7 ms·

> Intermediate versions have gone largely undetected, thus resulting in an exceptionally long branch leading to the most recent common ancestor (MRCA) of Omicro

> Intermediate versions have gone largely undetected, thus resulting in an exceptionally long branch leading to the most recent common ancestor (MRCA) of Omicron in the phylogenetic tree. We hereafter refer to this long branch as Branch O. > We found that mutations accumulated in ORF S at a rate of ∼0.45 mutations per month on average. In sharp contrast, 27 mutations accumulated in ORF S in Branch O during the 18 months spanning May 2020–November 2021, equivalent to ∼1.5 mutations per month, or ∼3.3 times faster than the average rate of other variants > We found that the Omicron spike protein sequence was subjected to stronger positive selection than that of any reported SARS-CoV-2 variants known to evolve persistently in human hosts, suggesting a possibility of host-jumping Although host jumping is undoubtedly occurring (eg infection has been serologically observed in white-tailed deer and other animals), I’m skeptical that it is the primary factor as this paper suggests. Another possibility is that viral mutation rates are underestimated, and/or infections are systematically underestimated. There is evidence of both in the literature. Combined with enhanced selective pressure on the spike protein RBD due to mass vaccination campaigns, these are scientifically supported alternative explanations for the observations in OP.

Scoundreller 5y ago
> Combined with enhanced selective pressure on the spike protein RBD due to mass vaccination campaigns Depends on the campaign. The major Chinese vaccines are “inactivated” and might pressure things differently than our spike-protein focussed viruses in the west. https://covid19.trackvaccines.org/country/china/ https://covid19.trackvaccines.org/country/china/
bunnie 5y ago
The science in the paper is fairly interesting. It observes that: 1) Certain types of mutations are favored by different host biologies. In other words, in humans, you would tend to see one type of coding substitution, in mice, pigs, bats, etc. you'd see another type of coding substitution. The paper gives specific mechanisms that underly this biases; I'm not an expert in these, so I can't say for sure if they are correct, but it the mechanisms as proposed make sense on a first read-through. 2) The early omicron variants have a set of mutations that would be consistent with evolution in a non-human host, overlapping most strongly with mice biology. 3) Perhaps even more significantly, _later_ omicron variants that have spread through human populations have picked up mutations that are once again more consistent with human biology. So the paper manages to show both positive and negative data toward their hypothesis, which makes it stronger. For the TL;DR crowd, figure 3 summarizes this pretty well. To analogize this in computer terms, it's as if someone was tracing the evolution of memes by observing the types of compression artifacts introduced in various re-compressions of the meme. For example, JPEG might introduce artifacts related to DCT math, whereas JPEG-2000 would introduce artifacts related to wavelet math. The analysis shows that the artifacts of this new Omicron meme has compression artifacts consistent with, say, Wavelet compression up until it jumped to being shared by JPEG-users, at which point newer modifications to the Omicron 'meme' show JPEG-consistent artifacts. That's basically the scientific core of the paper. So, to contest the validity of the paper, I think it would be helpful to find citations that dispute the observation that mutations accumulate with a certain bias based on the host biology, rather than whattaboutism pointing to other hypotheses and leaving it at "there are other alternative explanations" therefore this paper is not interesting. So, while I don't dispute your statement that there are other alternative explanations, what I would really like to see are comments addressing the core scientific thesis of the paper, which is that certain mutations appear more frequently in other host biologies; and that the first omicron cases showed a preponderance of these differently-biased mutations; and that since it has been circulating in humans, the later mutations are once again consistent with a human host. At the very least, I thought it was a very interesting analysis, as I had never seen the molecular bias of mutations used as a proxy for host biology before. If this is true, then viruses that can spread through alternate host biologies would gain a diversity of mutations that would be less available co-evolving with a single host, which could lead to evolutionary advantages over viruses that are unable to hop between hosts.
- AstralStorm 5y ago
