4 ms·

Yes, the input I'd provide is that the writer doesn't have a particularly good grasp of virology, but people in this community are upvoting as if this is author

by lvs 6y ago

Yes, the input I'd provide is that the writer doesn't have a particularly good grasp of virology, but people in this community are upvoting as if this is authoritative. People who write authoritative blog posts without expertise right now should consider themselves part of the disinfo problem. I'll be concrete: the expected correlation between the cited deletions and pathogencity should be considered to approach zero. No evidence supports the hypothesis that single codon or single nucleotide deletions correlate with attenuation of strains. Furthermore, a basic understanding of molecular biology is all that's needed to dismiss the notion of a generalized correlation between observing deletions (or even insertions! or any general mutation!) and the pathologic outcome of infection with a virus. Biology doesn't support general claims of this nature. This is not a well-informed line of reasoning. Even the title of the post is wrong! These are not "gene deletions." These are single codon deletions or deletions of a few nucleotides. No genes have been deleted!!

war1025 6y ago
His "About me" page states: """ I have been a tenured academic (Senior Lecturer) within the School of Pharmacy and Applied Science at La Trobe University, Australia teaching and researching in the areas of phage therapy (bacterial virology), pharmacy, environmental microbiology, bioinformatics and cancer. """ Since that seems easy enough to look up and call him out on if he were lying, I am inclined to believe that it's true. I am inclined to believe his take on things over yours, given that the only info I can see immediately about you is your info blurb stating, "Damn kids, get off my lawn." That said, I don't think anyone is treating what he says as gospel. But it's an interesting perspective.
- entee 6y ago
  At the risk of starting a flame war, lvs is mostly correct. These are NOT whole gene deletions, they are nucleotide deletions. Genes are usually longer than 33 nucleotides, by my count the largest deletion he sees. For reference, that’s 11 amino acids, rule of thumb for an average protein length is about 200 amino acids. The author highlights that many of these deletions are not codon aligned, which means that if you make this mutation, the resulting protein is highly unlikely to be translated properly. This is true, however devoid of context. Most of the mutations are very rare. The highest frequency one occurs 400 or so out of at minimum 10,000 examples. Next one is 36/10,000. It’s possible these matter, it’s also possible these viral sequences are just low quality and the mutations are an artifact. It’s also possible that these mutations don’t actually matter to viral function for whatever reason. For example, if the mutation is at the end of a protein, it could screw up everything downstream but the protein before the mutation works just fine, i.e. mutation doesn’t matter. It’s just hard to tell with the data in this article. The concept that maybe there are attenuated strains isn’t completely bogus, there is some thought a Singapore strain (with a massive deletion of 380 nucleotides, or 10x what we see here [1]) might be less infective. This is speculation and we don’t know yet, but that sounds maybe possible to me as a PhD Biochemist (if we’re gonna get all credential-spreading here). However saying “The really interesting deletion mutations are those in the non-structural accessory genes. These are the genes that are likely to play an important role in pathogenicity and it would be expected that some of these mutations may make the virus less dangerous (attenuated).” Is really pushing it. I don’t know of any science to believe this one way or another, viruses are pathogenic for a variety of reasons, both accessory and core (whatever that means) proteins matter. In short, given the uncertainty, we can hope there’s a less infectious strain out there, but this article provides precious little evidence to that effect. 1.) https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1.full.pdf https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....
