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Author
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Topic: Intelligently Designing Immunity
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charlie d.
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Member # 159
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posted 11. April 2003 09:35
quote:
It suddenly occurs to me that perhaps one reason for the super-duper immune systems of mammals is simply warm-bloodedness. Things can replicate alot faster when they are warm.
Ah, warmbloodocentrism! A common fallacy. ![[Wink]](wink.gif)
I would suspect that most pathogens that affect heterothermic organisms would be well adapted to replicate effectively at whatever temperature those organisms are. After all, we know bugs that replicate just as happily at close to freezing temperatures, or in close-to-boiling-point underwater heat vents, as E. coli does at 37C.
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yersinia
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posted 11. April 2003 20:29
Ah, the bacteria adapted to near-freezing temperatures may replicate quite happily in the cold, but can they do it as fast as bacteria adapted to high-temperature conditions in a warm environment?
IIRC there are some fundamental kinetic reasons reasons that biological reactions go faster in warm environments (assuming enzymes adapted for that temperature, etc.).
Although I do concede that stuff grows on the food in my fridge sooner or later...
![[Cool]](cool.gif)
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Nel
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Member # 614
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posted 12. April 2003 10:53
Charlie asked:
quote:
what's "antibody-diversity"?
Good question. First, here are some good references to start with:
Gellert M (1997): Recent advances in understanding V(D)J recombination. Adv Immunol 64:39-64.
Grawunder U, West, RB, Liber MR (1998): Antigen receptor gene rearrangement. Curr Opin Immunol 10:172-180
Antibody-diversity was a big research problem in Biology, showing how identifying the the function of antibody-diversity itself, which is a big part of deteriming whether something is IC, is so important and can guide biological research (which is why I think ID , with IC, can do a lot more for our current research programsand in a lot of ways is already doing so). The number of B and T cells with differenent specificities can number up to 10^18. If every single one was coded for by one gene, then you would have to have 10^18 genes in your genome coding for them. Thats extremely wasteful, and it would make up most of the genome. Due to research over the last 25 years, we now know that Ig and TCR genes use a unique strategies to achieve the degree of antibody-diversity required. So instead of using millions of genes, we use only hundreds. Again, VDJ recombinase/receptor system is not antibody-diversity, it's how you make them. I don't define receptors here as innate receptors because they look nothing like Ig or TCR and don't even bind specifically. They are analogous to them, but thats about it.
Why antibody-diversity is a function is not only important biologically in that identifying this function has done more to guide research and insights into the system itself, but it is also important for the life of the organism, in that if you don't have antibody-diversity, you don't get to "recognize the vast majority of potential pathogens it can be exposed to." I'd say thats pretty important. So the IC nature of this system is not "abstract".
Heck, it's not even a tautology. A tautology is defined as "Needless repetition of the same sense in different words; redundancy." However, there is no redundancy when I describe the components of the V(D)J recombinase/receptor system and it's function.
In response to your comment about tautology problems with respect to different ways of getting antibody-diversity, I very much disagree that there are any tautology problems. Thats as ridiculous as saying that the jeep doesn't need it's wheels in order to get you from point A to point B because I can get there with a steamboat, or the airplane doesn't need it's wings to fly because I get can there with a jeep. Yes if you go by steamboat you don't need any or just a few, and other components to replace them, of the jeep. If you go by jeep, you absolutely need those components. This is not a tautology, you're simply talking about different ways of doing it, all of them are complex. Try flying to Florida in an airplane with no wings, you'll learn quickly why VDJ recombinase/receptor system is IC, regardless of how chickens do it. If chose to fly to Florida with an airplane, could I have gotten there with a jeep? Absolutely. Did I? Nope. Are they both still intelligently designed? Yup. So, does it somehow refute any of my points that there are different mechanisms of accomplishing the same end? Not at all.
Furthermore, talking about somatic gene conversion is not removing one component of the VDJ recombinase/receptor system. It's removing the VDJ recombinase, and replacing it with other components. Homologous recombination is also complex, and in fact is used by intelligent agents for various genetic engineering activities --- part of the donor gene(s) is copied into an acceptor gene and the acceptor gene is altered.
