low rate of homologous recombination in negative sense RNA viruses
Monotreme:
I suppose I could agree to that. If that’s what it takes to keep the peace around here.
Seriously, I never actually objected to the idea of a mammalian reservoir, and speculating that the virus may be perking away unnoticed in some mammalian backwater certainly seems no less reasonable than speculating that pockets of human susceptibility may be quietly awaiting its arrival.
Anon_22:
We aren’t going to out-evolve this thing, that’s for sure. The good news is that we have already evolved some rapid-response mechanisms that give at least some of us a decent chance of beating it, just as at least some of us have beaten everything our microbial adversaries have ever managed to come up with. I’m not planning on actually needing any of that, of course — I’m planning to stay out of the bug’s crosshairs altogether.
we might try to out-evolve this thing with our larger genome, if we would
consider it important. You can’t do so many tricks with 13000 nucleotides
as you can do counter-tricks with 3 billion nucleotides.
In the computers analogy the operating system can beat viruses,
with a virus scanner.
But then, “it’s only influenza” as John Barry uses to say
and human genome has lots of other things to do.
Another possibility is to use our brain and vaccines or nanotechnology
to outperform evolution.
the monotreme-article costs $30 and bureaucratic efforts.
how about a H5N1 reservoir in insects ?
there once was a blowfly from Japan
who flew as fast as fly can
from Japan to Korea
then Indonesia
bringing flu from bird to man
ask niman about this “dead flies don’t fly”-nonsense.
Here’s the article anonymous is complaining about:
Just found this paper and haven’t had time to read the whole thing, but some interesting excerpts from the abstract below:
Evolution and adaptation of H5N1 influenza virus in avian and human hosts in Indonesia and Vietnam
Here, we genetically characterize 82 H5N1 viruses isolated from poultry throughout Indonesia and Vietnam and 11 human isolates from southern Vietnam together with sequence data available in public databases to address questions relevant to virus introduction, endemicity and evolution.
[snip]
Within Indonesia and Vietnam, H5N1 viruses have evolved over time into geographically distinct groups within each country. Molecular analysis of the H5N1 genotype Z genome shows that only the M2 and PB1-F2 genes were under positive selection, suggesting that these genes might be involved in adaptation of this virus to new hosts following interspecies transmission. At the amino acid level 12 residues were under positive selection in those genotype Z viruses, in the HA and PB1-F2 proteins. Some of these residues were more frequently observed in human isolates than in avian isolates and are related to viral antigenicity and receptor binding.
{Meant to bold the unbolded text for Racter’s attention.) Fixed - anon_22
in general it seems that H5N1-viruses do evolve more in China than in Vietnam or Indonesia and the wide-spread Qinghai-strain evolves very slowly.
anonymous. I think you should gave tagged ‘for now’ after your statement at 7:43.
Monotreme. I wonder how your observation (that H5N1 is more efficient in H-H transmission now then in B-H) fits into your positive selective pressure from an unknown tertiary mammal argument.
Could Humans be the unknown teriatry mammal in yet unknown pockets of genetic susceptibility (per Racter)?
As for the University of Hong Kong study:
As soon as the virus manages to infect a human host, selective pressures change immediately. That we begin to observe changes after the virus has passed through only a handful of hosts is disturbing, but not surprising. Of particular interest is the rate of change, and the loci of the changes, but, as we have observed, the ultimate proof of this pudding will be in the eating.
I always like to keep in mind what a distinct privilege it is to be among the tiny fraction, of all the humans who’ve ever lived on earth, to have a ringside seat for such an event — the danger notwithstanding. It’s a bit like a close encounter with a tornado; terrifying, but fascinating; perhaps even beautiful in its own way. A great many individual lifetimes have been devoted developing the tools that enable us to make the observations we’re making, and to bringing our theoretical understanding of these matters to a point where we can chat about them as casually as we might the outcomes of the weekend’s baseball games, all the while slinging concepts around that would have flabergasted the world’s leading theorists of only a few generations ago, the very ones who laid the foundations we stand upon.
We few; we happy few; we band of flubies.
Racter at 12:47: I have thought “it”, but not near that well! Kudos.
Now that our arms are tired from patting ourselves on the back, let’s get back to all this deep thinking so we can
Gather and solve.
Racter and Monotreme-
Are there clear studies that any of you can quote that will show definitely similar rates of genetic acquisition in the lab and in the wild, on influenza or any other organism?
We’ve had tagging programs on many host species for 50–80 years, so I’d expect some studies to have been conducted?
NS1: Thousands of scientists have already gathered to determine the influenza mutation rate. The problem is solved. It’s high. See my first series of posts on the first thread for references. In vitro, phylogenetic studies and animal experiments all yield the same result: influenza viruses mutate at a high rate.
I highly recomend this blog, by Dr. Tara Smith (hat tip to revere at Effect Measure). It discusses the evolution of H5N1 very clearly. She also alludes to a heated discussion with HIV deniers who want to dismiss the importance of that virus in AIDS. Apparently they doubt that HIV has a high mutation rate - sound familiar?
It should be noted that the Theory of Recombinomics is apparently also applied to HIV.
