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Author
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Topic: Organisms using GAs vs. Organisms being built by GAs
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charlie d.
Member
Member # 159
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posted 12. March 2003 18:25
Nelson:
I need to ask a question first, before I answer your objections. What would you define as the primary, original function of an antigen receptor molecule?
[ 12. March 2003, 18:41: Message edited by: charlie d. ]
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Nel
Member
Member # 614
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posted 12. March 2003 19:23
Charlie,
To recognize foreign substances.
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charlie d.
Member
Member # 159
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posted 12. March 2003 20:17
quote:
Charlie,
To recognize foreign substances.
Well, I'd say is to recognize molecules on pathogens, and to activate immune responses as a result, but that's good enough.
This is indeed the basic function of all antigen receptors. However, innate immune system antigen receptors do exactly the same thing without need for gene rearrangement at all. All that gene rearrangement does, really, is to add extensive variability to antigen recognition, but is not essential for antigen recognition, or for an effective immune function, for instance in invertebrates. Indeed, even many vertebrates (such as chickens, for instance) generate antigen receptor variability without use of VDJ recombination (they still have it, but it's not the source of variability); instead, their Ig genes use a gene conversion process that copies sequences from one of many variable region pseudogenes onto the single productive variable region segment they have, to diversify their antibody V region sequences - in other words, their Ig gene system seems derived, one step more evolved than ours - go figure.
(*)[Note: this is really debatable, many immunologists would say that the purpose of the immune system is more specifically to detect any molecule - not just pathogens - [/i] in the context of a "danger" situation - for example cell death and necrosis. But for our purposes, your definition is fine.]
quote:
Also, AFAIK, Rag-mediated transposition has never been found to be able to occur in cells.
Well, transposases do 2 things: they excise their targets, and they re-integrate it somewhere else. The first is what RAG proteins do all the time, using the exact same process transposases use. As for the second, it is not surprising integration activity would need to be tightly controlled. However, there is evidence that it also occurs, though rarely, and in some cases (as expected) the products can be oncogenic rearragements, for instance: quote:
Blood 2000 Sep 1;96(5):1947-52
V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma.
Vaandrager JW, Schuuring E, Philippo K, Kluin PM.
Using DNA fiber fluorescence in-situ hybridization (FISH) and 3-color interphase FISH, 2 cases of follicular lymphoma were identified in which the BCL2 gene was excised from 18q21 and inserted into the immunoglobulin heavy chain (IGH) locus at 14q32. Both the insertion breakpoint at 14q32 and the deletion breakpoint at 18q21 were cloned using inverse polymerase chain reaction. Sequence analysis showed that the JH sequences were juxtaposed to the 5'-side of BCL2, and the DH sequences were juxtaposed to the 3'-side of BCL2. There were breakpoints at both the JH and DH recombination signal sequences, and N-nucleotides were present at all breakpoint junctions. At the BCL2 locus, the 3'-breakpoints in both cases were localized at exactly the same nucleotide position, 6. 2 kilobase downstream of the major breakpoint region, directly adjacent to a complete cryptic recombination signal sequence (RSS) consisting of a heptamer, a nonamer, and a 23-base pair (bp) spacer. The BCL2 5'-breakpoints were approximately 600 bp upstream of the gene, within the CA repeats. Although less evident than for the BCL2 3'-breakpoints, cryptic RSSs were also identified at these breakpoints, with a 12-bp spacer. On the basis of structural characteristics of these rearrangements, a model is proposed in which the BCL2 gene is deleted from its locus by recombination activation gene-1/-2 (RAG-1/-2)-mediated excision. The gene is subsequently inserted into the recombining IGH locus, a process involving the formation of hybrid joints between the IGH coding ends and the BCL2 signal ends.
I think there is no doubt that the RAG complex is a full-fledged transposase.
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Nel
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Member # 614
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posted 12. March 2003 20:34
Charlie:
This is indeed the basic function of all antigen receptors. However, innate immune system antigen receptors do exactly the same thing without need for gene rearrangement at all. All that gene rearrangement does, really, is to add extensive variability to antigen recognition, but is not essential for antigen recognition, or for an effective immune function, for instance in invertebrates.