The fact that specificities or generic binders matters only if the immune system is successful is exactly the problem. And yes, it does in fact matter if you have 10^18 specificities or 10 specificities. In fact, it's a matter of life or death for the organism. Hundreds of thousands of receptors with single specificities are very useful. It's a very successful immune system. In fact, we only see organisms with successful immune systems that have this large amount of antibodies. Not a few, not one, hundreds of thousands. On the other hand, we may see an immune system that has many generic binders. We never see the situtation in between. Why not? Why is this intermediate step invisible? Precisely because innate receptors with single specificities are useless to the immune system, Behe was correct. A few receptors with single specificities can be bypassed or adapted to by a bacteria. There is also the problem of the loss of those receptors with single specificities through stochastic evolution. Which means if a pathogen whom that specific receptor was acting as an antibody for disappears from the population for a while, a mutation occurs where loss of that specied innate receptor or group of specified innate receptors are now gone, this is inherited in a population, the pathogen comes back, they all die.
With those organisms that have one or several antibodies, are in an arms race that may be too much for them. An organism making antibodies with single specificities is engaging in an excercise of redundancy, it's wasting resources, it's fodder for negative selection. You have to make a lot, you have to make them fast, and you have to do this from the get-go. This particular facet of combinatorial immunity had to appear abruptly, all at once.
So, not only is the VDJ recombinase/receptor system IC, but the problem for Darwinian evolution and it's support for Intelligent Design is exacerbated by the issue of minimal function (see p. 45 of Behe's book). It's not enough that you have all the components of the system,with respect to specificity, they have to work at a certain efficiency or you might as well not have the system. Charlie's assertion that the number of specificities "matters not a bit" is baseless. It's not a logical quibble it's a biological neccessity.
What we see in sharks is only relevant if we can show that the current system they have is ancestral to ours. It may be that they are currently in a niche where the secondary response has been lost. The reason I say this is because the transition from their system to ours is too much of a big jump requiring unselectable steps (which is why if it was ancestral to ours, it would still point to intelligent design). No specific antibodies are used by the shark immune system, and their Vs Ds and Js are clustered, (unlike our large arrays) fusing one to another would likely cause a frameshift or the production of useless antibodies, the strategy itself would be lost due to negative selection.
So IC doesn't fail here. Looking at the mammalian system, VDJ recombinase/receptor system is absolutely required and sufficient. If I were to focus on how other organisms do it (chickens), I would most likely not only conclude irreducible complexity of the same (if not more) degree but the same exact problems for Darwinian evolution. Unfortnately, the precise mecahnisms for how chickens do it is largely unknown. But the trend in science is the more we look at a system, the more complex it turns out to be.
[ 12. April 2003, 11:53: Message edited by: Nelson_Alonso ]
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yersinia
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Member # 324
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posted 12. April 2003 12:24
quote:
What we see in sharks is only relevant if we can show that the current system they have is ancestral to ours.
Well...sharks/cartilagenous fishes *are* in exactly the right phylogenetic position, being the most basal organisms with a combinatorial immune system.
As for common descent of the systems, people may not know this, but it has been well-accepted since at least 1979. In most vertebrates, the V(D)J recombination system genes are arranged something like this:
VVVVVV DDDDDD JJJJJJJ
...but in sharks, it's something like this:
VDJ VDJ VDJ VDJ VDJ VDJ
(or more less; I don't have access to the original graphic I'm thinking of, the webpage that has it is down. E.g. D is not in all antibodies).
This pattern is *screaming* a common ancestor at us from the depths of time. Readers will have already figured it out, but I'll give it here:
VDJ
...which Nelson says is "radically different" from the way our system works. But all it takes is gene duplication to get from VDJ to either the shark or higher vertebrate pattern.