Viruses are generally thought to evolve via shifting and drifting. Shifting occurs when viruses swap genes and drifting was thought to be due to a steady accumulation of mutations.
However, rapidly evolving viruses simply recycle old mutations via recombination. This method is much more efficient and follows specific rules. These rules appear to be followed by all viruses, including influenza, HIV, SARS, WNV. These rules allow vaccines to be prepared before viruses emerge. [-From Recombinomics - Paradigm Shift
Now, I don’t want to discourage anyone from believing in the Theory of Recombinomics, if they want to. Just understand what you’re signing up for. If you believe in this Theory, not only are all influenza scientists incompetent fools, but so are all HIV researchers. And everything we know about how all viruses evolve is wrong. If you really believe that, well, no amount of citations I provide are going to convince you.
Somehow, I don’t think alot of backpatting is coming my way.
Tom DVM – at 08:59
Could Humans be the unknown teriatry mammal in yet unknown pockets of genetic susceptibility (per Racter)?
This is possible, but no evidence for it and some evidence against it. The seroprevalence studies that have been done have not found any hidden human reservoir of asymptomatic carriers. OTOH, the few mammalian surveys that have been done have found infected mammals. My suspicion is that if they looked harder they’d find more, much more.
Monotreme. I agree. Where do we sign up to answer the question…the Chinese Embassy?
Why not birds to pigs to birds to pigs to birds etc.
Dude. Your hypothesis is entirely possible but my experience tells me it is too obvious…much in the same way that genetics alone caused the Karo cluster.
Nature is usually a little more subtle or sneaky. Like SARS it will be an obscure source but I would start with bats, mice, rats, cats and shoreline mammals as domestic livestock…somewhere in this group is the answer.
Sorry, should have read…as well as domestic livestock.
Tom DVM at 23:50
Where do we sign up to answer the question…the Chinese Embassy?
Well, first I’d ask the Chinese scientists who retracted all of these pig H5N1 sequences from GenBank why they did it.
Dude – at 23:56
Why not birds to pigs to birds to pigs to birds etc.
Possible. The only problem with this is that if the virus is adapted to birds it’s not going to do very well in mammals and vice versa. But there could be one out of the gazillion species of birds that could harbor mammalian adapted virus. The question is: which one?
Monotreme-
Expect a lot of backpatting from all of us.
I’m encouraged that you are pursuing this intellectual question with great vehemence.
When you say animal experiments are you indicating laboratory experiments or tagging and sampling wild animals?
In either case, in the animal studies have you noted any significant outliers in speed, faster or slower, and in what percentage of the total samples?
Brant geese, wood ducks and common flies.
Being totally ignorant of most wildlife, can anyone tell me if birds suffer with tics or fleas? gina
They get mites but never heard of them having ticks or fleas.
Pigs have both receptors - avian and mammal (human). Tom: Sometimes the most obvious solution is the most obvious solution. I would love to see extensive studies with current data. I even suggested on one thread that we form a company and go into an area and buy up a sample of the pigs, geese, ducks, etc. in a village that has an outbreak and do our own studies. How much could it cost?
If we are looking for an intermediate host (if one is really required), warm blooded animals suffer from mites as well. My thought is to start small and work my way up. Just looking for basic links between cold and warm blooded animals. gina
bump
bumpII
Birds suffer from a number of parasitic infestations including lice - tics infect most wrm blooded animals and are very wide spread - if they were a vector i would suspect we would be seeing a lot more spread of H5N1
Much earlier in this thread, the 1950 vs. 1997 “problem,” was discussed, i.e. how could a virus remain inactive for 27 years, then re-emerge? Scientists believe the virus had been frozen and that an actual freezer was the most likely source. What about receding glaciers? Could viruses be frozen in a glacier, then be thawed when the glacier receded in spring, refrozen when the glacier advanced in winter, etc? Re: 1918 and the unknown source…Could a glacier or glaciers have receded more that year than in previous years, uncovering a previously frozen virus? Could global warming now be a contributor, i.e. if glaciers are retreating more and advancing less in each cycle, could this leave viruses “exposed?” I just saw “An Inconvenient Truth”--maybe I’m just hypersensitive to global warming right now, but this just seems to make sense.
Also, I just recovered from a case of laryngotracheitis (croup), a herpes virus that infects both birds and humans. No one that I know of (human) had this virus before or after I did (within any reasonable incubation period), but my daily dog walk includes a roughly 100-ft. stretch of sidewalk beneath telephone and electric wires that double as bird perches, as evidenced by the amount of bird feces on the sidewalk. Hmmmm…. I’m walking the dog in the street now. But my question is: Could this herpes virus and the H5N1 virus exchange genetic sequences in birds?
NS1, thanks for your gracious reply. I am encouraged that we can discuss this contentious subject and still be civil.
