Answers.Body: <p>In summary, the authors are saying the complete opposite of "human intervention".</p>
  
  <blockquote>
    <p>While the analyses above suggest that SARS-CoV-2 may bind human ACE2
    with high affinity, computational analyses predict that the
    interaction is not ideal and that the RBD sequence is different from
    those shown in SARS-CoV to be optimal for receptor binding.</p>
  </blockquote>
  
  <p>The interaction with ACE2 is taking place on the Spike protein (S) in both COVID-19 and SARS-Cov. The S protein is very different between COVID-19 and SARS both in terms of sequence and COVID-19 includes an additional furin cleavage site, meaning structurally it is quite distinct. The "computational analysis predicts" is difficult because there is no crystal structure for COVID-19 S protein therefore modelling ligand binding is essentially guess work, particularly as it comprises an additional (furin) cleaved domain. What the authors appear to conclude is that they cannot map ACE2-Spike binding of COVID-19 using an established SARS S protein structure. I assume they are homology modelling SARS-CoV onto COVID-19 S protein sequence data.  In my personal opinion there is no way to homology model an additional furin protease cleavage site (furin is a host protease) so it would be difficult for "good fit" to occur, but it is just my opinion and the authors may have established methods to overcome this notable limitation, e.g. similar phenomena occur in influenza. </p>
  
  <blockquote>
    <p>Thus, the high-affinity binding of the SARS-CoV-2 spike protein to
    human ACE2 is most likely the result of natural selection..</p>
  </blockquote>
  
  <p>Their conclusion of "natural selection" is not strictly accurate and should be "Darwinian positive selection", but its a small issue. What they are saying is Darwinian adaptation has occurred as opposed to "purifying selection, i.e. conservation. Thus they are definitely excluding human intervention because that is not "natural selection"</p>
  
  <blockquote>
    <p>Furthermore, if genetic manipulation had been performed, one of the
    several reverse-genetic systems available for betacoronaviruses would
    probably have been used</p>
  </blockquote>
  
  <p>They appear to be saying that if a synthetic virus was constructed it would be created using an established reverse genetics system, and all those produced to date look nothing like COVID-19.</p>
  
  <p>The phylogenetics argument is always a stronger argument than either of the above (although my opinion isn't entirely objective).  Phylogeneticists have had a long history in opposing conspiracy theories, e.g. polio vaccination, HIV and the list goes on, so it is much more natural territory. An example of such an argument is <a href="https://bioinformatics.stackexchange.com/a/11306">here</a> which @terdon helpfully pointed out.</p>
  
  <hr>
  
  <p>To address the questions of @Hans</p>
  
  <p><strong>Question 1</strong></p>
  
  <ul>
  <li>Purifying selection = any evolutionary change is deleterious, so the virus is less able to transmit between humans. The vast majority of mutations are deleterious in classical Darwinian thinking*</li>
  <li>Adaptation = the amino acid change occurs to ensure the virus is better able to transmit between humans. In phylogenetics this is called 'positive selection' which is detected at a nucleotide level, this is however a very stringest test.</li>
  </ul>
  
  <p>*, There is something called nearly neutral theory, but thats just complicated</p>
  
  <hr>
  
  <p><strong>Question 2</strong></p>
  
  <p>What we are talking about is a virus infectious clone system. For a 30kb virus this would not be trival at all, but I agree for 10kb viruses it much easier. However, the phylogenetics are opposed to this, because SARS-CoV-2 is 5% divergent from a virus (RaTG13) isolated a long time before the current epidemic. You can't just engineer a virus that is 5% divergent from a bat virus across the entire genome and never been seen before. It would be a work of genius the likes we have never seen using bioinformatics as yet unheard of, because what would happen is you would encounter endless deleterious mutations. Even if you got over all those, how do you know what fitness traits you are aiming for?</p>
  
  <p><strong>Serial passage</strong> 
  This level of change is doable by serial passage of the virus, but this leads to attenuation of virus (less dangerous) not increased fitness. The yellow fever virus vaccine was created in this way. Even if a virus had been serially passaged we could tell, because we know the mutational patterns of other serially passaged viruses.</p>
  