Nelson:
But it is indeed essential for immune response to antigens in vertebrates who use V(D)J recombination to respond to antigen. (more on this below).
Charlie:
Indeed, even many vertebrates (such as chickens, for instance) generate antigen receptor variability without use of VDJ recombination (they still have it, but it's not the source of variability); instead, their Ig genes use a gene conversion process that copies sequences from one of many variable region pseudogenes onto the single productive variable region segment they have, to diversify their antibody V region sequences - in other words, their Ig gene system seems derived, one step more evolved than ours - go figure.
Nelson:
You're going off on a tangent. The claim was made that the V(D)J recombination system is not IC. However, in order for the recombination system to do it's job, it needs the RAG machine, it needs the signals, and if it doesn't have the receptors there is pretty much no point to the entire process. In biology, a lot of molecules bind to each other. Antigens binds antibodies (or vice versa) with a very high avidity/affinity. Proteins bind to receptors with a similarly high affinity. What makes an antibody unqiue is that it is manufactured in response to antigenic challenge. Innate immune receptors exist in the absence of any previous exposure to a molecule.
But anyway, these chickens do it via homologous recombination which is just as IC (if not more). But again, you're digressing.
Nelson:
Also, AFAIK, Rag-mediated transposition has never been found to be able to occur in cells.
Charlie:
Well, transposases do 2 things: they excise their targets, and they re-integrate it somewhere else. The first is what RAG proteins do all the time, using the exact same process transposases use. As for the second, it is not surprising integration activity would need to be tightly controlled. However, there is evidence that it also occurs, though rarely, and in some cases (as expected) the products can be oncogenic rearragements, for instance:
Nelson:
Thanks for the citation I'll give it a good read and give you my thoughts. However, granting that the VDJ recombinase can do transposition, I'm still left with the question of what the origin of either system is, if both are just as IC as the other. I mean to explore this further.
[ 12. March 2003, 20:47: Message edited by: Nelson_Alonso ]
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charlie d.
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Member # 159
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posted 13. March 2003 08:20
quote:
Nelson:
But it is indeed essential for immune response to antigens in vertebrates who use V(D)J recombination to respond to antigen. (more on this below).
Sure, but that's a big fat tautology. By your own, correct definition, the "core" function of an antigen receptor is to recognize antigens. That can be effectively accomplished without VDJ recombination, as it is by by scores of innate system receptors. quote:
Nelson:
You're going off on a tangent. The claim was made that the V(D)J recombination system is not IC. However, in order for the recombination system to do it's job, it needs the RAG machine, it needs the signals, and if it doesn't have the receptors there is pretty much no point to the entire process. In biology, a lot of molecules bind to each other. Antigens binds antibodies (or vice versa) with a very high avidity/affinity. Proteins bind to receptors with a similarly high affinity. What makes an antibody unqiue is that it is manufactured in response to antigenic challenge. Innate immune receptors exist in the absence of any previous exposure to a molecule.
But anyway, these chickens do it via homologous recombination which is just as IC (if not more). But again, you're digressing.
Actually, antibodies are not manufactured in response to antigenic challenge. Antibodies are manufactured all the time, through VDJ recombination, in bone marrow B lymphocyte precursors, regardless of antigen challenge. What happens after antigen challenge is that one of the billions of mature lymphocytes, each carrying a unique, randomly assembled antibody is selected by its recognition of antigen, expanded, and activated.
And this is not a tangent, it's the core of my argument (and, I think, Inlay's) that IC is built by co-option all the time. You are correct: our antibody system needs the signal sequences, and the RAG genes, and antibody genes, and none workes without the others. That's Behe's original claim. However, he was wrong: the function of antibodies (antigen recognition) can be expleted by non-rearranging antigen receptors (ie, you can preserve the core function without two of three components). Conversely, the activity of RAG proteins is expleted all the time, in the context of a different core fucntion, by transposases in the absence of antigen receptor genes. The two came together, given the appearance of an "IC" system, by co-option.
Similarly, the chicken example was just to show another co-option twist. Instead of generating variability through the available gene rearrangement system similar to ours, chickens evolved to exploit yet another pre-existing function, gene conversion/homologous recombination (that the latter also is "IC" is entirely irrelevant) - chicken now have a four-level "IC" antigen receptor system: they need antigen receptor genes, their RSSs, RAGs, and gene conversion. If we were chickens, we would call that the basic IC system, but to our human perspective it just seems as an "addendum", and not particularly essential (after all, we make perfectly good antibodies without gene conversion, which is only essential to the chicken system).
