagenesis, natural or otherwise, which respects codon boundaries. Codon boundaries don't exist in the DNA, then only arise through its interpretation by the ribosome.

On the contrary, if i was engineering a polypeptide to add a furin cleavage site, i probably would align it to codon boundaries, so as not to disrupt the sequence.

I don't understand that either.

Other virologists seem to interpret the out-of-frame insert as being counterproductive.

> 1. SARS-CoV-19 doesn't have a direct predecessor virus

That we know of. We do way way too little research on viruses in animals. We may never know predecessor in nature, and that doesn't mean it's created in a lab. Same as the fact that we don't know how universe behaved in first moments after big bang doesn't mean that god exists.

The counterargument mounted by Wade and others is that the world has been searching for such a transmission path for the last year with far greater resources than normally allocated, as obviously, China would very much like to find such a path. However no such animal has been found. The lack of any discovery despite great effort is not itself proof, as you can't prove a negative, but it does seem suggestive.

> but it does seem suggestive.

As pointed out by others, we don't even know who COVID's patient zero is, nor whether or not an intermediate host was even required after bats.

The original SARS-CoV virus has never been isolated in animals. HIV's origins in chimps is still murky.

The Spanish flu wasn't Spanish, but otherwise ... And, Ebola. ?

We humans aren't owed an answer, and juxtaposed against our investigative history, I don't understand how the current state of our understanding here is suggestive of anything.

> . it has a "weird" furin cleavage site on its spike protein, where "weird" means:

From what I know that is unusual but not rally that unusual or weird.

> SARS-CoV-19 doesn't have a direct predecessor virus

Us not knowing a "close by/directish" predecessor is also not uncommon for a virus which jumped from wield animals to humans. It's a different thing if it's a virus which was a well known one already spread in humans or human cattle/pets and then mutated. But if you look at the wield there are viruses which survived for decades e.g. in bat colonies with some small mutations here and there, for that example case it would be very strange if we would know a predecessor with might already have gone extinct... And similar thinks might very well apply to SARS-Cov-2.

It referred to the viral cDNA as the sequencing was performed on, hence the 'T'.

If this is the "peak lab leak" argument, which seems still more rejected than accepted by scientist, what is the general rebuttal? "Yes it's unlikely but less unlikely than a leak"? Or something more technical?

The rebuttal is that the above argument is a mischaracterization of the evidence. The fact we haven't seen an ancestor virus is absolutely expected and normal, and has happened for every other virus. Furin cleavage sites are present in a dozen other coronaviruses. The closest relative known is fairly likely not to be an ancestor, so there is no real expectation you wouldn't see an arginine. It's totally normal for there to be a misalignment, that's exactly what you would expect for random evolution, to find anything that works.

So basically, there is almost no argument above, and zoonoses have happened hundreds of times and are thus expected.

My understanding is that the interesting bit is not about the misalignment, but rather the fact that the furin site is an insertion, not a mutation. Additionally, a non-canonical codon that encodes a restriction site.

The idea as I understand is something like this:

1) I want to study what makes coronaviruses go from infecting bats to infecting humans

2) I add a furin site because my hypothesis is that a furin in the spike protein is important (because other coronaviruses like MERS have it)

3) I then try to passage the virus through many generations to see if it preserves the furin site I added (i.e. selects for it) because if it mutates at less than baseline, I know it's important (this also explains the "mosaic" aspect of the other mutations in the virus)

4) To be able to track that, when I add the furin site, I make sure to insert a restriction site that isn't found elsewhere in the genome, so I can do a quick RNA extraction, and restriction digest to see if it's preserved.

Please note. That is my understanding of this one aspect of the lab leak hypothesis. It's not necessarily what I believe to be true. Additionally, it is not the only piece of evidence cited as part of the lab leak hypothesis, either.

Thanks, this is really interesting.

What about the SARS-CoV-2 virus being a chimera of 2 other viruses? Is that wrong, or not unusual, or irrelevant? Sorry if I’m barking up a wrong tree...

Reply on news.ycombinator.com