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Answers.CreationDate: 2020-03-28T00:57:53.210Z
Answers.Text: Thank you @Michael. Meanwhile, I've found the following article, strongly opposing to the conclusions of the paper. I share the view of the author. What do you think about it? (And thank you for your time) https://harvardtothebighouse.com/2020/03/19/china-owns-nature-magazines-ass-debunking-the-proximal-origin-of-sars-cov-2-claiming-covid-19-wasnt-from-a-lab/
Answers.UserDisplayName: Lorenzo
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Answers.Text: @Lorenzo That article is pure, uninformed conspiracy theory codswallop. It presents zero evidence and presents highly implausible thought experiments as likely scenarios.
Answers.UserDisplayName: Konrad Rudolph
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Answers.CreationDate: 2020-03-28T19:37:28.747Z
Answers.Text: @Konrad ok, but throwing insults won't help anyone to understand. What do you think about what the author of the article says about the possibility that the virus was the result of induced natural selection "...scientists passed the H5N1 Bird Flu through a series of ferret hosts until it gained ACE2 affinity and then became incredibly virulent". I stress out POSSIBILITY, I'm not talking about "strong evidence".
Answers.UserDisplayName: Lorenzo
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Answers.CreationDate: 2020-03-29T11:39:23.247Z
Answers.Text: @Lorenzo You need to understand that there was no insult in my comment, but an entirely accurate, if somewhat exasperated, description of the contents of that website. It’s entirely possible to productively and intelligently discuss the plausibility (or lack thereof) of SARS-nCoV-2 being artificially engineered by that blog post cannot form part of such a discussion. Apart from that I have nothing to add to terdon’s comments, and this answer, which incidentally is written by an expert in the field (in contrast to you, me, and the authors of that blog post).
Answers.UserDisplayName: Konrad Rudolph
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Answers.Text: ... well someone looking to publish in this field (not an expert). I am backed by real experts (super experts). What I can say is that the spike protein is particularly weird in comparison to the RNA viruses I know, but thats not 'conspiracy theory', its just important yet difficult to understand.
Answers.UserDisplayName: M__
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Answers.CreationDate: 2020-03-29T16:03:07.367Z
Answers.Text: Thank you @Michael, and good work!
Answers.UserDisplayName: Lorenzo
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Answers.CreationDate: 2020-04-30T07:22:22.710Z
Answers.Text: 1) Could you please expand in details "What they are saying is Darwinian adaptation has occurred as opposed to 'purifying' selection, i.e. conservation."? How do you deduce "Thus they are definitely excluding human intervention because that is not 'natural selection' "?
  2) Why would not using an established reverse genetics system necessarily exclude genetic manipulation? Is this not premised on laziness or uncreativity of all possible perpetraters?
Answers.UserDisplayName: Hans
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Answers.Text: @KonradRudolph: But could you please refute in details the claim in that blog post that serial passages through animals would not only generate the efficient ACE2 binding affinity but also create the appearance of natural evolution/selection? 
  
