Mutations have a bad reputation: They can cause cancer and many genetic diseases. But our immune system benefits from genetic typos, which help create a wide variety of antibodies that cling tightly to their "prey," maximizing the chances that some will be effective. Now, researchers have identified one of the enzymes responsible for this blessedly sloppy work.
When challenged by a virus or other invader, some B cells churn out millions of highly specific antibodies as a first line of defense. These B cells then go through a boot camp in the lymphoid organs, where they are trained to fine-tune their antibody arsenal against the intruder. In a process called somatic hypermutation, the antibody genes accumulate random mutations a million times faster than the rest of the genome. The B cells that churn out the best antibodies get to proliferate, making the immune response much more effective the next time it encounters the same pathogen.
What's responsible for all these errors? Scientists have long suspected a DNA polymerase: an enzyme that usually copies DNA during cell division. Out of the dozen such polymerases in humans, immunologist Patricia Gearhart and her colleagues at the National Institute on Aging in Bethesda, Maryland, focused on DNA polymerase h, which was known to be highly error prone. They teamed up with clinicians studying a rare genetic disorder called xeroderma pigmentosum variant (XP-V). Patients with this disease have mutations in the gene for DNA polymerase h that might reveal a role for the polymerase in B cells.
It did. After Gearhart and her team sequenced more than 100 antibody genes from three XP-V patients, they discovered an "amazing thing" in the letters of the genetic code, Gearhart says: There were far fewer mutations in A's and T's, and far more in G's and C's. That suggested that DNA polymerase h, when fully functional, generates typos opposite A and T in the antibody genes. (The findings also imply that another polymerase, one that is particularly careless with G's and C's, takes over polymerase h's role in XP-V patients, Gearhart says.)
The results fit with a test tube study of DNA polymerase h by Thomas Kunkel of the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, and his colleagues, published alongside Gearhart's in the June issue of Nature Immunology. "The two studies complement each other nicely, and they imply that DNA polymerase h does indeed play a role in somatic hypermutation," says molecular biologist Ursula Storb of the University of Chicago.