Slack / Private Message Drop — page 24

Any new evidence on this? I haven't looked at e.g., dN/dS for a while. [2020-05-12 21:29:50] [Eddie Holmes] Got it. No new evidence. [2020-05-12 23:01:09] [Eddie Holmes] [thread - ID: 2020-05-12 23:01:09] Just to confirm: there's no evidence of the S1/S2 insertion site being deleted in any natural SARS-CoV-2 genome? Are there any synonymous/nonsynonymous mutations at this site in nature? If there's strong purifying selection indicative of functional constraint would this argue against it being acquired in cell culture? [2020-05-13 04:36:23] [Robert Garry] Couple of points. First, in the human sequencing most if not all of the seq are from nasal swabs taken at diagnosis, ie. near peak virus load. It might be interesting to look later in disease when Ct values have increased - that's where the variants if they exist will be found in vivo. Monkey studies can get to these late variants too if they exist and our primate center is sending samples to KGA. Def a bottleneck in human transmission of virus variants - there is a whole literature on this in HIV. Persistent HIV infection accumulates variants - usually only one or a few variants transmitted - macrophage tropic vs T-cell tropic viruses are selected for. Second, there are a lot of ways to do passage in cell culture. Here's an 40 year old paper I did in graduate school with CC King who - lets say had some challenges in gs but went on to be Taiwan's "greatest" virologist https://www.sciencedirect.com/science/article/abs/pii/0042682279901867?via%3Dihub Undiluted, diluted passage - different cells - incubation time generate different levels of DI particles (big deletions) substitutions etc. Would have been great to have a sequencer then - excuse me while I get in my time machine and go back to retrieve a few samples. [2020-05-13 04:47:04] [Robert Garry] "My first look at the virus suggested that the pattern of distribution of sequence variation across the genome looked natural, but that may too broad brush." ProfBill has a new long read on Virological on this topic - synonymous mutations look very normal from bat to pangolin. [2020-05-13 13:57:22] [Kristian Andersen] [thread - ID: 2020-05-12 23:01:09] @Eddie Holmes There's a little bit of activity in a few samples. A see a couple of samples where the P becomes L, 'turning off' the O-linked glycans. There's also a single example from a human patient where the site is deleted - the full 12bp. Other than that, not much going on - I'll take a look at the synonymous changes. [2020-05-13 14:34:02] [Kristian Andersen] [thread - ID: 2020-05-12 23:01:09] @Eddie Holmes @Eddie Holmes - based on a brief glance, not much on the Syn level either - maybe a little less, meaning this is probably evolving neutrally(ish). Formal analyses would be interesting. [2020-05-13 14:36:25] [Eddie Holmes] Thanks Bob. I'll take another look at Bill's post. I've met Prof King a number of times - she's certainly a 'character'. She has a plastic cover over her laptop keyboard that must have been there for 30 years...in shreds. [2020-05-13 14:57:31] [Robert Garry]