  https://harvardtothebighouse.com/2020/03/19/china-owns-nature-magazines-ass-debunking-the-proximal-origin-of-sars- through animal hosts would generate thecov-2-claiming-covid-19-wasnt-from-a-lab/
Answers.UserDisplayName: Hans
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Answers.Text: Hi @Hans I've addressed your point below.
Answers.UserDisplayName: M__
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Answers.Text: Thank you, Michael. Let me ask you some followup questions. First, on serial passage. Why should serial passage always attenuate the virulence of a virus? Can we not artificially select for the virulence or affinity to say, the ACE2 receptor? Can you explicate the claim "Even if a virus had been serially passaged we could tell, because we know the mutational patterns of other serially passaged viruses." How is serially passed mutation different from that from "natural" evolution/selection?
Answers.UserDisplayName: Hans
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Answers.CreationDate: 2020-05-01T07:25:40.587Z
Answers.Text: This is a separatte question.
Answers.UserDisplayName: M__
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Answers.CreationDate: 2020-05-01T15:06:10.153Z
Answers.Text: What do you mean by "a separate question"? Is it not a question on your claim? Or do you mean it is a deeper question requiring more in-depth knowledge to answer? Could you please explicate?
Answers.UserDisplayName: Hans
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Answers.Text: Dear @Hans, okay I agree "a separate question on this site" wouldn't be in a format that this site would permit, because you are starting from a base of limited understanding. So lets just its complicated but doable.
Answers.UserDisplayName: M__
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Answers.CreationDate: 2020-05-01T17:49:33.967Z
Answers.Text: I understand. I will open a new question and invite you to answer. Would you be willing to share your knowledge there?
Answers.UserDisplayName: Hans
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Answers.Text: Hi @Hans it wouldn't work because you would need a base of technical understanding to open a question here. If you look at the number "closed" questions on the site, I think you get the idea. The site is traditionally for programmars/coders. This question is better for an alternative site such as biology stackexchange where it is more discursive. Please don't post it here.
Answers.UserDisplayName: M__
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Answers.CreationDate: 2020-05-01T18:31:16.753Z
Answers.Text: By "base of technical understanding" do you refer to the technical understanding of programming/coding/statistics or (evolutionary) biology? I have quite a reasonable amount of the former but little of the latter. You said the site was for programmer/coder, would it not be fit for me to post the question here? Or perhaps you meant to say my question was more biological related per se than programming/coding related, thus more suitable for biology.stackexchange than here. Which is a more accurate interpretation of your statement?
Answers.UserDisplayName: Hans
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Answers.Text: Dear @Hans, firstly my apologise if you're a coder, so welcome :-). However,  I am recommending your question is posted on an alternative site, because I think the question here would be closed and that would be frustrating for you, and biology stackexchange is in my opinion the correct site. Apologies again for the misunderstanding.
Answers.UserDisplayName: M__
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Answers.CreationDate: 2020-05-02T05:24:51.030Z
Answers.Text: No worries, dear Michael. Thank you for your welcome and suggestion. After browsing the questions on this site, I think you are right that this site deals more with statistics while my question is more concerned with the evolution theory. I have posted my question: https://biology.stackexchange.com/q/93152/8344. Would you care to give an answer there?
Answers.UserDisplayName: Hans
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Answers.Text: Michael, I just want to alert you to my question https://biology.stackexchange.com/q/93152/8344 in case you have not read my last comment. Would you be so kind as to provide an answer there?
Answers.UserDisplayName: Hans
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Answers.Text: Actually, I just recalled that I found a paper before demonstrating virulence gain of H5N1 influenza virus, specifically acquisition of airborne transmission capacity, after 10 series passage through ferrets https://science.sciencemag.org/content/336/6088/1534?fbclid=IwAR3gLlNFHuYbx_8mMgR93CPspMefJSvmOZa5knKKyJRWv4ImN0G_LuEyvjc . This seems to contradict your assertion regarding serial passage.
Answers.UserDisplayName: Hans
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Answers.Text: Here https://www.biorxiv.org/content/10.1101/2020.05.02.073411v1.full.pdf is another paper and result negating your assertion of virulence attenuation after serial passage.
Answers.UserDisplayName: Hans
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Answers.CreationDate: 2020-12-02T06:23:38.803Z
Answers.Text: serial passage could be for increase patogenicity... instead of get the virus strain that make live mouse (as selection natural), get the virus strain that kill mouse first or kill more youngs etc this each passage, so you have to cancell last paragraph
Answers.UserDisplayName: RosLuP
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Answers.Text: they found that sars2 is adapted as well as humans to a particular transgenic mouse with human ace2 gene and human immune system model... end discussion
Answers.UserDisplayName: RosLuP
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Answers.CreationDate: 2020-12-03T08:22:27.030Z
Answers.Text: Very interesting @RosLuP thanks
Answers.UserDisplayName: M__
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Answers.CreationDate: 2020-12-06T22:55:17.427Z
Answers.Text: @Michael  they found that 
  <<A massive heptapeptide sharing exists between SARS-CoV-2 spike glycoprotein and human proteins. Such a peptide commonality is unexpected and highly improbable from a mathematical point of view, given that, as detailed under the “Methods”>>
  in here https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499017/  and see the graph
  is very strange too the same number of peptide proteins in common with sars2 is found in "Mouse (Mus Musculus)"
  too... someone has said
Answers.UserDisplayName: RosLuP
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Answers.CreationDate: 2020-12-07T06:17:58.287Z
Answers.Text: Is it true that viruses adapt to the species they invade using also parts of protein that the host uses (e.g. to camouflage)?
Answers.UserDisplayName: RosLuP
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Answers.CreationDate: 2020-12-07T12:30:03.703Z
Answers.Text: if that is true, if exist Mouse "Mus Musculus" GMO with humans genes that are find in sars2... that mouse has the more big set of peptides in common with sars2 more than humans and all mouses...
Answers.UserDisplayName: RosLuP
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Answers.CreationDate: 2020-03-27T13:34:23.503Z
Answers.LastActivityDate: 2020-04-30T09:51:57.353Z
Answers.LastEditDate: 2020-04-30T09:51:57.353Z
Answers.UserDisplayName: M__
Body: <p>I don't have any background in genetics and bioinformatics, so I ask you if you think that the arguments provided in the article <a href="https://www.nature.com/articles/s41591-020-0820-9?fbclid=IwAR3KyrFty1XSXDsNrYcFfchr8ijK6qZeCria_y5VsAj-Oxdiei--fLOiviY" rel="nofollow noreferrer"><em>The proximal origin of SARS-CoV-2</em></a> by Andersen <em>et al.</em> are convincing. In particular:</p>
  
