Origin of the Immune System

Science 1 May 2009:
Vol. 324. no. 5927, pp. 580 – 582
DOI: 10.1126/science.324_580

On the Origin of the Immune System
John Travis

“The elucidation of VDJ recombination gradually exposed immunology’s big bang, recalls David Schatz of the Yale School of Medicine. By 1990, he and other colleagues then working in David Baltimore’s lab at the Whitehead Institute for Biomedical Research in Cambridge had identified two genes essential to VDJ recombination, RAG1 and RAG2 (for recombination-activating genes). Sharks and all the other jawed vertebrates with adaptive immunity have these genes, but all the evidence at the time indicated that hagfish, lampreys, and invertebrates didn’t. So, where did RAG1 and RAG2 come from?

Several clues, including that the two genes are located immediately next to each other, prompted Schatz and his colleagues to wonder whether the pair had once been part of a DNA recombination system in fungi or viruses that got incorporated into vertebrates. As immunologists teased out what the proteins encoded by the two did, they realized the molecules are the scissors and knitting needles that cut out all but one V, D, and J and stitch those remaining three gene segments together.

In 1995, Craig Thompson, then at the University of Chicago in Illinois, formally proposed that the DNA now encoding RAG1 and RAG2 was once a mobile genetic element called a transposon. Transposons can cut themselves out of one DNA sequence and stick themselves back in another, so immunologists could envision those skills being co-opted to recombine V, D, and J gene segments. In this “transposon hypothesis,” Thompson suggested that at some point after jawed and jawless vertebrates split into two branches, about 450 million years ago, a transposon invaded the former lineage, perhaps brought in by a virus that infected a germ cell. Boom—the enzymes that would ultimately provide adaptive immunity, by creating diverse antibodies and T cell receptors, were now in place and could mutate into that new role.

Many research teams began trying to verify the transposon hypothesis. In 1998, for example, Schatz’s team and one led by Martin Gellert of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, independently showed that the enzymes encoded by RAG1 and RAG2 could, in addition to cutting out DNA sequences, actually insert one stretch of DNA into another. In a commentary in Nature, immunologist Ronald Plasterk of the Netherlands Cancer Institute in Amsterdam expressed the awe of many at this solid evidence of the transposon hypothesis. “We may owe our existence to one transposition event that occurred 450 million years ago,” he wrote.”

VDJ are different variable, diversity, and joining genes that generate incredible diversity in immunoglobulin (Cellular Immunology blog) and thus in our immune systems. RAG1 and RAG2 are recombination activating genes.

The VDJ recombination mechanism in jawed vertebrates is catalyzed by the RAG1 and RAG2 proteins, which are believed to have emerged approximately 500 million years ago from transposon-encoded proteins. Although no transposase sequence similar to RAG1 or RAG2 has been found, the approximately 600-amino acid “core” region of RAG1 required for its catalytic activity is significantly similar to the transposase encoded by DNA transposons that belong to the Transib superfamily. It has been demonstrated that recombination signal sequences (RSSs) were derived from terminal inverted repeats of an ancient Transib transposon. Furthermore, the critical DDE catalytic triad of RAG1 is shared with the Transib transposase as part of conserved motifs.[r] These findings refute one of [Michael] Behe’s claims for irreducible complexity of complex biochemical features.

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