  - danieltillett 6y ago
    Lvs is mostly wrong. I am not claiming any of these mutant strains are attenuated, I am saying that deletion mutants exists and we should investigate them to see if they are attenuated. I am not providing evidence that an attenuated strain exists, just evidence that it could exist because the right type of mutations are found in SARS-CoV-2. The only way we are going to find out if there are attenuated strains is to look for them which as far as I know nobody is trying.
    - lvs 6y ago
      So let's remember how evolution works, shall we? Evolution selects for strains that reproduce the most and selects against ones with attenuated reproduction rates. That's the whole basis of biology. If you've observed a wild strain sequenced in a database, that should be considered direct evidence that it reproduces well enough to have been sampled as a representative isolate. > as far as I know nobody is trying Of course we are. We are deeply engaged in studying the key residues that mediate all aspects of viral infection, reproduction, and clinical pathology. That's another way of saying that an incredible number of researchers have dropped everything to study the genetic and molecular determinants of pathogenicity. Don't worry -- we are on it.
      - danieltillett 6y ago
        Who is “we”? If you are doing this get in contact with me so I can give you money.
  - lvs 6y ago
    > we can hope there’s a less infectious strain out there But how? We are able to surveil only a tiny fraction of genomes, relative to strains circulating. How would a "less infectious strain" ever emerge to the extent we'd have a high probability of sampling it? Darwin argues against this version of the idea. Nevertheless, the OP is also wrong that it's faster to produce a live attenuated vaccine by finding one in the wild than it is to use tried-and-true viral vectors that are easy to reengineer, have previously received regulatory approval, and indeed are already in active trials (e.g. Oxford's adenoviral trial). It's also easier to trial heat-killed virus -- and indeed, that too is being trialed.
- lvs 6y ago
  Perhaps you should consider the arguments and disregard a superficial comparative analysis of our credentials.
  - war1025 6y ago
    I don't know enough about any of it to consider arguments. I apologize for the probably overly snarky comment. I woke up in the middle of the night and was having a hard time falling back to sleep. I really wouldn't be surprised if the two of you are in more agreement than either of you realize. "Violent agreement" as I've sometimes heard it called. Also for the record, I didn't downvote you. Just provided my response of why I was inclined to believe the author over you.
  - mythrwy 6y ago
    But....you went on the attack against the authors credentials in your top level post without apparently even reading them!
T-A 6y ago
> No evidence supports the hypothesis that single codon or single nucleotide deletions correlate with attenuation of strains https://www.mdpi.com/1999-4915/11/11/1016 https://www.mdpi.com/1999-4915/11/11/1016
- lvs 6y ago
  The citation does not refute or pertain to my statement. Yes, very specific mutations/indels can attenuate strains -- welcome to biology -- but the broad claim that the general observation of mutations/indels is somehow indicative of attenuated strains circulating in the wild is entirely unsupported and facially ridiculous.
  - danieltillett 6y ago
    I am not claiming any of this. I am saying that the right type of mutations exist in the SARS-CoV-2 genomes that attenuated strains COULD exist. If they do I am arguing we should look for them rather than sitting in our armchairs coming up with possible reasons they don’t and so not even bothering.

