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Diverse Immunity Traced to Rogue Genes

A small piece of parasitic DNA that appears to have invaded the ancestral vertebrate genome some 450 million years ago may be the key to the incredible diversity of the human immune system. Researchers report in tomorrow's Nature that the enzymes responsible for shuffling immune genes into new combinations are relics of an ancient transposon, a piece of DNA that can slip in and out of a genome and is usually thought to serve no other purpose than to ensure its own replication.

The powerful diversity of the immune system arises from white blood cells, which cut and paste their genes to create proteins capable of recognizing a wide variety of pathogens. Two enzymes, called Rag1 and Rag2, help rearrange the genes. Since the genes for these enzymes are located near each other on the human chromosome 11 and are compact, molecular biologist David Schatz of Yale University and his colleagues suspected that Rag1 and Rag2 are transposases--enzymes whose genes are usually part of a transposon and which help this mobile piece of DNA move in and out of genomes.

To check, they purified the enzymes, added them to a solution containing synthetic DNA, and watched what happened. As in white blood cells, the enzymes linked together and cut out a specific piece of DNA. In the body, this stretch would immediately form a closed circle and be discarded. But during this experiment, the team observed the enzyme-escorted DNA behaving much more like a transposon: The enzymes caused the DNA strand to insert into other DNA. In some cases, its free ends linked with the middle of the strand, much as transposons are observed to do.

The finding helps explain why the adaptive immune system seems to have appeared so abruptly during evolution. Unlike most vertebrate features, the immune system has no counterpart in invertebrates, which have a fixed repertoire of cellular and biochemical defenses against infections, says Ronald Plasterk, a molecular biologist at the Netherlands Cancer Institute in Amsterdam. And because jawless vertebrates lack this modern immune system as well, Schatz thinks the transposon entered the vertebrate genome just as jaws began to arise, some 450 million years ago. A well-timed snip from a transposon could have set the stage for the many gene duplications that make the immune system so versatile. "We may owe our existence to this one event," says Plasterk. "We wouldn't be here without this flexibility."