The whole story just shows how entirely pervasive co-option is in evolution, and how it commonly generates the appearance of more and more complex "IC" systems.
[ 13. March 2003, 08:21: Message edited by: charlie d. ]
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yersinia
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Member # 324
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posted 13. March 2003 16:32
quote:
Nelson:
But it is indeed essential for immune response to antigens in vertebrates who use V(D)J recombination to respond to antigen. (more on this below).
This is rather like saying,
"The 9+2 arrangement of cilia is indeed essential for motility in protozoans who use 9+2 cilia for motility."
nic
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yersinia
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posted 13. March 2003 16:36
quote:
The whole story just shows how entirely pervasive co-option is in evolution, and how it commonly generates the appearance of more and more complex "IC" systems.
I would say that evolution *does* produce IC systems, full stop, *if* IC is defined on criteria other than evolvability.
The reason the definition of IC sometimes gets shifted to *include* evolvability is that, if IC can evolve, then it ceases to become a reliable indicator of ID. Including evolvability in the definition safely removes it from potential falsification by showing that X, Y, or Z evolved. Dembski's "specified complexity" and Bracht's "hypervolume" figured out this trick long ago...
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Nel
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Member # 614
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posted 14. March 2003 23:38
Charlie, the various elements that particpate in innate immunity do not exhibit specificty against the foreign substances I referred to. In fact, with aquired immunity, it always exhibits such specificity. Aquired immunity is a response to antigenic challenge. The first encounter with an antigen that has gotten through innate defenses triggers a chain of events that induces an immune response with specificity against that antigen.
Secondly, we don't see IC being built by co-option all the time. What see is the use of different machines for the same purpose. Which is why your foray into how chickens do it was completely irrelevant to my discussion of whether the V(D)J recombinase is IC. You stated that with respect to this system IC "dissolves". It doesn't. I can get to florida by a lot of different kinds machines, organisms can achieve antibody diversity through different kinds of machines. This doesn't show that it isn't IC at all. The fact that homologous recombination is IC is not irrelevant, as IC is in an indicator of an intelligent origin for the system in question, and presents a problem for Darwinian pathways, in my opinion at least.
Thirdly, note that the co-option story here is pretty much like the flagellar stories. Function is not preserved. This does not show Behe is wrong, because such indirect pathways are accessible to IC systems. There is no evidence that these systems came together via RM&NS. In fact, this is a case where I think aquired immunity was poised to evolve, but I doubt, because of IC, that a stochastic process had anything to do with it.
Inlay , and yourself, erroneously state that Behe is wrong because innate receptors exist. So what? That wasn't Behe's point. You say that Behe is wrong because you can think of a different function for V(D)J recombinase, so what? That wasn't Behe's point either. In fact, that you can make the system do something different because of it's subsets is expected from machines.
Presevering the function, if the function of the V(D)J recombinase is to mediate the rearrangement of receptor genes in B and T cells, then you absolutely need these receptors or the whole thing is pointless. I don't see why showing me a transposase shows he is wrong. Secondly, Inlay, in my opinion misinterepreted Behe when he talked about a few antibodies.But I'll get into that later.
[ 14. March 2003, 23:50: Message edited by: Nelson_Alonso ]
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Nel
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posted 14. March 2003 23:43
Yer wrote:
This is rather like saying,
"The 9+2 arrangement of cilia is indeed essential for motility in protozoans who use 9+2 cilia for motility."
Nelson:
Well actually no. If you are born in a gnotobiotic environment,and hence never are colonized or invaded by bacteria, you will still have LPS receptors, peptidoglycan receptors, Fc receptors, CD11/CD18, etc.
The actual binding events are the same. But as I said, thats true of a lot of things in Biology. It doesn't show that Behe was wrong in this case.
In my opinion, the more complex an IC system, the harder it is for indirect Darwinian pathways to get to one. And we are seeing that with systems like these.
[ 14. March 2003, 23:49: Message edited by: Nelson_Alonso ]
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yersinia
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posted 15. March 2003 02:44
?????