  The bigger and more interesting question is whether it was originally in mice or it hopped from human to mouse and back. If SARS-COV-2 jumps this easily, well, we'll have serious problems predicting the mutations, a challenge for vaccine and drug design.
  - CorrectHorseBat 5y ago
    I don't think that anyone seriously questions that Omicron is a mutation of the original strain from Wuhan? So yes, if Omicron comes from mice it's a jump from humans to mice and back.
    - AstralStorm 5y ago
      Not necessarily. It could be same ancestral source or the mouse could have been the original vector, not the bats. Vector and mutation tracing is not an exact science, but a probability game - nobody catches all mice everywhere, or has access to all intermediate variants. Now, the origin in a different country does suggest a human host somewhere but it is not strictly necessary.
- criticaltinker 5y ago
  > dispute the observation that mutations accumulate with a certain bias based on the host biology To be clear that is not being disputed. IMO the central thesis of the paper is: > the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans That hypothesis is primarily supported by statistical evidence related to the frequency of certain amino acid mutations in the viral genome. For example: > Considering that these two amino acid mutations are uncommon in human patients infected by non-Omicron SARS-CoV-2 variants (0.005% and 0.002%, respectively) we proposed the hypothesis that the progenitor of Omicron evolved in mice. > searching against the GISAID database using Omicron’s backbone sequence. The top hits were again from the B.1.1 lineage, which differed from Omicron by 31 mutations, indicating that human SARS-CoV-2 variants reported to date could not provide a backbone for Omicron While the paper certainly presents intriguing preliminary evidence, critically there was no analysis performed which accounted for variation or underestimates in viral mutation rates, number of infected hosts, or gaps in genomic DBs, etc. As such, there are certain hidden assumptions that were not explicitly addressed or conclusively proven. Moreover, the "pleiotropic effect" is a significant confounding factor: > predictions showed that the adaptation of Omicron to mice also promoted its adaptation to other species, such as humans, camels, and goats, via stronger RBD-ACE2 interaction (Fig. 6). Such a “pleiotropic effect” of mutations was likely caused by structural similarity of ACE2 across species Finally, given that selective pressure due to mass distribution of S protein targeted vaccines was also not considered, I think it's fair to say that the evidence pointing to mice is fairly tenuous at this point. But the paper is still valid & interesting (I did not intend to suggest otherwise).
peterburkimsher 5y ago
Assumption 1: resonant frequency is correlated with physical size (where COVID is 0.1-0.5 = normal distribution around 0.3 µm) https://visualcapitalist.com/visualizing-relative-size-of-particles/ https://visualcapitalist.com/visualizing-relative-size-of-pa... Hypothesis 1: UV-C light at 300 nm can make the COVID dance itself to pieces. Hypothesis 2: UV-A or UV-B light at different wavelengths can cause mutations. Assumption 2: masks are COVID concentrators. They catch the droplets and virus particles so our lungs don't get it. Hypothesis 3: putting masks in environment leads to increased risk of mutations. Flies lick masks, bats eat flies, bats give us COVID again. Conclusion: pick up the COVID concentrators (masks) and put then in a biohazard bin. All people are responsible for all litter seen. We're only responsible for what we see, but we are personally responsible for everything we see.
- AstralStorm 5y ago
  I suppose we'll start giving everyone free biohazard bins when there's no place to store them, and handle them specially too. No, that's not going to happen. Biohazard disposal is expensive even for hospitals, and applying that to everyone... ruinous.
  - dasv 5y ago
    Eliminating the middle step could be an option, then: isn't biowaste incinerated after collection? Just tell people to set fire to their discarded masks, many people are carrying hydroalcoholic gel which is quite a convenient accelerant. Half kidding.
  - peterburkimsher 5y ago