  <blockquote>
    <p><em>While the analyses above suggest that SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding. Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection...</em></p>
  </blockquote>
  
  <p>I interpret this passage as "if the virus had been engineered, they would have done a better job". Is this interpretation correct? And if it is, does it sound convincing to you as a proof that the virus developed in nature?</p>
  
  <p>The second motivation given in the article is the following:</p>
  
  <blockquote>
    <p><em>Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for betacoronaviruses would probably have been used</em></p>
  </blockquote>
  
  <p>Again, do you think that this exclude the possibility of a human intervention in the creation of the virus?</p>
  
  <p>Thank you for your opinions.</p>
  
  <p>Edit: I am a fan of Occam razor, I know that the scenario in which the virus originated in the wild is by far more likely than the human engineered scenario. I just want to know if, given our current knowledge in genetics, would have been possible for some high skilled researchers to engineered COVID19 (without implying that they did this with any bad purpose)?</p>
  
  <p>Edit 2: I share the concerns of the author of this post, that is, that the findings of the article are merely opinions and some of arguments are misleading. Anyone having a solid technical background can comment on this? <a href="https://harvardtothebighouse.com/2020/03/19/china-owns-nature-magazines-ass-debunking-the-proximal-origin-of-sars-cov-2-claiming-covid-19-wasnt-from-a-lab/" rel="nofollow noreferrer"><em>China owns Nature magazine’s ass – Debunking “The proximal origin of SARS-CoV-2” claiming COVID-19 definitely wasn’t from a lab</em></a></p>
  
