October 4, 1999

 

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BERKELEY, CA ó 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 individualís 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.