Oh wait, I found the graphic. It is from this page:
Just so that readers know that we're not crazy internet posters proposing this idea, here is a graphic from the research description of Dr. Hsu at SUNY Brooklyn.
quote:
Figure 1. Hypothetical scheme for evolution of IgL chain genes. The ancestral Ig gene underwent gene duplication, generating V and C exons. Sometime in the early Devonian, a mobile DNA sequence was inserted in the V exon, splitting it into V and J gene segments. Dark arrows on the DNA insert indicate RSS. Gene duplication of the individual genes in tandem generated the overall L chain gene arrangement in tetrapods, whereas duplication of V, J, and C genes produced multiple clusters. Based on a diagram from Sakano et al., 1979, Nature 280:288. The top arrow indicating rearrangement refers to somatic recombination in lymphocytes as well as recombination in the shark germ cells (Lee et al., 2000, J. Exp. Med. 191:1637): we suggest the latter is on-going in evolution.
Note the date for the figure: 1979. This is not revolutionary, novel science we are proposing here.
Regarding the ICness of the adaptive immune system, Nelson can't seem to keep his story straight. He repeatedly tells us how crucial specificity is to the ICness of the adaptive immune system, but when the problematic case of sharks is brought up, he says, with a straight face:
quote:
It may be that they are currently in a niche where the secondary response has been lost.
But I thought that IC meant that you couldn't remove parts and retain function! What Nelson just told us is equivalent to saying that a 20-parts-required flagellum could have 10 parts removed, while still insisting that the 20-part flagellum was IC.
Is ICness now ecology-dependent? I could go for this, but I doubt very much that Behe et al. would.
(It bears pointing out that the "niche" of most cartilagenous fishes is basically shallow coastal oceans. This is shared by most of the world's fish species, as well as being where most of deuterostome evolution occurred. So Nelson is implying that the adaptive immune system is IC for us terrestial mammals, but not for our aquatic ancestors. I am happy to agree with this, but somehow I doubt that Nelson will feel the same...)
[edit to fix graphic size]
[ 12. April 2003, 12:28: Message edited by: yersinia ]
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charlie d.
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Member # 159
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posted 12. April 2003 13:08
Nelson:
thanks a lot for the immunology lesson. LOL.
Of course, my point was - and I have made it in a dozen different ways now, though you keep ignoring it - that "antibody-diversity" is not a function in any meaningful biological sense. The real function is "recognition of diverse antigens", for which quite obviously multiple functionally valid strategies exist in nature. Indeed, despite your assertions, it is still unclear to me why you think the mammalian immune system is any better than a shark's, or a lobster's.
And since we are talking about sharks, in fact the ability to undergo affinity maturation during an immune response appears rather late in evolution, being lowest in cartilagineous fish, somewhat higher in other exothermic vertebrates, and being fully functional only in birds and mammals. Thus, there is really little reason to doubt that the low affinity/polyspecific antibody system is ancestral to ours. Here's a review by Hellen Hsu again: quote:
Mutation, selection, and memory in B lymphocytes of exothermic vertebrates.
Hsu E.
Immunol Rev 1998 Apr;162:25-36
Unlike mammals, cold-blooded vertebrates produce antibodies of low heterogeneity that show little increase in binding affinity with time after immunization. In secondary responses, antibody titers and affinities are often little, if any, higher than in primary responses. That is, specificity, diversity, and memory--the hallmarks of the immune system--are rather meager in the humoral immune responses of exothermic vertebrates. As the genetic components of the immunoglobulin (Ig) gene systems in fishes, amphibians or reptiles are not deficient in number or diversity, their responses probably do not stem from restrictions in the primary antibody repertoire. Somatic hypermutation at the Ig locus, which generates diversity and higher affinity antibodies in mammals, is not lacking in the South African frog Xenopus or in the shark. However, the Ig mutants recovered are strongly biased toward alterations at GC pairs, an indication that they have not undergone effective selection. While cells resembling follicular dendritic cells are present in cold-blooded vertebrates, germinal centers do not form. It is suggested that this absence of germinal centers, the site of selection for the mutants with higher affinity receptors and of differentiation into memory B cells in mammals, may explain the principal differences between cold and warm-blooded vertebrates.