Comments.ContentLicense: CC BY-SA 4.0
Comments.CreationDate: 2020-03-26T13:00:26.153Z
Comments.Text: Hi @Lorenzo , this is on-topic because of the ligand binding modelling, however could you add citations?
Comments.UserDisplayName: M__
Comments.ContentLicense: CC BY-SA 4.0
Comments.CreationDate: 2020-03-26T13:02:43.350Z
Comments.Text: Yes, the title of the article is in the question, you can find it here https://www.nature.com/articles/s41591-020-0820-9?fbclid=IwAR3KyrFty1XSXDsNrYcFfchr8ijK6qZeCria_y5VsAj-Oxdiei--fLOiviY
Comments.UserDisplayName: Lorenzo
Comments.ContentLicense: CC BY-SA 4.0
Comments.CreationDate: 2020-03-26T13:47:05.823Z
Comments.Text: Please read @Michael's excellent answer here: [Is it possible for coronavirus or SARS to be synthetic?](//bioinformatics.stackexchange.com/a/11306). I think that might even be essentially a duplicate of your question. And yes, if we were to actually try and make this, we could do a better job. But that is only one of many reasons why it isn't reasonable to believe that this virus has been manufactured, as explained in the answer I link to.
Comments.UserDisplayName: terdon
Comments.ContentLicense: CC BY-SA 4.0
Comments.CreationDate: 2020-03-26T13:47:20.717Z
Comments.Text: Does this answer your question? [Is it possible for coronavirus or SARS to be synthetic?](https://bioinformatics.stackexchange.com/questions/11301/is-it-possible-for-coronavirus-or-sars-to-be-synthetic)
Comments.UserDisplayName: terdon
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Comments.CreationDate: 2020-03-26T13:48:59.857Z
Comments.Text: @Michael I would like to know if the content of the article excludes possible conspiracy theories with more valid arguments than "human intervention is conspiracy theory". I really want to understand the strenght of the arguments of the author
Comments.UserDisplayName: Lorenzo
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Comments.CreationDate: 2020-03-26T14:24:02.267Z
Comments.Text: @terdon, no it doesn't but you did address my questions. "And yes, if we were to actually try and make this, we could do a better job". I assume that if someone can do a "better" job, it is true that the virus could have been created in a lab.
Comments.UserDisplayName: Lorenzo
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Comments.CreationDate: 2020-03-26T15:31:13.377Z
Comments.Text: @Lorenzo created? No. But yes, it is possible to _modify_ existing viruses, and the point made in the paragraph you quote is that if this _had_ been modified, if it _had_ been engineered from another virus, then it would have been more efficient. But the main reasons we can safely conclude this is not a man-made virus are nicely outlined in Michael's answer. If your question is generally about whether "man-made" viruses are possible and what, exactly, would "man-made" even mean in this context, then please as a new one without referencing SARS-Cov-19.
Comments.UserDisplayName: terdon
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Comments.CreationDate: 2020-12-01T22:41:11.703Z
Comments.Text: sars2 was the result of serial passage with gmo mouse has human ace2 and human immune sys model
Comments.UserDisplayName: RosLuP
Tags: <phylogenetics><phylogeny><covid-19><sars-cov-2>
Title: Are the conclusions in "The proximal origin of SARS-CoV-2" legit?
ThreadText: # Are the conclusions in "The proximal origin of SARS-CoV-2" legit?
  
  (Asked by: username_0 on 2020-03-26)
  
  I don't have any background in genetics and bioinformatics, so I ask you if you think that the arguments provided in the article [*The proximal origin of SARS-CoV-2*](https://www.nature.com/articles/s41591-020-0820-9?fbclid=IwAR3KyrFty1XSXDsNrYcFfchr8ijK6qZeCria_y5VsAj-Oxdiei--fLOiviY) by Andersen *et al.* are convincing. In particular:
  
  > *While the analyses above suggest that SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding. Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection...*
  
  I interpret this passage as "if the virus had been engineered, they would have done a better job". Is this interpretation correct? And if it is, does it sound convincing to you as a proof that the virus developed in nature?
  
  The second motivation given in the article is the following:
  
  > *Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for betacoronaviruses would probably have been used*
  
  Again, do you think that this exclude the possibility of a human intervention in the creation of the virus?
  
  Thank you for your opinions.
  
  Edit: I am a fan of Occam razor, I know that the scenario in which the virus originated in the wild is by far more likely than the human engineered scenario. I just want to know if, given our current knowledge in genetics, would have been possible for some high skilled researchers to engineered COVID19 (without implying that they did this with any bad purpose)?
  
  Edit 2: I share the concerns of the author of this post, that is, that the findings of the article are merely opinions and some of arguments are misleading. Anyone having a solid technical background can comment on this? [*China owns Nature magazine’s ass – Debunking “The proximal origin of SARS-CoV-2” claiming COVID-19 definitely wasn’t from a lab*](https://harvardtothebighouse.com/2020/03/19/china-owns-nature-magazines-ass-debunking-the-proximal-origin-of-sars-cov-2-claiming-covid-19-wasnt-from-a-lab/)
  