by lvs 6y ago

war1025 6y ago

His "About me" page states: """ I have been a tenured academic (Senior Lecturer) within the School of Pharmacy and Applied Science at La Trobe University, Australia teaching and researching in the areas of phage therapy (bacterial virology), pharmacy, environmental microbiology, bioinformatics and cancer. """ Since that seems easy enough to look up and call him out on if he were lying, I am inclined to believe that it's true. I am inclined to believe his take on things over yours, given that the only info I can see immediately about you is your info blurb stating, "Damn kids, get off my lawn." That said, I don't think anyone is treating what he says as gospel. But it's an interesting perspective.

entee 6y ago
At the risk of starting a flame war, lvs is mostly correct. These are NOT whole gene deletions, they are nucleotide deletions. Genes are usually longer than 33 nucleotides, by my count the largest deletion he sees. For reference, that’s 11 amino acids, rule of thumb for an average protein length is about 200 amino acids. The author highlights that many of these deletions are not codon aligned, which means that if you make this mutation, the resulting protein is highly unlikely to be translated properly. This is true, however devoid of context. Most of the mutations are very rare. The highest frequency one occurs 400 or so out of at minimum 10,000 examples. Next one is 36/10,000. It’s possible these matter, it’s also possible these viral sequences are just low quality and the mutations are an artifact. It’s also possible that these mutations don’t actually matter to viral function for whatever reason. For example, if the mutation is at the end of a protein, it could screw up everything downstream but the protein before the mutation works just fine, i.e. mutation doesn’t matter. It’s just hard to tell with the data in this article. The concept that maybe there are attenuated strains isn’t completely bogus, there is some thought a Singapore strain (with a massive deletion of 380 nucleotides, or 10x what we see here [1]) might be less infective. This is speculation and we don’t know yet, but that sounds maybe possible to me as a PhD Biochemist (if we’re gonna get all credential-spreading here). However saying “The really interesting deletion mutations are those in the non-structural accessory genes. These are the genes that are likely to play an important role in pathogenicity and it would be expected that some of these mutations may make the virus less dangerous (attenuated).” Is really pushing it. I don’t know of any science to believe this one way or another, viruses are pathogenic for a variety of reasons, both accessory and core (whatever that means) proteins matter. In short, given the uncertainty, we can hope there’s a less infectious strain out there, but this article provides precious little evidence to that effect. 1.) https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1.full.pdf https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....
- danieltillett 6y ago
  Lvs is mostly wrong. I am not claiming any of these mutant strains are attenuated, I am saying that deletion mutants exists and we should investigate them to see if they are attenuated. I am not providing evidence that an attenuated strain exists, just evidence that it could exist because the right type of mutations are found in SARS-CoV-2. The only way we are going to find out if there are attenuated strains is to look for them which as far as I know nobody is trying.
  - lvs 6y ago
    So let's remember how evolution works, shall we? Evolution selects for strains that reproduce the most and selects against ones with attenuated reproduction rates. That's the whole basis of biology. If you've observed a wild strain sequenced in a database, that should be considered direct evidence that it reproduces well enough to have been sampled as a representative isolate. > as far as I know nobody is trying Of course we are. We are deeply engaged in studying the key residues that mediate all aspects of viral infection, reproduction, and clinical pathology. That's another way of saying that an incredible number of researchers have dropped everything to study the genetic and molecular determinants of pathogenicity. Don't worry -- we are on it.
    - danieltillett 6y ago
      Who is “we”? If you are doing this get in contact with me so I can give you money.
- lvs 6y ago
  > we can hope there’s a less infectious strain out there But how? We are able to surveil only a tiny fraction of genomes, relative to strains circulating. How would a "less infectious strain" ever emerge to the extent we'd have a high probability of sampling it? Darwin argues against this version of the idea. Nevertheless, the OP is also wrong that it's faster to produce a live attenuated vaccine by finding one in the wild than it is to use tried-and-true viral vectors that are easy to reengineer, have previously received regulatory approval, and indeed are already in active trials (e.g. Oxford's adenoviral trial). It's also easier to trial heat-killed virus -- and indeed, that too is being trialed.
lvs 6y ago
Perhaps you should consider the arguments and disregard a superficial comparative analysis of our credentials.
- war1025 6y ago
  I don't know enough about any of it to consider arguments. I apologize for the probably overly snarky comment. I woke up in the middle of the night and was having a hard time falling back to sleep. I really wouldn't be surprised if the two of you are in more agreement than either of you realize. "Violent agreement" as I've sometimes heard it called. Also for the record, I didn't downvote you. Just provided my response of why I was inclined to believe the author over you.
- mythrwy 6y ago
  But....you went on the attack against the authors credentials in your top level post without apparently even reading them!

T-A 6y ago

> No evidence supports the hypothesis that single codon or single nucleotide deletions correlate with attenuation of strains https://www.mdpi.com/1999-4915/11/11/1016 https://www.mdpi.com/1999-4915/11/11/1016

lvs 6y ago
The citation does not refute or pertain to my statement. Yes, very specific mutations/indels can attenuate strains -- welcome to biology -- but the broad claim that the general observation of mutations/indels is somehow indicative of attenuated strains circulating in the wild is entirely unsupported and facially ridiculous.
- danieltillett 6y ago
  I am not claiming any of this. I am saying that the right type of mutations exist in the SARS-CoV-2 genomes that attenuated strains COULD exist. If they do I am arguing we should look for them rather than sitting in our armchairs coming up with possible reasons they don’t and so not even bothering.