In terms of “tagging” a virus and letting it loose in the wild and following, that’s a neat idea, but would be hard to implement. Any artificial “tag” radioactive, fluorescent, etc. would quickly be diluted after a few rounds of replication. There are however, sequence tags. The strategy is to take a specific mutant, with only one difference from the normal strain, and measure how fast it changes after infecting an animal. This was done way back in 1988. Here is the reference:
L and H2 mutants of the A/NJ/11/76 H1N1 strain of swine influenza virus differ by having either a lysine or a glutamic acid at position 153 of the hemagglutinin glycoprotein of the virus. In two separate experiments, experimental infection of swine with various doses of the H2 mutant resulted in the emergence in 11 of 20 animals of virus with the L phenotype. All evidence indicates that the H2----L mutation, selection, and evolution to predominance occurred within the 7-day span of individual infections.
Mutations are acquired at different rates. There is alot of discussion regarding mutator strains, strains that mutate more rapidly than others, presumably due to differences in the polymerase complex. In addition, because mutations are random events, they do not occur at predictable intervals, if they did, they wouldn’t be random ;-) So, we can’t just count Missippi’s and expect mutations to occur on every 5th one. It’s more like gambling. Each game has a well-defined rate of “winning”. Although this percentage always favors the House, someone may have a “lucky streak” that appears to defy these odds. However, if they keep playing long enough, and they usually do, eventually their performance will match the predicted odds and they will go home poorer. So, onc cannot predict that a mutation will occur in a specific interval, but one can predict that over a long period of time X mutations will occur.
SoCal, expeditions went looking for bodies that had been buried in permafrost regions of the world in order to find live 1918 virus. There was alot of speculation about the dangers of this. No live virus was found, although viral fragments were found that contributed to our understanding of this virus. Repeated freeze-thawing would be very bad for a virus.
There are many herpes viruses. I don’t know which one you are referring to. However, I doubt very much that influenza could exchange genetic segments with the herpes viruses I am familiar with. They are completely different types of virus.
dr Kockosh:
I agree.
I can distinctly recall reading an article discussing the fact that influenza virus is unable to survive exposure to digestive enzymes in the gut of a mosquito — but I haven’t had any luck finding it again. It could be because I distinctly remember wrong, but if not, the same would likely apply to other blood-suckers, and might help to explain why influenza is not a vector-borne pathogen (the fact that it almost never infects blood helps too).
Does anyone have any idea what parasitic infestations are shared by both warm and cold blooded animals? This could also be a good question for Tom.
Hi Gina. I am not an expert on all animal species but I am not aware of any parasites shared by warm and cold-blooded animals.
schistosomaisis
To come back on the subject of mutation in the virus, I was wondering if we could re-read the article on mutations of the H7N7 virus in The Netherlands, as well as what is not said in the United Kingdom DEFRA report on H7N3 and draw some ideas from them…
Sorry if this post is very long, I find it difficult, with the abundance of information, to write very concisely.
I think there are a number of questions raised by the UK DEFRA report Report which was published today. I made a post in the thread entitled News Reports July 11th. The report, at first glance, looks very complete, well done, as expected from a Government agency. It is what would be expected in an industrialised country, with good medical/veterinary science, good report writers, etc. Yet, the more I read it over and over, the more unease I feel, at things that are not mentioned in this report. It keeps going around in my mind, awakening distant reading of other studies/reports on similar subjects, without my being able, for lack of expertise in the subject, to pinpoint what is wrong or missing in the DEFRA report. I would like Fluwikians to make additional observations on this report and try to fill in my blanks or understatements, because I think it’s going to be more and more important to have the ability to read between the lines of such reports in the near future, if, or when, H5N1 becomes pandemic. It’s from that sort of information that we’ll start understanding at which level of threat we are, before press releases start coming in of many clusters around the world.
In other words, please second guess me on this report. And clarify the inferences for other non-scientific fellow lurkers please. I can start a train of thoughts, but I don’t have the synthetic ability to put it all together. Some of you might well do it.
Hereafter some my original post on News Reports July 11, and its reply from Confused Exec, plus some more remarks of mine on the subject.
QUOTE
To note, page 24, paragraph 98, ultimate and penultimate sentences of the DEFRA report:
The most likely explanation for this finding is that the virus increased in virulence with its transmission between birds and between flocks. There are number of findings which support this hypothesis
I tried to compile the figures mentioned in an easier way to understand them:
In brackets number of cases tested
Seropositivity on two different dates
First infected premises were No.2 and No.3, then No.1. bUT premises No.1 were declared first. And figures for premises No.1 are incomplete (not in a table or not given, or else I did not understand them :-)
(I’ll try and make this table look ok!!!)
- - - - - - - - - - - - - - Premises 1 - - - Premises 2 - - - - - Premises 3
Mortality per Thousand - - - - - ? - - - - - - - 7.9 - - - - - - - - - 12.9
Seropositivity - - - - - Incomplete figures - - 75%(20) - - - - - - - 45% (20)
- - - - - - - - - - - - - - - - - - - - - - - - 57%(100) - - - - - - - 96% (100)
Significance (X^2) - - - - - - - - - - - - not significant - - - significant: p<0.001
Me thinks aloud… if this is LOW pathongenic AI, with the worst mortality rate of 1.29 percent and 96% seropositivity… Anyone wants to calculate what would happen if such figures were translated into human figures for H5N1 ??? What figures would one need to use to describe HIGHLY pathogenic AI?