    Not going to happen? It can easily happen at every bus stop. Will it be perfect? Of course not perfect. But better than nothing. Reduce the entropy a little, and then it'll be easier to handle. Handle them specially? I handled 122 masks in the car parks of Botany Town Centre, east Auckland, with bare hands yesterday, gathering them into a rubbish bag. Today I saw 180 COVID concentrator masks, and was able to pick up 136 of them (for the other 44 masks, I was on a bus or in a car and couldn't stop to get down) Putting masks into regular bins (e.g. landfill) will delay the feedback loop by 100 years. That's good enough for now, so that's my recommendation for those who don't have access to mask recycling. However, I do have access to mask recycling. My usual work is automated software testing and language translations for embedded systems, specifically the Fisher & Paykel Healthcare Airvo device. I've come to believe that we need to run an anti-virus algorithm on the world, and it's more efficient with a real-time distributed model, where we all love our neighbour by cleaning up what we see. https://en.wikipedia.org/wiki/Antivirus_software#Real-time_protection https://en.wikipedia.org/wiki/Antivirus_software#Real-time_p... Also, I'm triple-vaccinated (2x Pfizer + booster), am a young man with no family and a psychological martyrdom complex. I'll take the risk. And wash my hands thoroughly for 20 seconds afterwards. And shower when I get home. Be a tidy Kiwi. Clean as you go. Always leave the code (and world) better than you found it. (Robert C. Martin (Uncle Bob)) https://github.com/dwmkerr/hacker-laws#the-scout-rule https://github.com/dwmkerr/hacker-laws#the-scout-rule
mschuster91 5y ago
> Another possibility is that viral mutation rates are underestimated, and/or infections are systematically underestimated. What is especially underestimated is viral mutation in HIV-positive and other immunodeficient people. It is suspected [1] that Omicron may have been "bred" aka accumulated its mutations in the body of such a person in South Africa... and once again, the failure of the Western nations to provide access to medical service and at least basic wealth in Africa for decades - and that in general, not just in HIV treatment and prevention - bites us in the behinds here. As long as large swaths of the continent live in utter poverty and war, it will be a giant petri dish for all kinds of pathogens. [1]: https://www.npr.org/sections/goatsandsoda/2021/12/01/1055803031/the-mystery-of-where-omicron-came-from-and-why-it-matters https://www.npr.org/sections/goatsandsoda/2021/12/01/1055803...
- xxpor 5y ago
  Hard to make that argument when SA is one of (the?) wealthiest country in all of Africa, and they only have something like 35% vaccine uptake even though it's broadly available. Granted, SA has enormous wealth inequality issues for well known reasons, but blaming everything on the west for the situation there seems short sighted at best. One of the recent presidents was an AIDS denialist!
  - _djo_ 5y ago
    It’s not quite as simple as that. First, it’s not certain that Omicron emerged in South Africa, but in another nearby sub-Saharan African country without the same resources. All of South Africa’s neighbours with the exception of Botswana (which Moderna was making pay an eye-watering $30 per shot) are reliant on external aid for vaccination. So South Africa’s relative wealth is probably irrelevant here, and the argument about how insane the rich world’s refusal to help mass vaccinate the rest of the world is still applies. Second, South Africa only hit uptake constraints in the past month or so, until then it was affected by serious supply constraints like those other developing countries experienced, with the rich world getting production priority. Price, too, was a factor with pharmaceutical companies refusing to provide doses at anywhere close to their estimated actual cost. As a result money that the South African government could have spent on more vaccination outreach and infrastructure, especially in more rural and poor areas, was instead spent on buying doses. The long-standing supply constraints also meant that during a crucial time when public sentiment was more in favour of vaccination South Africa could not get enough doses to meet the demand and the delay allowed misinformation campaigns to wreak havoc. Had it been able to source enough supply in those crucial months, South Africa might have overcome a substantial portion of that hesitancy as people saw their friends, families, and colleagues get safely vaccinated. Third, there’s also a point to be made about the effect of predominantly American anti-vaccine misinformation on social networks, especially Facebook and YouTube, that has had a massive impact on South African society and the willingness of people to get vaccinated. Researchers have seen the same in other African countries. Not sure how that in particular can be solved or dealt with, but it needs to be taken into account when trying to understand global vaccine hesitancy.
phkahler 5y ago
>> Combined with enhanced selective pressure on the spike protein RBD due to mass vaccination campaigns, these are scientifically supported alternative explanations for the observations in OP. Gotta be careful saying stuff like that in places other than HN ;-) People freak out at the notion of vaccines driving the evolution of new strains.
- lamontcg 5y ago
  Of course prior host immunity drives immune escape, but this isn't isolated to vaccination and is expected with natural immunity as well. New variants are impossible to stop.

