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
"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,"
said Nancy Craig, 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," Craig said.
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
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
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
and Rupak Mitra 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,"
Craig said. "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 noted. 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
The Hopkins researchers were funded by the Howard
Hughes Medical Institute. Authors on the paper are Zhou,
Mitra and Craig, all of Johns Hopkins; Peter Atkinson,
University of California, Riverside; and Alison Burgess
Hickman and Fred Dyda, National Institute of Diabetes and
Digestive and Kidney Diseases.