  **Tags:** phylogenetics, phylogeny, covid-19, sars-cov-2
  
  > **Comments:**
  > **username_1**: Hi @username_0 , this is on-topic because of the ligand binding modelling, however could you add citations?  
  > **username_0**: Yes, the title of the article is in the question, you can find it here https://www.nature.com/articles/s41591-020-0820-9?fbclid=IwAR3KyrFty1XSXDsNrYcFfchr8ijK6qZeCria_y5VsAj-Oxdiei--fLOiviY  
  > **username_2**: Please read @Michael's excellent answer here: [Is it possible for coronavirus or SARS to be synthetic?](//bioinformatics.stackexchange.com/a/11306). I think that might even be essentially a duplicate of your question. And yes, if we were to actually try and make this, we could do a better job. But that is only one of many reasons why it isn't reasonable to believe that this virus has been manufactured, as explained in the answer I link to.  
  > **username_2**: Does this answer your question? [Is it possible for coronavirus or SARS to be synthetic?](https://bioinformatics.stackexchange.com/questions/11301/is-it-possible-for-coronavirus-or-sars-to-be-synthetic)  
  > **username_0**: @Michael I would like to know if the content of the article excludes possible conspiracy theories with more valid arguments than "human intervention is conspiracy theory". I really want to understand the strenght of the arguments of the author  
  > **username_0**: @username_2, no it doesn't but you did address my questions. "And yes, if we were to actually try and make this, we could do a better job". I assume that if someone can do a "better" job, it is true that the virus could have been created in a lab.  
  > **username_2**: @username_0 created? No. But yes, it is possible to _modify_ existing viruses, and the point made in the paragraph you quote is that if this _had_ been modified, if it _had_ been engineered from another virus, then it would have been more efficient. But the main reasons we can safely conclude this is not a man-made virus are nicely outlined in Michael's answer. If your question is generally about whether "man-made" viruses are possible and what, exactly, would "man-made" even mean in this context, then please as a new one without referencing SARS-Cov-19.  
  > **username_3**: sars2 was the result of serial passage with gmo mouse has human ace2 and human immune sys model  
  
  ---
  
  ## 1 answers
  
  ### Answer by username_1 on 2020-03-27. Score: 4 | Accepted answer
  
  In summary, the authors are saying the complete opposite of "human intervention".
  
  > While the analyses above suggest that SARS-CoV-2 may bind human ACE2
  > with high affinity, computational analyses predict that the
  > interaction is not ideal and that the RBD sequence is different from
  > those shown in SARS-CoV to be optimal for receptor binding.
  
  The interaction with ACE2 is taking place on the Spike protein (S) in both COVID-19 and SARS-Cov. The S protein is very different between COVID-19 and SARS both in terms of sequence and COVID-19 includes an additional furin cleavage site, meaning structurally it is quite distinct. The "computational analysis predicts" is difficult because there is no crystal structure for COVID-19 S protein therefore modelling ligand binding is essentially guess work, particularly as it comprises an additional (furin) cleaved domain. What the authors appear to conclude is that they cannot map ACE2-Spike binding of COVID-19 using an established SARS S protein structure. I assume they are homology modelling SARS-CoV onto COVID-19 S protein sequence data. In my personal opinion there is no way to homology model an additional furin protease cleavage site (furin is a host protease) so it would be difficult for "good fit" to occur, but it is just my opinion and the authors may have established methods to overcome this notable limitation, e.g. similar phenomena occur in influenza.
  
  > Thus, the high-affinity binding of the SARS-CoV-2 spike protein to
  > human ACE2 is most likely the result of natural selection..
  
  Their conclusion of "natural selection" is not strictly accurate and should be "Darwinian positive selection", but its a small issue. What they are saying is Darwinian adaptation has occurred as opposed to "purifying selection, i.e. conservation. Thus they are definitely excluding human intervention because that is not "natural selection"
  
  > Furthermore, if genetic manipulation had been performed, one of the
  > several reverse-genetic systems available for betacoronaviruses would
  > probably have been used
  
  They appear to be saying that if a synthetic virus was constructed it would be created using an established reverse genetics system, and all those produced to date look nothing like COVID-19.
  
  The phylogenetics argument is always a stronger argument than either of the above (although my opinion isn't entirely objective). Phylogeneticists have had a long history in opposing conspiracy theories, e.g. polio vaccination, HIV and the list goes on, so it is much more natural territory. An example of such an argument is [here](https://bioinformatics.stackexchange.com/a/11306) which @username_2 helpfully pointed out.
  