Scoundreller 5y ago

> Combined with enhanced selective pressure on the spike protein RBD due to mass vaccination campaigns Depends on the campaign. The major Chinese vaccines are “inactivated” and might pressure things differently than our spike-protein focussed viruses in the west. https://covid19.trackvaccines.org/country/china/ https://covid19.trackvaccines.org/country/china/

bunnie 5y ago

The science in the paper is fairly interesting. It observes that: 1) Certain types of mutations are favored by different host biologies. In other words, in humans, you would tend to see one type of coding substitution, in mice, pigs, bats, etc. you'd see another type of coding substitution. The paper gives specific mechanisms that underly this biases; I'm not an expert in these, so I can't say for sure if they are correct, but it the mechanisms as proposed make sense on a first read-through. 2) The early omicron variants have a set of mutations that would be consistent with evolution in a non-human host, overlapping most strongly with mice biology. 3) Perhaps even more significantly, _later_ omicron variants that have spread through human populations have picked up mutations that are once again more consistent with human biology. So the paper manages to show both positive and negative data toward their hypothesis, which makes it stronger. For the TL;DR crowd, figure 3 summarizes this pretty well. To analogize this in computer terms, it's as if someone was tracing the evolution of memes by observing the types of compression artifacts introduced in various re-compressions of the meme. For example, JPEG might introduce artifacts related to DCT math, whereas JPEG-2000 would introduce artifacts related to wavelet math. The analysis shows that the artifacts of this new Omicron meme has compression artifacts consistent with, say, Wavelet compression up until it jumped to being shared by JPEG-users, at which point newer modifications to the Omicron 'meme' show JPEG-consistent artifacts. That's basically the scientific core of the paper. So, to contest the validity of the paper, I think it would be helpful to find citations that dispute the observation that mutations accumulate with a certain bias based on the host biology, rather than whattaboutism pointing to other hypotheses and leaving it at "there are other alternative explanations" therefore this paper is not interesting. So, while I don't dispute your statement that there are other alternative explanations, what I would really like to see are comments addressing the core scientific thesis of the paper, which is that certain mutations appear more frequently in other host biologies; and that the first omicron cases showed a preponderance of these differently-biased mutations; and that since it has been circulating in humans, the later mutations are once again consistent with a human host. At the very least, I thought it was a very interesting analysis, as I had never seen the molecular bias of mutations used as a proxy for host biology before. If this is true, then viruses that can spread through alternate host biologies would gain a diversity of mutations that would be less available co-evolving with a single host, which could lead to evolutionary advantages over viruses that are unable to hop between hosts.

