rafe gutman
Posts: 27
Joined: May 2002
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although it doesn't reference anything, i came across a post of mine where i present a model for the origin of the adaptive immune system. since it's original material (the wording, that is, the model itself has been around for awhile), i thought i'd post it here as well:
| Quote | here's a run down of the general details of this model
1. the RAG genes and RSSs were originally a transposon, and the RAG proteins had transposase activity.
2. a gene existed in the ancestor to the jawed vertebrates that encoded a receptor with at least one immunoglobulin domain
3. this gene was only expressed in a somatic lineage, like hemocytes
4. the receptor could activate a pathway somehow involved in immune-related function
5. the RAG transposon integrated into the receptor near the binding site-coding region.
6. once inserted, the transposase
would be under the receptor's transcriptional control.
7. the RAG's ability to reassemble the receptor gene once activated was sloppy, and made slight sequence changes upon reassembly.
8. those changes were beneficial to the host
and the evidence supporting it:
1. there seems to be ample evidence suggesting that the RAG genes were once transposases, do you dispute this? the fact that they have transposase activity (in vitro) basically says it all.
2. the immunoglobulin domain is well-represented in nearly all organisms (even prokaryotes, i think). because its structure is so stable, a large portion of cell-surface molecules possess it, even some related to immunity (outside of the jawed vertebrates). however, no direct homologue to the antibody proteins have been found. so here is a prediction of the model: a non-rearranging receptor with an immunoglobulin domain existed in the ancestor to the jawed vertebrates. of course, this ancestral gene may no longer exist, but if it is ever discovered, that would fill in a major hole.
3. a lot of genes have tissue specific expression. as for the extant antibody genes, they are heavily regulated by enhancers (because of the need to prevent premature recombination, or recombination on both alleles). there's no reason to think that the enhancer wasn't there in the ancestral receptor (such as, if it was located between the V and J segments).
4. see 2.
5. this is the only step that appeals to chance. as yersinia said, there could have been many integrations by transposons (our genome is littered with remnants of retrotransposons). all it takes is one to be beneficial, and it will become fixed into the population.
6. a common molecular technique is transgenics, where whole genes are inserted into the chromosome randomly. one of the main problems with this approach is the lack of consistency in transgene expression. this is because the transgene becomes subject to the local transcription control. unless the transgene has a really powerful promoter, it's uncertain whether or not it will be expressed correctly.
7. the current mechanism of RAG-mediated recombination is sloppy. one of the reason is through the generation of hairpin loops at the two exposed ends. this is intrinsic to the activity of the RAG and is common to transposases (in fact, this is one of the observations that led scientists into thinking the RAGs were originally transposons).
8. here the evidence may never be to your satisfaction, but it's very reasonable to suppose that a high rate of mutation would benefit immune receptors. why do you think new flu vaccines come out every season? because the influenza's receptors can mutate very rapidly to avoid host recognition. furthermore, they don't need to mutate drastically and change the total structure of their receptors, only just enough to hamper the host's receptor's binding ability. if during tthe lifetime of the first RAG-integrated organism, one of the thousands to millions of hemocytes alive at the time form a receptor beneficial to the host, this will increase the host's chances for survival and the nature will have something to select upon.
maybe this requires more evidence to convince you, but is it really that unreasonable? |
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