  ---
  
  To address the questions of @username_5
  
  **Question 1**
  
  * Purifying selection = any evolutionary change is deleterious, so the virus is less able to transmit between humans. The vast majority of mutations are deleterious in classical Darwinian thinking\*
  * Adaptation = the amino acid change occurs to ensure the virus is better able to transmit between humans. In phylogenetics this is called 'positive selection' which is detected at a nucleotide level, this is however a very stringest test.
  
  \*, There is something called nearly neutral theory, but thats just complicated
  
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  **Question 2**
  
  What we are talking about is a virus infectious clone system. For a 30kb virus this would not be trival at all, but I agree for 10kb viruses it much easier. However, the phylogenetics are opposed to this, because SARS-CoV-2 is 5% divergent from a virus (RaTG13) isolated a long time before the current epidemic. You can't just engineer a virus that is 5% divergent from a bat virus across the entire genome and never been seen before. It would be a work of genius the likes we have never seen using bioinformatics as yet unheard of, because what would happen is you would encounter endless deleterious mutations. Even if you got over all those, how do you know what fitness traits you are aiming for?
  
  **Serial passage**
  This level of change is doable by serial passage of the virus, but this leads to attenuation of virus (less dangerous) not increased fitness. The yellow fever virus vaccine was created in this way. Even if a virus had been serially passaged we could tell, because we know the mutational patterns of other serially passaged viruses.
  