AstralStorm 5y ago
The bigger and more interesting question is whether it was originally in mice or it hopped from human to mouse and back. If SARS-COV-2 jumps this easily, well, we'll have serious problems predicting the mutations, a challenge for vaccine and drug design.
- CorrectHorseBat 5y ago
  I don't think that anyone seriously questions that Omicron is a mutation of the original strain from Wuhan? So yes, if Omicron comes from mice it's a jump from humans to mice and back.
  - AstralStorm 5y ago
    Not necessarily. It could be same ancestral source or the mouse could have been the original vector, not the bats. Vector and mutation tracing is not an exact science, but a probability game - nobody catches all mice everywhere, or has access to all intermediate variants. Now, the origin in a different country does suggest a human host somewhere but it is not strictly necessary.
criticaltinker 5y ago
> dispute the observation that mutations accumulate with a certain bias based on the host biology To be clear that is not being disputed. IMO the central thesis of the paper is: > the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans That hypothesis is primarily supported by statistical evidence related to the frequency of certain amino acid mutations in the viral genome. For example: > Considering that these two amino acid mutations are uncommon in human patients infected by non-Omicron SARS-CoV-2 variants (0.005% and 0.002%, respectively) we proposed the hypothesis that the progenitor of Omicron evolved in mice. > searching against the GISAID database using Omicron’s backbone sequence. The top hits were again from the B.1.1 lineage, which differed from Omicron by 31 mutations, indicating that human SARS-CoV-2 variants reported to date could not provide a backbone for Omicron While the paper certainly presents intriguing preliminary evidence, critically there was no analysis performed which accounted for variation or underestimates in viral mutation rates, number of infected hosts, or gaps in genomic DBs, etc. As such, there are certain hidden assumptions that were not explicitly addressed or conclusively proven. Moreover, the "pleiotropic effect" is a significant confounding factor: > predictions showed that the adaptation of Omicron to mice also promoted its adaptation to other species, such as humans, camels, and goats, via stronger RBD-ACE2 interaction (Fig. 6). Such a “pleiotropic effect” of mutations was likely caused by structural similarity of ACE2 across species Finally, given that selective pressure due to mass distribution of S protein targeted vaccines was also not considered, I think it's fair to say that the evidence pointing to mice is fairly tenuous at this point. But the paper is still valid & interesting (I did not intend to suggest otherwise).

peterburkimsher 5y ago

Assumption 1: resonant frequency is correlated with physical size (where COVID is 0.1-0.5 = normal distribution around 0.3 µm) https://visualcapitalist.com/visualizing-relative-size-of-particles/ https://visualcapitalist.com/visualizing-relative-size-of-pa... Hypothesis 1: UV-C light at 300 nm can make the COVID dance itself to pieces. Hypothesis 2: UV-A or UV-B light at different wavelengths can cause mutations. Assumption 2: masks are COVID concentrators. They catch the droplets and virus particles so our lungs don't get it. Hypothesis 3: putting masks in environment leads to increased risk of mutations. Flies lick masks, bats eat flies, bats give us COVID again. Conclusion: pick up the COVID concentrators (masks) and put then in a biohazard bin. All people are responsible for all litter seen. We're only responsible for what we see, but we are personally responsible for everything we see.

AstralStorm 5y ago
I suppose we'll start giving everyone free biohazard bins when there's no place to store them, and handle them specially too. No, that's not going to happen. Biohazard disposal is expensive even for hospitals, and applying that to everyone... ruinous.
- dasv 5y ago
  Eliminating the middle step could be an option, then: isn't biowaste incinerated after collection? Just tell people to set fire to their discarded masks, many people are carrying hydroalcoholic gel which is quite a convenient accelerant. Half kidding.
- peterburkimsher 5y ago
  Not going to happen? It can easily happen at every bus stop. Will it be perfect? Of course not perfect. But better than nothing. Reduce the entropy a little, and then it'll be easier to handle. Handle them specially? I handled 122 masks in the car parks of Botany Town Centre, east Auckland, with bare hands yesterday, gathering them into a rubbish bag. Today I saw 180 COVID concentrator masks, and was able to pick up 136 of them (for the other 44 masks, I was on a bus or in a car and couldn't stop to get down) Putting masks into regular bins (e.g. landfill) will delay the feedback loop by 100 years. That's good enough for now, so that's my recommendation for those who don't have access to mask recycling. However, I do have access to mask recycling. My usual work is automated software testing and language translations for embedded systems, specifically the Fisher & Paykel Healthcare Airvo device. I've come to believe that we need to run an anti-virus algorithm on the world, and it's more efficient with a real-time distributed model, where we all love our neighbour by cleaning up what we see. https://en.wikipedia.org/wiki/Antivirus_software#Real-time_protection https://en.wikipedia.org/wiki/Antivirus_software#Real-time_p... Also, I'm triple-vaccinated (2x Pfizer + booster), am a young man with no family and a psychological martyrdom complex. I'll take the risk. And wash my hands thoroughly for 20 seconds afterwards. And shower when I get home. Be a tidy Kiwi. Clean as you go. Always leave the code (and world) better than you found it. (Robert C. Martin (Uncle Bob)) https://github.com/dwmkerr/hacker-laws#the-scout-rule https://github.com/dwmkerr/hacker-laws#the-scout-rule

