A team led by Johns Hopkins scientists has found the first clear evidence that the process behind the human immune system's remarkable ability to recognize and respond to a million different proteins might have originated from a family of genes whose only apparent function is to jump around in genetic material.
"Jumping genes" essentially cut themselves out of the genetic material, and scientists have suspected that this ability might have been borrowed by cells needing to build many different proteins from a specific, single set of instructions -- the key to recognizing a million immune-stimulating proteins. But until now, no jumping gene was known to behave just right.
Writing in the Dec. 23 issue of Nature, the researchers show that a jumping gene called Hermes, still active in the common house fly, creates changes in DNA very much like those created by the process behind antigen recognition.
"Hermes behaves more like the process used by the immune system to recognize a million different proteins, called antigens, than any previously studied jumping gene," says Nancy Craig, Ph.D., professor of molecular biology and genetics in Johns Hopkins' Institute for Basic Biomedical Sciences and a Howard Hughes Medical Institute investigator. "It provides the first real evidence that the genetic processes behind antigen diversity might have evolved from the activity of a jumping gene, likely a close relative of Hermes."
Recognition of so many antigens allows the immune system to fight infection and distinguish friend from foe. The "big picture" behind this ability is that cells build proteins called antibodies that bind to particular antigens, but the early steps of that process have been difficult to study. Hermes should help reveal some secrets of this process, the researchers say.
"The immune system takes an approach to protein building similar to that of diners creating a meal at a cafeteria, but how the immune system's 'a la carte' process happens is still murky," says Craig.
But the a la carte approach provides great diversity from a limited number of choices, whether in the immune system or in a cafeteria. For example, at a cafeteria, one diner could have a meal of mashed potatoes, broccoli and a pork chop, and another French fries, salad and a hamburger, and so on through all the possible combinations of offerings.
While the choices aren't as tasty, immune cells select sections of certain genetic instructions in order to make instructions for a protein that will recognize a particular antigen. Machinery snips out unwanted genetic sections and reconnects the leftover ones, creating a unique gene (the cellular equivalent of the diner's meal). Snipping out different sections will lead to a different gene, carrying instructions for a different protein that will recognize a different antigen, and on and on.
This a la carte process, known as V(D)J recombination, is similar to the excision of jumping genes, but none had matched one of its characteristic oddities: As the unwanted DNA is being removed, the remaining DNA forms a tiny loop.
Unexpectedly, when Hermes is being cut out of the DNA, the leftover DNA also forms a hairpin loop, temporarily doubling back on itself, postdoctoral fellows Liqin Zhou, Ph.D., and Rupak Mitra, Ph.D.,discovered in experiments in test tubes and with E. coli bacteria.
Although this loop distances Hermes from its well-studied cousins, the Hermes protein still has an important family trait, the researchers report. Colleagues at the National Institutes of Health found that a few key building blocks in the protein's DNA-snipping crevice are identical to those in other jumping genes' proteins, even though the overall sequence is quite different.
"Because of its similarities both to V(D)J recombination and to other families of jumping genes, Hermes is the first real link between the two processes," says Craig. "It also is likely to be a good model to figure out what's happening early on in V(D)J recombination."
Understanding how Hermes and other jumping genes work also holds clues to fighting bacterial infections, improving gene therapies and tackling disease-carrying insects, Craig notes. Bacterial jumping genes can protect bacteria from certain antibiotics. Scientists also are studying jumping genes as vectors to carry gene therapies and as potential modifiers to disrupt the growth-controlling genes of organisms such as mosquitoes and medflies.
The Hopkins researchers were funded by the Howard Hughes Medical Institute. Authors on the paper are Zhou, Mitra and Craig of Hopkins; Peter Atkinson of the University of California, Riverside; and Alison Burgess Hickman and Fred Dyda of the National Institute of Diabetes and Digestive and Kidney Diseases.
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