Confused Exec – at 09:05
FrenchieGirl – at 08:52
I understand your concern with the terminology. High Pathogenic AI is measured by injecting the live virus into young chicks and over the course of the next week or so, see how many succomb to the infection. If say three quarters of them die, then it’s High Path. If less than that, Low Path.
So, its High or Low Path only with respect to chickens, not other animals. The H5N1 virus injected into young chicks typically kills all of them within 48 hours. So the mortality described in the report for H7N3 is clearly Low Path by definition.
Hope this helps.
UNQUOTE
So I continue my disorganised thinking. To put all this here, I have used info from the DEFRA report, and from an Osterhaus et al. article and some of Niman’s commentaries.
I thought that only virus from the H5 and H7 type could be classified as High Path – depending on the subtype N, whether in chicken or in humans. That the definition of High Path” was made according to particulars in the protease cleavage site’‘ of the virus (Avian influenza A virus (H7N7) – Osterhaus et al.). As the chicken mortality rate in this UK outbreak is not more that a minuscule 1.29 percent in chickens, ok, so it’s low path. Still, I wonder…
At any rate, the UK DEFRA report mentioned describes real events, not testing in laboratory setting.
As yet, if H7N3 is caught by a human, it only causes conjonctivitis. This Low Path H7N3 seems to have, as suggested in the report, the ability to increase lethality in farm chickens as it goes around the farms, increasing from a mortality rate of 7.9‰ to 12.9‰, with seropositivity penetration from 57% to 96%. This begs the following questions/remarks:
(A) what are the differences in the sequences/genetic make-up of the H7N3 virus from the least to the most affected flock? (Such differences are described for H7N7 in the article above)
(B) The human with the conjunctivitis, did he have H7N3 from the least or from the most affected flock?
© if from the least affected flock, is it possible to infer what could have happened had this human caught the virus from the most affected flock?
(D) the H7N7 2003 outbreak study in the Netherlands showed, of those exposed to the sick poultry, a high number of humans afflicted/with antibodies/conjunctivitis/flu symptoms and one death (testing of staff and contacts of staff), and according to the figures published, we’re at about a rate of one death for 89 infected, which for a high path virus is just a little less than 1%
(E) By contrast, the English H7N3 outbreak only showed one human with conjunctivitis and no antibodies in the only seven people tested (staff only, the vet and occasional visitors were not tested…).
(E) so either the English tested too little people for any result to be statistically significant (well, one can hardly generalize from a 7 people-sample), or the virus truly does not provoke antibody reactions, you either get ill or not. Though the outcome (conjunctivitis) in no way compares with ARDS/death, one may wonder what would happen if H7N3 were to increase lethality with its travels, both in chickens AND humans.
(F) Osterhaus, with respect to the H7N7 Netherlands strain, found in the human who died, says – One mutation in PB2 (E627K) is of particular interest because this mutation was shown to affect the virulence of H5N1 AIV in mice.
(G) Niman writes that all mammalian sero-types isolated from humans have E627K. Similarly, all Qinghai strains of H5N1 also have E627K Niman commentary. Did the UK DEFRA ever test for this in the H7N3 outbreak?
(H) Osterholm et al.: H7N7 AIV was detected in three individuals who had not been in contact with infected poultry, but who were family members of individuals with H7N7 conjunctivitis, indicating that transmission of virus from human to human had occurred.
(I) What alarmed me was the raised possibility in the DEFRA report that the H7N3 low-path virus could increase in lethality. Shouldn’t we also keep an eye on such H7 AI outbreaks?
(J) at another level, DEFRA writes that the initial outbreak of the H7N3 virus in the Norfolk Farm was likely caused by wild birds, and then extended on the various premises by foxes which ate dead/sick chickens. I have nothing against this theory, except these two reservations: foxes are mammals, didn’t they get sick at all? Since their earth was found, couldn’t they be caught and tested? If the animals (including the youngs) could not be found, were they dead, eaten by other predators, which might have spread H7N3 further? Had the foxes gone away disturbed by all the human activity around the incident, and spread (or not) the virus elsewhere?
(K) Couldn’t the other farms have been also infected by wild birds rather than by the foxes? Here I am reminded of Tom DVM’s post on some other thread, possible infection by other mammals - shore-line mammals, whether rodents or mustelids . I am reminded also of the marten, found in Germany, a carrier of H5N1. This free-range English chicken farm is located where the numerous small ponds and free-range nature of the enterprise attract significant numbers of waterfowl (especially mallards and Egyptian geese); there are also large active rookeries on both of these premises, doves (and possibly swallows) nesting in the farm buildings at LPAI 2006/02, and a variety of other wild species (moorhens, sparrowhawks, owls, skylarks, game species, etc.) to be seen. While LPAI 2006/01 abuts an area of scrub woodland, and mallards and pheasants can be seen in close proximity to the site,[…] - Can’t see that they wouldn’t at least have rats around! Why not test some of those?
As to my last remark, Me thinks aloud… if this is LOW pathogenic AI, with the worst mortality rate of 1.29 percent and 96% seropositivity… Anyone wants to calculate what would happen if such figures were translated into human figures for H5N1 ??? What figures would one need to use to describe HIGHLY pathogenic AI?.