Dang. Maybe the designer slapped the entire fancy somatic recombination system together, and simply forgot to add all the bells and whistles to make it really work until birds and mammals came around. But then, how does that relate to the problem of "minimal function"? "It's not enough that you have all the components of the system,with respect to specificity, they have to work at a certain efficiency or you might as well not have the system." I guess that only counts some times and not others.
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Nel
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posted 12. April 2003 13:13
Yersinia,
Whether sharks are basal or not is irrelevant. My concern is whether the immune system they have is ancestral to ours, or represents a loss of the secondary response.
With respect to the pattern of VDJ segments, I already discussed this in two previous posts in this thread, and as always, the transition here would be mighty difficult, again a matter of life or death, which is why it's better to say that the system may be a broken down version of ours, or simply a different system.
We have large arrays of Vs Ds and Js that can rearrange. However, sharks do it in clusters. In other words, although we have long strings of Vs and Ds and Js, sharks have V1-D1-J1-C V2-D2-J2-C,etc. When you try to get something like what humans have, you'll probably end up with something like a V1-V2-J2-C which is garbage. Fusing these segments has a chance of a frameshift.
Of course, this points out that VDJ segments are required for a functioning antibody, thus antibodies themselves may be IC.
As for losing the secondary response, it is simply not true that removing the secondary response is like removing 10 parts from the flagellum and it's still IC. One of the facets that is IC about the immune system's response is that the VDJ recombinase/receptor system is required to make a whole lot of specific antibodies. If you make a whole lot of generic antibodies, thats ok too, the IC system is there. However, the problem for the gradual route with respect to specificity is making one, or a few antibodies wouldn't make a difference. You'd have to start making a lot right away, millions, for it to be selectively advantageous and not lethal.
I never said that the primary-second response relationship is IC.
[ 12. April 2003, 13:27: Message edited by: Nelson_Alonso ]
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Nel
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posted 12. April 2003 13:24
Charlie, you're welcome ![[Smile]](smile.gif) .
As far as your assertion that "antibody-diversity is not a function in any meaningful biological sense", I never ignored this I directly responded to it. "Recognition of diverse antigens" can be done with a One gene-One antibody system. So it gives absolutely no insight into the mammalian immune response, how it works, why it works, or why it is required for an effective immune response. With regard to antibodies with single specificities "recognition of diverse antigens" begs the question of "how?"
Our immune response may or may not be "better than a shark's or a lobsters". Maybe it isn't, or maybe it is. Thats not important right now, lets stick to basics. What's important is if you have an antibody with single specificities you better be making a lot of them, and, with respect to the mammalian system, you need the Rag genes, RSS, and the receptors or you won't get it.
Your review by Hsu has me scratching my head. All it does is discuss the
quote:
principal differences between cold and warm-blooded vertebrates.
And the differences to me suggest that it is easier to get from the mammalian system to the shark version then it is for the shark version to get to the mammalian system in my VDJ discussion.
As already mentioned, with respect to minimal function, this has absolutely nothing to do with what sharks are lacking, they make generic binders, the issue of minimal function of specific binders does not apply. With the mammalian system the issue of minimal function is staring you right in the face:
quote:
"It's not enough that you have all the components of the system,with respect to specificity, they have to work at a certain efficiency or you might as well not have the system."
One or a few antibodies are not sufficient to make a difference, even if you have the VDJ recombinase/receptor system.
[ 12. April 2003, 13:29: Message edited by: Nelson_Alonso ]
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yersinia
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posted 12. April 2003 13:53
It looks to me like "unbridgable gap" has, in the course of Nelson's discussions moved from being between
non-combinatorial immunity --> combinatorial immunity (jawless-->jawed vertebrates)
to being between:
combinatorial immunity --> combinatorial immunity with late-stage specificity (cold-blooded vertebrates --> warm-blooded vertebrates)
...this is quite a bit of migration for the "big bang".
