Estimates of both the substitution rate and the generation time for SARS-CoV-2 vary. When I surveyed a number of estimates a couple of weeks ago, I ended up with an estimate of 0.4 substitutions per transmission.
There are far more than 23 replications in a year. So this tells us that there is less than 1 neutral/positive mutation per replication. Mutation rates include deleterious mutations, but they are largely screened out in viral populations. Virulence reducing mutations often fix because they increase fitness, helping the virus spread by reducing the negative impact on the host.
Did you catch that? Reducing the lethality of the virus makes it more fit.
Deleterious mutations are mostly screened out quickly ā before transmission ā but some do linger for a while. The substitution rate decreases as you increase the time over which you sample. (E.g. the measured substitution rate within Ebola virus outbreaks is higher than the measured rate between outbreaks.)
I donāt see how you can go from the nb of replication per year to the replication error rate I am interested in. I remember having read that it was about 1 error/substitution per genome per replication but was unable to find confirmation.
Figure 1 in Sanfordās paper contradicts this claim, for it shows a regular increase in the accumulation of deleterious mutations as the number of generation increases.
I think this assumption doesnāt work in the case of Covid-19 for 1) the virus is infectious during the pre-symptomatic phase and 2) itās lethality is much too weak.
Scientists have been monitoring the virus since it first emerged, so there should be data on how the viral genome has changed over the last 5 months or so.
The substitution rate(*) is right around 1e-3 mutations/bp/year, or 30 mutations per virus per year. Mean time between transmissions is less well known, but is around 5 days. That gives 0.4 mutations per transmission.
(*) Which is NOT the mutation rate ā the mutation rate is much higher and very hard to measure, since most mutations are weeded out within a single host.
Well to be fair, it isnāt really a contradiction to say that deleterious mutations can accumulate as generations increase, while most of those that occur are largely (but ofc not completely), as a proportion, screened out by selection.
This is a problem with keeping the discussion of these ideas at this kind of somewhat vague verbal level, as opposed to giving precise quantitative statements with actual numbers.
Yes, this is a place where Sanford is saying something that contradicts what the data shows. We very much agree with you that his work, on this point, is in conflict with the evidence.
Your confutation of my hypothesis would have merit if it was the case that SARS-CoV-2 had a single origin but there are reasons to believe this is not true. For example, here is an interesting passage I found in a recent publication: We look for the origin of SARSāCoVā2, because we see it as a single entity against which we could act using a series of established approaches, since the virus would follow a predictable route of contagion. The epidemic would resolve after āherd immunityā had been created. Yet, SARSāCoVā2 is not a single entity (e.g., see Forster et al ., 2020) and may not have a single origin: contemplating herd immunity with a heterogeneous population of viruses may be very misleading, at best.
And here is the whole article: https://sfamjournals.onlinelibrary.wiley.com/doi/full/10.1111/1462-2920.15053
Sure, when that is what happens. But how often is it the case that host-to-host transmission is facilitated by a single viral particle? There must be some sort of distribution of typical transmission particle loads, and I highly doubt single or even double-digit transmission numbers are common.
In the real world, natural selection works just fine to prevent the accumulation of deleterious mutations in RNA viruses within a host. Deleterious mutations can accumulate, with consequent loss of fitness, during transmission bottlenecks, but only if those bottlenecks are extremely and artificially tight. There is no loss of fitness for realistic bottlenecks, and in fact low fitness viruses that have accumulated deleterious mutations can regain fitness if the artificial bottlenecks are removed (thanks to that high mutation rate). See https://mmbr.asm.org/content/76/2/159 and Viral quasispecies.
Your doubt may not be warranted, as this passage shows: Genetic bottlenecks are likely to occur quite frequently with RNAābased respiratory viruses since respiratory droplets often contain only one to two infectious particles per droplet.7Modeling suggests that such bottlenecks likely drive down the virulence of a pathogen due to stochastic loss of the most virulent phenotypes
The whole article here: https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26067