Monday, April 03, 2006

Details about the RAG genes used in the human immune system.

RAG genes are involved in shuffling human antibody genes.

V and J segments mentioned below are the parts of the antibody gene that get shuffled as part of a complex and important normal human reponse to infection.

RAG1 evolved from mobile genes called transposons , otherwise called transposable elements (TEs) that move between species.

This posting is background, documentation of scientific detail, and explanation for an item about Transib transposons which perhaps should be read first

Readers who are new to mobile DNA might also find it good to read more about Mariner.

Another useful post for orientation is here.

In the review quoted Margaret Kidwell provides a good discussion of RAG1 genes plus key references in a marvellously readable and ground-breaking article in Trends in Ecology & Evolution, only part of which is quoted below.

Transposable elements and host genome evolution

Margaret G. Kidwell and Damon R. Lisch
Dept of Ecology and Evolutionary Biology, The University of Arizona,
Dept of Plant and Microbial Biology University of California at Berkeley

Selected quote:

Dramatic evidence has been provided that V(D)J recombination in vertebrate lymphocytes is the product of ‘domesticated’ TE activity[37 and 38]. V(D)J recombination is a site-specific recombination reaction that occurs specifically in developing oocytes of vertebrates and plays a part in generating their vast repertoire of immunoglobulins and T-cell receptors. In this reaction the V (variable), J (joining) and D (diversity) gene segments that encode the variable portion of the T-cell antigen receptors are joined together to form the exon that encodes the antigen-binding portion of the polypeptide. Experiments using the products of the Rag1 and Rag2 genes demonstrate that these enzymes can catalyse transposition events in vitro, therefore supporting earlier speculation that these genes were carried by a TE originally (Fig. 4). These results suggest that a fundamental component of the vertebrate immune system probably evolved from a transposon, whose capacity for DNA rearrangement was exploited to produce rapid somatic variability in specific host cells.

Trends in Ecology & Evolution
Volume 15, Issue 3 , 1 March 2000, Pages 95-99

37. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system.

Immunoglobulin and T-cell-receptor genes are assembled from component gene segments in developing lymphocytes by a site-specific recombination reaction, V(D)J recombination. The proteins encoded by the recombination-activating genes, RAG1 and RAG2, are essential in this reaction, mediating sequence-specific DNA recognition of well-defined recombination signals and DNA cleavage next to these signals. Here we show that RAG1 and RAG2 together form a transposase capable of excising a piece of DNA containing recombination signals from a donor site and inserting it into a target DNA molecule. The products formed contain a short duplication of target DNA immediately flanking the transposed fragment, a structure like that created by retroviral integration and all known transposition reactions. The results support the theory that RAG1 and RAG2 were once components of a transposable element, and that the split nature of immunoglobulin and T-cell-receptor genes derives from germline insertion of this element into an ancestral receptor gene soon after the evolutionary divergence of jawed and jawless vertebrates.

A. Agrawal et al.,
Nature 394 (1998), pp. 744–751.

38. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations.

The RAG1 and RAG2 proteins are known to initiate V(D)J recombination by making a double-strand break between the recombination signal sequence (RSS) and the neighboring coding DNA. We show that these proteins can also drive the coupled insertion of cleaved recombination signals into new DNA sites in a transpositional reaction. This RAG-mediated DNA transfer provides strong evidence for the evolution of the V(D)J recombination system from an ancient mobile DNA element and suggests that repeated transposition may have promoted the expansion of the antigen receptor loci. The inappropriate diversion of V(D)J rearrangement to a transpositional pathway may also help to explain certain types of DNA translocation associated with lymphatic tumors.

K. Hiom et al.,Cell 94 (1998), pp. 463–470.

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