At present, Indonesia is showing us that the mortality rate - actually the CFR - of those humans affected is extremely high, circa 77%. We have forecasters of doom and politicians, all use different figures, based themselves on extrapolations of the 1918 Spanish flu figures. Depending on which expert is speaking, H5N1 at a 2% CFR will mean so many billions of dead. Well, my question was, if I use the chicken figure at a hypothetical 1.29 percent CFR in humans — using H7N3 UK example, or a 1.12% CFR – using H7N7 Netherlands example, how many dead humans do we get on earth? I can’t even imagine if the Indonesia CFR from H5N1 stays the same in a pandemic, how many dead humans???
Thanks Tom, OK, now I can move on to another dumb theory. Or should I say process of elimination. Not being a pro. in said area, I’m most likely going to stay in the dark. At least I’m not alone. I think some scientists are like me at this point,”Blind as a bat.” So, why not take a stab in the dark? LOL It can’t hurt.
Next crazy question. Are there any breeding grounds in Laos? gina
“Thanks Tom, OK, now I can move on to another dumb theory. Or should I say process of elimination. Not being a pro. in said area, I’m most likely going to stay in the dark. At least I’m not alone. I think some scientists are like me at this point,”Blind as a bat.” So, why not take a stab in the dark? LOL It can’t hurt.”
There are scores of parasites that infect fish/humans, insects/humans, etc. Do some research and don’t depend on pronouncements from those who admit ignorance of the topic.
FrenchieGirl – at 12:24
I agree with your interest in the possibility of Low Path AI mutating into High Path, and then infecting humans and making them sick. I believe we can safely say that Michael Leavitt of HHS also shares that concern as he recently stated that we must also keep an eye out for other influenza viruses, not just H5N1.
As to your very last question about the number of human deaths, it is fairly easy to calculate a figure from the CFRs given if you also know the Clinical Infection Rates. So, for example, if the CIR in the US was 30%, that means that 90 million people in that country are going to get sick. Applying the CFR of 1.12% (H7N7 rate), that’s just over 1 million fatalities. At the CFR 1.29%, another 160,000 people would be expected to die from the disease, all other things being equal. To get to world figures, just substitue the global population figures in place of the 300 million Americans.
Does that make any sense?
“I highly recomend this blog, by Dr. Tara Smith (hat tip to revere at Effect Measure). It discusses the evolution of H5N1 very clearly. She also alludes to a heated discussion with HIV deniers who want to dismiss the importance of that virus in AIDS. Apparently they doubt that HIV has a high mutation rate - sound familiar?
It should be noted that the Theory of Recombinomics is apparently also applied to HIV. “
Oh, nice — another sly ad hominem attack. Aren’t you clever? Yes, it does sound familiar. You are much less objectionable when you stick to the facts than when you try to paint those with whom you disagree as closet creationists or HIV-deniers.
Who me – at 14:05 Exactly. I also read both the text of the blog and Monotreme’s subtext. He can’t seem to rise above the incessant digs at people he disagrees with, or who have the temerity to disagree with him.
By the way, what do you think of the mismatch between the human strain polybasic cleavage sites and the swine and chicken polybasic cleavage sites? I notice nobody on this thread has offered an explation on why the human case sequences in Indonesia don’t match those of the local chickens.
Do we have human case sequences from Indonesia and local chickens to study? If so, please provide a link so that we might have a go at your quesion.
Much thanks.
Monotreme,
“But there could be one out of the gazillion species of birds that could harbor mammalian adapted virus. The question is: which one?”
You know, the whole theory of aquatic birds as natural reservoirs of flu viruses rest on the fact that they can find all the different subtypes in those birds without them getting sick. But just because something can be found in one place does not mean that this is the ultimate source/reservoir/hiding place of that thing.
In fact, the problem is we haven’t really looked. There has not been a systematic surveillance of all birds in a particular habitat to figure out which virus does what in which species etc. The only one that I know of is by Taubenberger & Scott Layne (I think) in Alaska, which hopefully will give us some urgently needed information.
So I can think of 2 related questions:
1) is it true that aquatic birds are the ultimate reservoir from which flu viruses arise, or do the birds acquire them from another as yet unknown species?
2) what are the effects on the flu virus genome of having resided in particular species of birds? I would imagine there must be a tremendous range of host-virus responses in the difference species and so it is entirely possible for the virus to acquire certain characteristics in some species but not in others.
anon_22.
Thank you for your #1 question. This is the question I have wanted answered. It makes no sense that birds are the only species to have this virus. In 1918 the research was limited. That does not have to happen in our world today. Why are the areas testing positive for h5n1 not swarming with scientists testing everything in sight? It is actually the only way to get to the bottom of this situation.
There is one glarringly real fact. There is not enough data to solve this situation. If important information is being witheld by any government or scientific group, the rest of the world needs to take action against that group. We are not talking about one organization or government verses another. We are talking one organization or government verses the world. Afterall, who is the parent and who is the child.
Can the world at least try to get a handle on this virus? gina
I agree that there is not enough data. Part of that has to do with lack of will/withholding by governments, but it is also partly to do with the state of science. Tracking the natural history of flu viruses does not always have to take place in the Third World. We have no data even from the US, for example, as to what happens to flu viruses in the different species of birds. As I said, Taubenberger’s group’s effort is a good start, but it may be a while before we can get those answers.
