I can follow the argument about the furine clearing house, but it still falls short. Of course, it is indeed a virus that was capable of causing a pandemic and therefore not any random sarbeco virus. But the FCS is not necessary to cause a pandemic. SARS has none and neither have some endemic coronaviruses that occur in humans. So it is an enabling factor and not a necessary one. So it is certainly not the case that P(FCS|ZW, pandemic) = 1. An alternative proposition could be: how likely is it that researcher inserts an FCS into a sarbeco virus, given the fact that he knows this increases the infectivity of a virus.
Much more important is to consider that the FCS is in a 'module' that includes S2. Given the explanation of insertions, deletions, mutations and recombinations given for the emergence of the FCS, the question should be: how likely is it that an FCS emerges spontaneously in a sarbeco virus, without changing anything in the whole S2 module in the process, given that that FCS would have to have gotten into it through a combination of recombinations, insertions, deletions and mutations. Indeed, whoever removes the FCS from SARS-CoV-2 is left with the S2 module of RaTG13. What are the chances of a sarebecovirus with an FCS causing an outbreak in a city, in which an immediate family member with an exactly identical S2 unit is in the freezer of a laboratory researching coronaviruses
Yes, FCS is not necessary for a pandemic. There can be other routes, e.g. other types of cleavage. The point is that I don't know that P(FCS|ZW)<<1. Maybe it's 0.7, maybe 0.1. It's also not 1.0 for LL. It doesn't make sense here to include a ratio that could easily just be ~1.
For your other points, the idea here is to separate likelihood factors as much as possible and evaluate them separately. There are cases where that isn't appropriate because they don't really factorize (I discuss two such cases). The thing to watch out for, however, is the enormous temptation to let the factor for one observation influence the result for another even when there is not a logical connection. I've tried hard to fight that temptation.
Thanks for your comments. Fair enought. I'm afraid I'll have to read it once more to understand it fully. I realise that Bayesian thinking seems counterintuitive to many people, as I often noticed among the residents I was teaching. And I know all too well as a neurologist, how your brain can present you with a pattern where there is no pattern at all.
But the reason why I mentioned the FCS has to do with another point that you do include in your analysis, while I doubt it has that much eloquence. And that is about the CGGCGG sequence as encoding the two arginines in the FCS. I am not a molecular biologist, but I have done some reading by now, and it is quite possible that I misunderstood, but I found the defence given by Kristian Andersen to be valid. I then searched the literature to find what percentage of arginines in coronaviruses are encoded by the triplet CGG, and I do not come to very different findings. Is the percentage of this codon really that rare? If Andersen is right, no.
Great point. You should check my revised v3.0, linked up at the top. The Arg codon frequencies I used are correct for the genome as a whole. Andersen's anecdotal examples don't in themselves provide much counter-argument. But a pseudonymous twitter user, "Guy Gadboit", pointed out that long inserts like the 12nt in SC2 don't have the same codon frequencies as the rest of the genome. This turns out to require an embarrassingly large correction, which is done in v3.0,.V3.0 also includes a temporal coincidence factor, analogous to the spatial coincidence factor. In some sense it captures the FCS-rarity but based on an observed frequency that's not distorted by observational selection bias.
I can follow the argument about the furine clearing house, but it still falls short. Of course, it is indeed a virus that was capable of causing a pandemic and therefore not any random sarbeco virus. But the FCS is not necessary to cause a pandemic. SARS has none and neither have some endemic coronaviruses that occur in humans. So it is an enabling factor and not a necessary one. So it is certainly not the case that P(FCS|ZW, pandemic) = 1. An alternative proposition could be: how likely is it that researcher inserts an FCS into a sarbeco virus, given the fact that he knows this increases the infectivity of a virus.
Much more important is to consider that the FCS is in a 'module' that includes S2. Given the explanation of insertions, deletions, mutations and recombinations given for the emergence of the FCS, the question should be: how likely is it that an FCS emerges spontaneously in a sarbeco virus, without changing anything in the whole S2 module in the process, given that that FCS would have to have gotten into it through a combination of recombinations, insertions, deletions and mutations. Indeed, whoever removes the FCS from SARS-CoV-2 is left with the S2 module of RaTG13. What are the chances of a sarebecovirus with an FCS causing an outbreak in a city, in which an immediate family member with an exactly identical S2 unit is in the freezer of a laboratory researching coronaviruses
Yes, FCS is not necessary for a pandemic. There can be other routes, e.g. other types of cleavage. The point is that I don't know that P(FCS|ZW)<<1. Maybe it's 0.7, maybe 0.1. It's also not 1.0 for LL. It doesn't make sense here to include a ratio that could easily just be ~1.
For your other points, the idea here is to separate likelihood factors as much as possible and evaluate them separately. There are cases where that isn't appropriate because they don't really factorize (I discuss two such cases). The thing to watch out for, however, is the enormous temptation to let the factor for one observation influence the result for another even when there is not a logical connection. I've tried hard to fight that temptation.
Thanks for your comments. Fair enought. I'm afraid I'll have to read it once more to understand it fully. I realise that Bayesian thinking seems counterintuitive to many people, as I often noticed among the residents I was teaching. And I know all too well as a neurologist, how your brain can present you with a pattern where there is no pattern at all.
But the reason why I mentioned the FCS has to do with another point that you do include in your analysis, while I doubt it has that much eloquence. And that is about the CGGCGG sequence as encoding the two arginines in the FCS. I am not a molecular biologist, but I have done some reading by now, and it is quite possible that I misunderstood, but I found the defence given by Kristian Andersen to be valid. I then searched the literature to find what percentage of arginines in coronaviruses are encoded by the triplet CGG, and I do not come to very different findings. Is the percentage of this codon really that rare? If Andersen is right, no.
https://twitter.com/K_G_Andersen/status/1391507266050748418
In any case, thank you for your reply. I am going to read your piece again.
Great point. You should check my revised v3.0, linked up at the top. The Arg codon frequencies I used are correct for the genome as a whole. Andersen's anecdotal examples don't in themselves provide much counter-argument. But a pseudonymous twitter user, "Guy Gadboit", pointed out that long inserts like the 12nt in SC2 don't have the same codon frequencies as the rest of the genome. This turns out to require an embarrassingly large correction, which is done in v3.0,.V3.0 also includes a temporal coincidence factor, analogous to the spatial coincidence factor. In some sense it captures the FCS-rarity but based on an observed frequency that's not distorted by observational selection bias.
Great! Thanks again. I'm gonna read it.