PS: Forgive me if I'm clueless, but is not high specificity in mammalian Igs primarily a matter of *selection* -- i.e., you generate a few zillion receptors, all of them "specific" to one or a few possible antigens and "general" to many more -- and then *those cells with receptors that happen to match the invader* get replicated, and *that* is when you have a large amount of a receptor specific to the invader.
"Specifity" is not a property of a diverse group of receptors -- each receptor in a diverse group will be specific to some things and general to many more things. The only trick then is to replicate the cell that happens to have a receptor that matches the antigen. As this is repeated the high-affinity antibody results.
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Nel
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posted 12. April 2003 14:07
My gap has never moved, it's always been about specificitiy, and since sharks were brought up, I think that there system has gaps of their own. I think that the Big Bang of immunity did occur in sharks, maybe it occured completely with the secondary response and long strings of Vs Ds and Js, and then they lost it, or it became deranged, those with clusters were able to survive because they started making, or already had, generic binders. We retained the full blown original system.
With respect to specificity here are the three postulates:
1. T and B lymphocytes of myriad single specificities exist before there is any contact with the foreign antigen.
2. The lymphocytes in the immune response have antigen-specific receptors on their surface membranes. This undergoes the membrane, signal, secreted form response.
3. Each lymphocyte carries on it's surface receptor molecules of only a single specificity, in both B cells and T cells.
These three postulates make up a large repertoire of possible specificities formed by cellular multiplication.
When the foreign antigen arrives, the selection process occurs, they are made into clones of cells with the corresponding identical receptors to the epitope of the antigen. Several different clones of B cells will be stilumlated to produce antibody, whose sum total is an antigen specific antiserum that comporises antibodies of differing specificity; all the T cell clones that recognize various epitopes on the same antigen will also be activitated. There's a lot more but you get the gist.
By the way, we are focusing here on one facet that is IC about the immune system. Let me just remind everyone reading this thread that there are two other IC systems with combinatorial immunity that were discussed in my OP but have not been discussed after that (yet).
[ 12. April 2003, 14:15: Message edited by: Nelson_Alonso ]
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charlie d.
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posted 12. April 2003 15:02
Nelson:
that's the point: if the "quantum leap" is specificity, as you say, it occurred a few hundred million years after the appearance of combinatorial diversity, which are the elements you claim are responsible for specificity. -[incidentally, what happened to "diversity"? I thought two posts ago you were saying diversity was the thing. Oh, well...]
Your idea that sharks somehow lost affinity maturation has neither legs nor fins, because the same should have occurred independently in all extant bony fish, amphibians and reptiles. In other words, you would have to postulate that all but one clade of cartilagineous fish lost affinity maturation, but that clade gave rise to bony fish and then became extinct with no other descendants. Then all but one clade of bony fish lost affinity maturation, but that one clade gave rise to amphibians, and left no other descendant. Then all but one clade of amphibians lost affinity maturation, but that clade gave rise to reptiles, and then became extinct without leaving descendants. And finally all but at most a couple of clades of reptiles lost affinity maturation, but those clades gave rise to all mammals and birds, all of which miracolusly retained affinity maturation. Talk about a improbability! Ever heard of "parsimony"?
[ 12. April 2003, 15:03: Message edited by: charlie d. ]
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Nel
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posted 12. April 2003 15:17
Charlie,
The evidence suggests that specificity didn't come that long after, but it's irrelevant anyway, the issue is that it is here and it needs to be explained. Secondly, the ICness of the VDJ recombinase/receptor causing diversity and it's relation to the minimal function of specificity has always been the issue in every single post I have ever written about this subject and always will be.
There is no reason why the same thing that occured to sharks had to occur to other organisms, that is called a non-sequitor. Secondly, after the system was stable in mammals, it is quite possible that sharks lost the second response, this is of course after the rise of bony fish and amphibians.
My idea here has both legs and fins. As I stated, the clustered VDJ system they now possess would unlikely give rise to our large arrayed system, in fact, that is most unparsimonous in my view, since it's a matter of life or death. Furthermore, the issue of specificity once again raises it's ugly head, as well as the issue of garbage antibodies and frameshifts.
[ 12. April 2003, 15:18: Message edited by: Nelson_Alonso ]
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charlie d.