But it is still important to ask these questions, even if we know that we won’t get good answers any time soon, because it is good science to clearly delineate what we do know, what we don’t know, and what we are guessing.
WHO Me, anonymous,
I’m sorry if I gave you the wrong impression. I am *not* attacking Dr. Niman, I am attacking his Theory of Recombinomics, with no apologies. See this post.
I am quite sure Dr. Niman is not a creationist - he has made many derogatory comments regarding them. I have no reason to think he is an HIV denier. This is not the point I was making and indeed quite irrelevant to it. Some creationists believe HIV causes AIDs. Most HIV deniers believe in evolution. That is not where there similarity lies.
Creationists, HIV deniers and the Theory of Recombinomics all reject conventional science. Conventional scientists are viewed as incompetent or corrupt.
The Theory of Recombinomics rejects the idea that mutations occur frequently in influenza viruses and HIV viruses. See below.
Paradigm Shift
The analysis of recombination will generate a paradigm shift in the way molecular evolution is viewed. Influenza is an ideal system for studying molecular evolution. Viruses are generally thought to evolve via shifting and drifting. Shifting occurs when viruses swap genes and drifting was thought to be due to a steady accumulation of mutations.
However, rapidly evolving viruses simply recycle old mutations via recombination. This method is much more efficient and follows specific rules. These rules appear to be followed by all viruses, including influenza, HIV, SARS, WNV. These rules allow vaccines to be prepared before viruses emerge. These observations will produce a paradigm shift in the study of molecular evolution via recombination, which will provide solutions for unmet health needs
This statement puts the Theory of Recombinomics at variance, not only with influenza researchers, of which there are thousands, but also with HIV researchers. I’m not sure that everyone who believes in Recombinomics knows this. They should.
It seems to me that if “These rules allow vaccines to be prepared before viruses emerge.”…then by extension the final pandemic virus must be able to be predicted beforehand.
I think it is time to deliver on the components of probably the most dangerous virus to be observed in the last thousand years…don’t you think?
No, Tom, I think it is his time to try to make money off a boast you can’t or won’t prove. At least that is more likely given the detail and the length of all of the discussions I have followed on the subject of Recombinomics. I do not generalize that in other areas and instances, the man has flashes of brilliance and attention to detail and the ability to sense pattern out of detail. In general, I find him insulting and not the other way around. I am just an interested observer.
sorry, it should read..he can’t or won’t prove.
Dude. I wrote that post and erased it. /:0)
Grin. It is all a conspiracy I tell ya….Tin foil hat, pants, shirt, underwear, and socks. If you even think it they know…
this is an interesting thread, but also very long. Can we have a summary, please ?
Confused Exec — at 13:52 - Thank you.
I knew there was some reason in the back of my mind why I was trying to understand the failings of the DEFRA (H7N3) report and how it might have been important to list those and compare with the Netherlands H7N7 outbreak and H5N1…
Would someone explain in simple terms what is the significance of: «H7N3 isolates from England in 2006 have Niger H5N1 polymorphism» (Niman at Flutrackers), and «The Niger polymorphisms are unusual in that they are not widely shared with a subset of Qinghai isolates. Remarkably, G1240T was shared with a Mongolian Qinghai isolate as well as H7 isolates, including isolates from the H7N3 outbreak in England, A/chicken/England/4054/2006(H7N3) and A/chicken/England/4266/2006(H7N3).» (Niman’s Niger-Nigeria Commentary).
I am not talking about the recombination theory, but the actual practical significance of finding a H5N1 Hig Path virus piece from Niger/Africa inside the H7N3 Low Path virus in the United Kingdom outbreak.
I don’t think, there is any significance, since Niger is H5 and England is H7. They are very different. Not even Niman would suggest that they recombined in HA to form that polymorphism.
FrenchieGirl – at 05:27
I am not talking about the recombination theory, but the actual practical significance of finding a H5N1 Hig Path virus piece from Niger/Africa inside the H7N3 Low Path virus in the United Kingdom outbreak.
Actually, your statement assumes the Theory of Recomibinomics is correct. Polymorphisms can be acquired in three ways: Random mutation, reassortment, or recombination. Most of Dr. Niman’s commentaries assume that most polymorphisms are acquired by recombination. He is isn’t simply reporting the data, he is interpreting it as well. I realize that this is not obvious. This is because his commentaries don’t clearly separate out the data from his interpretation.
The sequences he cites probably have the polymorphsims he indicates, I haven’t checked. What other polymorphisms do they have? Are they reassortants? What are the odds that two sequences have share a polymorphism as a result of independent random mutation? None of these were possibilities are considered in the commentaries. Which one of the 3 possible sources of variantiation you think obtains in a particular case is at least partially determined on the relative frequency that you think each of the three types of variation occurs. Since the Theory of Recombination states that random mutations are extremely rare and recombination is very common, all polymorphisms that Dr. Niman sees are interpreted through this lens.
Conventional scientsts looking at the same sequences may interpret them differently.
anonymous – at 07:14
Me thinks you will be very surprised.