  > **Comments:**
  > **username_0**: Thank you @Michael. Meanwhile, I've found the following article, strongly opposing to the conclusions of the paper. I share the view of the author. What do you think about it? (And thank you for your time) https://harvardtothebighouse.com/2020/03/19/china-owns-nature-magazines-ass-debunking-the-proximal-origin-of-sars-cov-2-claiming-covid-19-wasnt-from-a-lab/  
  > **username_4**: @username_0 That article is pure, uninformed conspiracy theory codswallop. It presents zero evidence and presents highly implausible thought experiments as likely scenarios.  
  > **username_0**: @username_4 ok, but throwing insults won't help anyone to understand. What do you think about what the author of the article says about the possibility that the virus was the result of induced natural selection "...scientists passed the H5N1 Bird Flu through a series of ferret hosts until it gained ACE2 affinity and then became incredibly virulent". I stress out POSSIBILITY, I'm not talking about "strong evidence".  
  > **username_4**: @username_0 You need to understand that there was no insult in my comment, but an entirely accurate, if somewhat exasperated, description of the contents of that website. It’s entirely possible to productively and intelligently discuss the plausibility (or lack thereof) of SARS-nCoV-2 being artificially engineered by that blog post cannot form part of such a discussion. Apart from that I have nothing to add to username_2’s comments, and this answer, which incidentally is written by an expert in the field (in contrast to you, me, and the authors of that blog post).  
  > **username_1**: ... well someone looking to publish in this field (not an expert). I am backed by real experts (super experts). What I can say is that the spike protein is particularly weird in comparison to the RNA viruses I know, but thats not 'conspiracy theory', its just important yet difficult to understand.  
  > **username_0**: Thank you @Michael, and good work!  
  > **username_5**: 1) Could you please expand in details "What they are saying is Darwinian adaptation has occurred as opposed to 'purifying' selection, i.e. conservation."? How do you deduce "Thus they are definitely excluding human intervention because that is not 'natural selection' "? 2) Why would not using an established reverse genetics system necessarily exclude genetic manipulation? Is this not premised on laziness or uncreativity of all possible perpetraters?  
  > **username_5**: @username_4: But could you please refute in details the claim in that blog post that serial passages through animals would not only generate the efficient ACE2 binding affinity but also create the appearance of natural evolution/selection?   https://harvardtothebighouse.com/2020/03/19/china-owns-nature-magazines-ass-debunking-the-proximal-origin-of-sars- through animal hosts would generate thecov-2-claiming-covid-19-wasnt-from-a-lab/  
  > **username_1**: Hi @username_5 I've addressed your point below.  
  > **username_5**: Thank you, Michael. Let me ask you some followup questions. First, on serial passage. Why should serial passage always attenuate the virulence of a virus? Can we not artificially select for the virulence or affinity to say, the ACE2 receptor? Can you explicate the claim "Even if a virus had been serially passaged we could tell, because we know the mutational patterns of other serially passaged viruses." How is serially passed mutation different from that from "natural" evolution/selection?  
  > **username_1**: This is a separatte question.  
  > **username_5**: What do you mean by "a separate question"? Is it not a question on your claim? Or do you mean it is a deeper question requiring more in-depth knowledge to answer? Could you please explicate?  
  > **username_1**: Dear @username_5, okay I agree "a separate question on this site" wouldn't be in a format that this site would permit, because you are starting from a base of limited understanding. So lets just its complicated but doable.  
  > **username_5**: I understand. I will open a new question and invite you to answer. Would you be willing to share your knowledge there?  
  > **username_1**: Hi @username_5 it wouldn't work because you would need a base of technical understanding to open a question here. If you look at the number "closed" questions on the site, I think you get the idea. The site is traditionally for programmars/coders. This question is better for an alternative site such as biology stackexchange where it is more discursive. Please don't post it here.  
  > **username_5**: By "base of technical understanding" do you refer to the technical understanding of programming/coding/statistics or (evolutionary) biology? I have quite a reasonable amount of the former but little of the latter. You said the site was for programmer/coder, would it not be fit for me to post the question here? Or perhaps you meant to say my question was more biological related per se than programming/coding related, thus more suitable for biology.stackexchange than here. Which is a more accurate interpretation of your statement?  
  > **username_1**: Dear @username_5, firstly my apologise if you're a coder, so welcome :-). However,  I am recommending your question is posted on an alternative site, because I think the question here would be closed and that would be frustrating for you, and biology stackexchange is in my opinion the correct site. Apologies again for the misunderstanding.  
  > **username_5**: No worries, dear Michael. Thank you for your welcome and suggestion. After browsing the questions on this site, I think you are right that this site deals more with statistics while my question is more concerned with the evolution theory. I have posted my question: https://biology.stackexchange.com/q/93152/8344. Would you care to give an answer there?  
  > **username_5**: Michael, I just want to alert you to my question https://biology.stackexchange.com/q/93152/8344 in case you have not read my last comment. Would you be so kind as to provide an answer there?  
  > **username_5**: Actually, I just recalled that I found a paper before demonstrating virulence gain of H5N1 influenza virus, specifically acquisition of airborne transmission capacity, after 10 series passage through ferrets https://science.sciencemag.org/content/336/6088/1534?fbclid=IwAR3gLlNFHuYbx_8mMgR93CPspMefJSvmOZa5knKKyJRWv4ImN0G_LuEyvjc . This seems to contradict your assertion regarding serial passage.  
  > **username_5**: Here https://www.biorxiv.org/content/10.1101/2020.05.02.073411v1.full.pdf is another paper and result negating your assertion of virulence attenuation after serial passage.  
  > **username_3**: serial passage could be for increase patogenicity... instead of get the virus strain that make live mouse (as selection natural), get the virus strain that kill mouse first or kill more youngs etc this each passage, so you have to cancell last paragraph  
  > **username_3**: they found that sars2 is adapted as well as humans to a particular transgenic mouse with human ace2 gene and human immune system model... end discussion  
  > **username_1**: Very interesting @username_3 thanks  
  > **username_3**: @Michael  they found that  <<A massive heptapeptide sharing exists between SARS-CoV-2 spike glycoprotein and human proteins. Such a peptide commonality is unexpected and highly improbable from a mathematical point of view, given that, as detailed under the “Methods”>> in here https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499017/  and see the graph is very strange too the same number of peptide proteins in common with sars2 is found in "Mouse (Mus Musculus)" too... someone has said  
  > **username_3**: Is it true that viruses adapt to the species they invade using also parts of protein that the host uses (e.g. to camouflage)?  
  > **username_3**: if that is true, if exist Mouse "Mus Musculus" GMO with humans genes that are find in sars2... that mouse has the more big set of peptides in common with sars2 more than humans and all mouses...  
  
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