(By this, I mean that I find Nelson's previous post entirely uninterpretable...perhaps someone could help me out, what is he trying to say?)
[ 15. March 2003, 02:46: Message edited by: yersinia ]
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yersinia
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posted 15. March 2003 02:56
quote:
Thirdly, note that the co-option story here is pretty much like the flagellar stories. Function is not preserved.
Sure it is. Antigen receptors existed long before rearranging. They still exist today, encoded in genomes to recognize common invader proteins like bacterial flagellins. Rearranging is just an add-on perk that increases receptor diversity and allows for acquired immunity (reducing the chances of re-infection). Most metazoans get by with just regular antigen receptors today.
Now sure, you can set up a definition where "rearranging antigen receptor" is the function instead of just "antigen receptor" but this just goes to show how subjective it is to define "function" in biology. With the same logic I can declare the 9+2 cilium IC because the 9+2 structure is required to have 9+2-dependent motility.
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charlie d.
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Member # 159
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posted 15. March 2003 08:40
Nelson:
I don't have much time today. I think your definition of ICness for the antigen receptor system now goes against your own initial definition, and is entirely tautological.
I even notice that now your functional focus has changed from the "antigen receptors" to "VDJ recombinase", to better support your "change-of-function-is-excluded" rhetorical argument. Alas, what matters to an organism are functional antigen recpetors, no matter how assembled, not functional VDJ recombinase.
It just goes to show what an empty shell of the original claim IC has now become. It's a problem for evolution, and evidence for intelligent design, only under carefully crafted, entirely artificial argumentation rules that exclude all the viable evolutionary alternatives to ID. Well, big deal. The world does not act according to such rules, so the point is mute.
Finally, you are still misunderstanding the immunology - but today almost feels like spring and I'll be darned if I spend it here. Maybe later tonight. See y'all.
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Nel
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posted 15. March 2003 18:46
Yersinia and Charlie,
As for the reply you didn't understand, I was showing that my definition is not a tautology. And this reply is relevant to your second post as well. This has nothing to do with the logic that you employ with 9+2 cilia. In both cases, with your cilia illustration, we are talking about the same pattern, and the same cilia.
However, as I clearly showed in my posts in this thread, Behe correctly defined an antibody when he described them as having single specificities. As I showed, Inlay was wrong when he said that innate receptors have single specificities. For example, the scavenger receptor A recognizes ac-LDL, altered forms of bovinew serum albumin, pI:pC, and more.
This is relevant to both Inlay's and Behe's point. A receptor that had only a single specificity is useless, since an organism is likely to encounter various foreign substances. Thats why, although some organisms can get by with only an innate immune response, they don't do so for very long, most likely you and I wouldn't get by at all.
This is a point I mean to get into a lot more, but let me respond to Charlie then I'm going to enjoy the sun as I have been living under 100 feet of snow for the past two months.
Charlie,
Behe's point is that the Rag machine, the signals, and yes, the antibodies are needed for function. Neither you nor Inlay have shown otherwise. And a vertebrate with just a few antibodies would quickly die when it gets eaten alive by the foreign substance that it had no specificity for. Telomerases and innate receptors are irrelevant. Most likely I'll find the same errors when looking at the other aspects of the immune response. But one at a time.
Charlie thinks that I somehow changed my definition of IC. He didn't go into this so I'll just wait until he comes back, hopefully he will explain it then.
[ 15. March 2003, 18:59: Message edited by: Nelson_Alonso ]
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yersinia
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posted 15. March 2003 20:16
quote:
This is relevant to both Inlay's and Behe's point. A receptor that had only a single specificity is useless, since an organism is likely to encounter various foreign substances. Thats why, although some organisms can get by with only an innate immune response, they don't do so for very long, most likely you and I wouldn't get by at all.
They "get by" long enough to reproduce, don't they?
Anyway, are you saying that organisms with short lifespans can get by with just an innate immune system, but that e.g. higher vertebrates need more? I would agree with you that this is at least a plausible general pattern (I'm sure there are some exceptions, there always are in biology...).
But first, is this why you think that rearranging receptors are IC? That their specific function is necessary for e.g. long-lived vertebrates?
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