Is there a way that both Niman (N) and 1,000 virologists (1KV) could be right? At the same time, I mean. So what if there is a high observed error rate in vitro? 1KV are right about in vitro error rates. Suppose that a strain has, say, 5 substitutions at 5 different places and was found in 2005 in Italy (the milkman). Suppose these exact same 5 substitutions show up in Nigeria a year later, but in what looks like a different background strain. Could somebody please calculate the odds of that happening at random? Isn’t the most parsimonious interpretation that they were swapped in, not that they just happen to resemble the milkman by accident?
And how about those trees? Nidom’s phylogenetic tree shows clear evidence that the strains do not evolve in simple divergent patterns, but have places where 2005 sequences are better matches than 2006 sequences, which suggests both a low mutation rate, and some kind of partial swapping of genetic information across the tree.
There is mounting evidence that in vivo behaviour does not match in vitro. Deal with it.
Monotreme — at 07:17 - Thank you. “He is isn’t simply reporting the data, he is interpreting it as well. I realize that this is not obvious.” In other words, one should be careful not to twist the facts to fit one’s biais. Or to equate correlation with cause and effect. Or to invoke fallacies as truth…
We have this gigantic puzzle to put together that frustrates me so, unfortunately, it’s a pity my science is so rudimentary as not being able to search for an answer to the questions you have raised: What other polymorphisms do they have? Are they reassortants? What are the odds that two sequences have share a polymorphism as a result of independent random mutation?.
I occasionally try to point out what I think may have some relevance, with some of my small abilities, hoping someone will pick on them and use whatever I can contribute. As I keep saying from the beginning of my joining the FW community, we need experts in all areas to put some order with the pieces of the puzzle. Biologists, PCR specialists, mathematicians, statisticians, etc. to do a big brainstorming session. Then we need good writers to give us the final opinions, written for us lesser mortals (smile)!
“this is an interesting thread, but also very long. Can we have a summary, please ?”
We’re doomed. Maybe.
Frenchiegirl- Thank you for trying to pull a lot of information together. There’s a book waiting for you “Monster at the Door”, to read on the subject of all the bird influenzas. The H7 and H9 are legally required to be reported and are under surveillance. They can pop up to high path occasionally, again and again, but they are not continuously a high path virus, as H5N1 has been for 10 years. H7 and H9 do have pandemic potential but have been contained so far in each outbreak. For example that Netherland strain that killed one person, did not continue to exist. But it shows the potential of a sudden outbreak. H5N1 is the front runner in being so uncontained.
Thanks to all contributing to a very sensible and civilised discussion. Very informative thread.
A few questions to interject into this very interesting conversation, if I may:
1) If I understand it correctly, recombination would rely on the availability of spare parts (pre-existing polymorphisms) lying around to recycle. If that’s true, wouldn’t it be relatively simple to set up a lab experiment in which one flu virus is allowed to reproduce without any spare parts to recycle, while a twin is supplied with lots of material to recombine with. This wouldn’t tell the whole story, but might offer some helpful clues, it occurs to me.
2) Could statistical analysis of past studies shed some light on the argument over whether polymorphisms in the wild are aquired more often by random mutation or recombination, as someone alluded to above? What is the statistical probability of random mutation producing the observed polymorphisms that Niman cites as evidence of recombination?
3) Might the truth lie somewhere in between? That is, the “random” mutations we see aren’t entirely random. For example, that certain mutations might occur more frequently (or perhaps more frequently in certain contexts), for reasons not yet understood, or else that perhaps selection pressures are happening so quickly that this influences which mutations we do tend to observe?
4) And finally, (this may be self-evident, but just thinking out loud here) a better understanding of H5N1’s ecosystem model, including the role of potential reservoirs and wild/artificial system interplay in its evolution, might help resolve the above questions, no? I guess we can all at least agree that we need more data!
(I’ll add for the record that while it seems foolish to dismiss the weight of mainstream research and opinion (especially for the vast majority of us who don’t fully understand all that’s gone into it), it wouldn’t be the first time that an unconventional/cranky maverick has turned mainstream science on it head. While Niman hasn’t proved anything publicly, it seems the mainstream will be uncomfortable until it can explain the odd holes that he’s pointing to in the conventional theories. This is all good, though—conventional wisdom is rarely if ever the last word on any subject, as we keep finding out—and the pressure will quite likely result in a deeper understanding.)
1) yes. Double infect some mice,ferrets,cats,pigs with two
fkus at the same time and see what happens. Has it been done ?
2) yes, http://www.setbb.com/fluwiki2/viewtopic.php?t=92&mforum=fluwiki2
3) yes, the occurring mutations are not entirely random. Even not
the synonymous ones. At some places you won’t see mutations at all.
Name,
“Could statistical analysis of past studies shed some light on the argument over whether polymorphisms in the wild are aquired more often by random mutation or recombination, as someone alluded to above? What is the statistical probability of random mutation producing the observed polymorphisms that Niman cites as evidence of recombination?”
I don’t know if this answers your question exactly but the best review I have come across is still this paper originally posted by Theresa42 Phylogenetic analysis reveals a low rate of homologous recombination in negative-sense RNA viruses, Chare et al, Oxford UK
The whole paper is very instructive and I would recommend it to everyone interested in the subject.