mschuster91 5y ago

> Another possibility is that viral mutation rates are underestimated, and/or infections are systematically underestimated. What is especially underestimated is viral mutation in HIV-positive and other immunodeficient people. It is suspected [1] that Omicron may have been "bred" aka accumulated its mutations in the body of such a person in South Africa... and once again, the failure of the Western nations to provide access to medical service and at least basic wealth in Africa for decades - and that in general, not just in HIV treatment and prevention - bites us in the behinds here. As long as large swaths of the continent live in utter poverty and war, it will be a giant petri dish for all kinds of pathogens. [1]: https://www.npr.org/sections/goatsandsoda/2021/12/01/1055803031/the-mystery-of-where-omicron-came-from-and-why-it-matters https://www.npr.org/sections/goatsandsoda/2021/12/01/1055803...

xxpor 5y ago
Hard to make that argument when SA is one of (the?) wealthiest country in all of Africa, and they only have something like 35% vaccine uptake even though it's broadly available. Granted, SA has enormous wealth inequality issues for well known reasons, but blaming everything on the west for the situation there seems short sighted at best. One of the recent presidents was an AIDS denialist!
- _djo_ 5y ago
  It’s not quite as simple as that. First, it’s not certain that Omicron emerged in South Africa, but in another nearby sub-Saharan African country without the same resources. All of South Africa’s neighbours with the exception of Botswana (which Moderna was making pay an eye-watering $30 per shot) are reliant on external aid for vaccination. So South Africa’s relative wealth is probably irrelevant here, and the argument about how insane the rich world’s refusal to help mass vaccinate the rest of the world is still applies. Second, South Africa only hit uptake constraints in the past month or so, until then it was affected by serious supply constraints like those other developing countries experienced, with the rich world getting production priority. Price, too, was a factor with pharmaceutical companies refusing to provide doses at anywhere close to their estimated actual cost. As a result money that the South African government could have spent on more vaccination outreach and infrastructure, especially in more rural and poor areas, was instead spent on buying doses. The long-standing supply constraints also meant that during a crucial time when public sentiment was more in favour of vaccination South Africa could not get enough doses to meet the demand and the delay allowed misinformation campaigns to wreak havoc. Had it been able to source enough supply in those crucial months, South Africa might have overcome a substantial portion of that hesitancy as people saw their friends, families, and colleagues get safely vaccinated. Third, there’s also a point to be made about the effect of predominantly American anti-vaccine misinformation on social networks, especially Facebook and YouTube, that has had a massive impact on South African society and the willingness of people to get vaccinated. Researchers have seen the same in other African countries. Not sure how that in particular can be solved or dealt with, but it needs to be taken into account when trying to understand global vaccine hesitancy.

phkahler 5y ago

>> Combined with enhanced selective pressure on the spike protein RBD due to mass vaccination campaigns, these are scientifically supported alternative explanations for the observations in OP. Gotta be careful saying stuff like that in places other than HN ;-) People freak out at the notion of vaccines driving the evolution of new strains.

lamontcg 5y ago
Of course prior host immunity drives immune escape, but this isn't isolated to vaccination and is expected with natural immunity as well. New variants are impossible to stop.