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posted 12. April 2003 16:05
What's the "issue of frameshifts"? I know it probably sounds cool but I have a feeling you don't realize what it is. Frameshifts are inherent to the VDJ recombination process, due to imprecision at the rearrangement junctions. Thus, frameshift frequency/rearrangement is the same in sharks as in mammals (2 out of 3 rearrangements), and can't be otherwise. Although we don't really know how locus selection is effected in sharks, they have the advantage that their multigene structure theoretically allows more tries per cell (one per locus, many loci) than our clustered structure (one per allele, two alleles for one locus at the heavy chain and 4 on 2 loci for light chains). Thus, if anything sharks would have the upper hand there.
And also you still don't understand what the issue of parsimony. Let me explain. Mammals and birds independently evolved from reptiles, which evlved from amphibians which evolved from bony fish which evolved from cartilagineous fish. Agree so far? Good. Now, let's assume that affinity maturation was there at the beginning, and now is left only in mammals and birds, as you say. To gave the picture we see now, all sharks must independently have lost affinity maturation after divergence of bony fish, all bony fish after divergence of amphibians, all amphibians after divergence of reptiles and all reptiles after the independent divergence of birds and mammals. I trust you see the problem, right? The alternative is that affinity maturation was not there at the beginning, and that it evolved once (in a hypothetical common ancestors of birds and mammals) or twice (independently in retiles and mammals). That's called "parsimony".
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yersinia
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posted 12. April 2003 16:42
Nelson's problem is even worse as "fish" "amphibians" and "reptiles" are not monophyletic, i.e. tetrapods are really just one small branch of bony fish, reptiles a branch of amphibians, etc. So in many cases it is multiple lineages losing things even within each group. See the Gnathostomes page at TOL.
(re-reading, I guess Charlie basically said this, so never mind)
Thus Nelson, in order to maintain his "dangerous gap" and the "big bang" of specific combinatorial immunity or whatever you want to call his very peculiarly defined "IC system" here, is now relegated to proposing multiple independent losses of the supposedly key part of the IC mammalian system which supposedly originated in the first jawed vertebrates even though today it is only present in mammals and maybe birds (don't know much about bird immune systems, I would expect substantial differences in detail based on phylogeny).
[ 12. April 2003, 16:45: Message edited by: yersinia ]
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Nel
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posted 12. April 2003 16:45
Yes frameshifts sound really cool and presents a problem for just that transition. The fact that it has a 2/3 chance of frameshift poses a boundary for getting to the human arrangement, (i.e. long strings of Vs Ds and Js) from the clusters that sharks have, fusing VDJ segments has a chance of a frameshift occuring.
Secondly, to say that it was lost in any clade is more parsimounous than to say it evolved from the shark system, even if what you say is true. The question of one or a few antibodies with single specificities comes up, again it's more likely that they lost that instead of wasting resources or completely dying out because they had a few antibodies that were completely useless due to the fact that they had single specificities. Or the problems I describe above concerning useless antibodies altogether due to nonsense combination. But I have no problem in thinking that another Big Bang had to occur when it came to the mammalian system.
In response to Yersinia, no part of the IC system is being discussed here when I say the secondary response may have been lost, the VDJ recombinase/receptor system is still there. As such I have no problem with either saying that another "big bang" had to occur when it came to mammals, and the evidence does show this, or that it was lost in sharks, and present day clades reflect that loss. Either one is fine with me and squares with the evidence. If saying that the mammalian immune system complete with affinity maturation and secondary responses occured abruptly is a more parsimounous scenario for Charlie, he can be my guest and go with that one. This is brainstorms after all.
[ 12. April 2003, 16:53: Message edited by: Nelson_Alonso ]
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yersinia
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posted 12. April 2003 17:55
quote:
In response to Yersinia, no part of the IC system is being discussed here when I say the secondary response may have been lost, the VDJ recombinase/receptor system is still there.
So, single specificities are *not* required for the successful origin of the IC system of combinatorial immunity. Is that what you are saying?
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