The authors acknowledged “the potential importance of recombination in RNA virus evolution” and used as sample “all those negative-sense RNA viruses for which population samples are available currently in GenBank; this comprised 35 viruses from six families and totalled 2154 individual gene sequences.”
This was a very large sample, in fact, as large as you’re ever going to get.
They analyzed the sequence alignments in 3 different ways:
1) Phylogenetic incongruence: Basically they looked for portions where the sequence alignments caused changes in phylogenetic position, then they determined if this was more than what could happen by chance alone and also determined the most likely breakpoints using a maximum likelihood (ML, Holmes et al, 1999) method. Then they estimated the ML (maximum likelihood) phylogenetic trees of the sequences on either side of the breakpoints and analyzed those (for ‘bootstrap support’) to see if they support the notion that this was indeed a location of phylogenetic incongruence. “Strong evidence for phylogenetic incongruence, and hence recombination, is deemed to be present if the conflicting tree positions are each supported by >75% of bootstrap replicates.”
2) Sawyer’s runs test. In this test, a search is made for unusually long fragments within an alignment over which a pair of sequences are identical, or nearly identical, even though these sequences do not share common ancestry. Whether these runs of similarity are longer than expected by chance is assessed using randomly permuted data sets derived from the same data. ie comparison with other regions of the same set of sequences.
3) Informative sites test. This test looks for sequence variation or polymorphism. (Could this be what Niman refers to frequently?) It detects recombination by distinguishing the ‘apparent rate heterogeneity’ among nucleotide sites caused by recombination from the ‘real rate heterogeneity’ among sites caused by mutation. Such a distinction is possible because mutation and recombination affect the pattern of variability at polymorphic sites in different ways, The values of this variability q computed for the real data are then compared to values obtained by simulating 200 data sets along a ML tree assuming no recombination. This test is useful for detecting recombination in more closely related sequences which may not show up in the other 2 tests.
The first 2 methods gave similar results: they found evidence of recombination in some strains of 5 of the 35 viruses: the G2 gene from Hantaan virus, the F gene from Mumps virus, and the HNgene from Mumps virus, the HN gene from Newcastle disease virus, and the N gene from Newcastle disease virus.
The informative site test, however, showed 10 other viruses in addition to these 5 (ie total 15) as showing evidence of recombination, including one for the HA gene of influenza A H1N1/South Carolina/1918.
To explain this discrepancy between the informative sites test and the other two tests, the authors suggested 2 possibilities. First, it could be that recombination has occurred but “that the effects on tree topology are so slight that they have not resulted in clear phylogenetic incongruence.”
Alternatively, it is possible that this test produces frequent false-positives because of positive natural selection,eg in immune escape. This positive selection “can cause unrelated strains to show similar sequences, but with changes that are too localized to show up as phylogenetic incongruence.” The fact that there are more surface antigens that show positive only on informative sites test may support this explanation, as these antigens are under strong selection pressure.
In the case of the HA gene from 1918 H1N1, suggestions that this was a result of recombination (Gibb 2001) had been previously refuted by Worobey 2002 as due to an error of ‘midpoint rooting’ in constructing the phylogenetic tree (ie starting with human and swine strains instead of the parental avian lineage) which masked the uneven rate of evolution of HA1 and HA2 in the human lineage as compared to the swine, so that Gibb’s alignment showed an apparent (false) recombination event using the informative sites test but which when properly aligned with rooting from avian lineage, showed the supposed recombinant regions to be ‘almost identical’.
The authors of this current study re-examined Gibb’s alignment and showed that even with this alignment it did not fulfill the criteria for the first 2 tests discussed here ie phylogenetic incongruence and Sawyer’s runs test. Thus they concluded that “At present, therefore, the case for RNA recombination in Influenza A virus remains unproven, with extensive rate variation producing a similar phylogenetic signal in this case.”
Name,
“That is, the “random” mutations we see aren’t entirely random. For example, that certain mutations might occur more frequently (or perhaps more frequently in certain contexts), for reasons not yet understood, or else that perhaps selection pressures are happening so quickly that this influences which mutations we do tend to observe?”
I have a suspicion that the word ‘random’ in ‘randeom mutation’ has never been proven correct. That is, this might have been an accidental left-over from very early hypotheses about mutations that nobody ever bothered to prove or disprove, and we just end up (sloppily IMHO) repeating the phrase until we have dug ourselves into a hole in our thinking.
Does anyone know the answer to this? Could we have been (rather foolishly) repeating this without thinking?
There are mutation hotspots. And certain types of mutations are more likely than others, so mutations are not completely random. However, I don’t think this is the real problem in understanding the data. People are confusing mutation and evolution. They are leaving out the effects of selection which very definitely has non-random effects. Will try to post on this tommorrow.
I don’t know if this is new information or already known here:
http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/jul1206mutate.html
see [http://www.fluwikie2.com/pmwiki.php?n=Forum.FamilyTragedySpotlightsFluMutations|this] thread about
the Karo mutations.
Yes, mutations are not random. At some places we don’t see any mutations
at others many. How is this encoded ?
close and continue here