BERKELEY, CA — Researchers at the U.S.
Department of Energy's Lawrence Berkeley National Laboratory (Berkeley
Lab) have announced the discovery of two genes that contribute to the
development of asthma. The finding suggests that decreasing the activity
of these two genes could help reduce susceptibility to asthma attacks.
A team led by Dr. Edward Rubin and Derek Symula of Berkeley Lab's Life
Sciences Division, and including scientists from the University of
California, San Francisco campus, worked with transgenic mice (mice that
carry human genes) and found that even subtle changes in the activity of
the interleukin genes IL4 and IL13 can have an important effect on asthma
susceptibility. Their research results were reported in the October 1
issue of the journal Nature Genetics.
More than 14 million people in the United States suffer from asthma and
other chronic respiratory ailments. The number of victims has doubled over
the last 15 years and is still on the rise, with children living in urban
areas particularly susceptible. Medical researchers have no explanation
for this upsurge but it is approaching epidemic stature.
"Thousands of years ago the ancient Greeks observed that asthma
ran in families," says Symula, a post-doctoral fellow who joined
Rubin's research group nearly four years ago to begin an intensive hunt to
identify the genetic factors. "What we knew, at the outset of our
studies, was that one region of the human genome, on chromosome 5, tended
to be inherited in individuals with asthma."
Rubin's group has previously developed mouse models from a variety of
human conditions including Down syndrome, sickle cell disease, and
atherosclerosis. For the asthma study, they eschewed the conventional
approach for identifying genetic links to a specific disease.
Explains Rubin, "Rather than looking at one gene at a time, we
chose to simultaneously examine several genes in parallel, by introducing
8-10 human genes at a time into the genome of mice."
Adds Symula, "We had this several million base pair region from
human chromosome 5 that we knew was somehow involved. The strategy was to
subdivide the region into a few large pieces of DNA and then introduce
these pieces, each composed of several hundred thousand letters of the
genetic alphabet coding for several genes into mice. We expected to then
see changes in processes that are controlled by these genes."
By genetically engineering a library of transgenic mice, each
containing a different segment of the human chromosome, Rubin and Symula
and the other members of the team were able to rapidly sift through 25
genes located in the genetic interval where the "asthma
suspicious" genes had been localized. They then matched physical
features, or phenotypes, of these mice with those characteristics seen in
human asthmatics, to eventually identify IL 4 and IL13 as the genes
responsible for asthma susceptibility in these animals.
Says Rubin, "Although these studies were conducted in mice, not
humans, there are several different lines of evidence supporting the role
of these interleukins in human asthma susceptibility."
Interleukins have long been known to play a role in regulating the
immune system and in particular modulating the inflammatory response.
Evolutionarily IL4 and IL13 are thought to prevent parasitic infection by
generating localized inflammation.
In addition to his research group at Berkeley Lab, Rubin also leads the
functional genomics program at DOE's Joint Genome Institute (JGI), a
collaborative effort between Berkeley Lab and the Lawrence Livermore and
Los Alamos national laboratories as part of DOE's contribution to the
Human Genome Project. Rubin credits his affiliation with JGI as a factor
in the success of the asthma research.
"Our asthma research is a prime example of biology made possible
by the Human Genome Project," he says. "It was our proximity to
the actual group engaged in the genome mapping effort at JGI that led us
into this investigation."
Because asthma is a complex genetic condition in which several genes,
working in concert, ultimately determine an individual’s susceptibility,
it posed a major challenge to the traditional approach to genetic research
which was used to identify single genes responsible for disorders such as
cystic fibrosis and sickle cell disease.
Says Rubin, "The approach we used to pursue asthma genes may now
be applied to other common complex genetic conditions, for instance
hypertension and obesity, where large genomic regions have been implicated
as containing genes contributing to a particular disease."
In addition to Rubin and Symula, other contributors to the Nature
Genetics paper were Kelly Frazer, Yukihiko Ueda, and Mary Stevens, of
Berkeley Lab, plus Richard Locksley and Zhi-En Wang at the University of
California's San Francisco campus. The project was supported by the U.S.
Department of Energy (DOE), and the National Institutes of Health.
Berkeley Lab is a U.S. Department of Energy national laboratory located
in Berkeley, California. It conducts unclassified scientific research and
is managed by the University of California. |