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Release: Feb. 19, 2002
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UI researchers find additional genes that may code for body's natural
IOWA CITY, Iowa -- To defend against everyday encounters with bacteria,
the human body's immune system produces a shield of natural peptide and protein
antibiotics. Beta-defensin genes are known to code for one class of these
antimicrobial peptides. Yet only five beta-defensin genes previously were
identified in the human genome.
Using a completely computer-based search strategy, investigators in the
UI Colleges of Medicine and Engineering have found 28 additional human beta-defensin
genes, bringing the total to 33. The findings, which could have implications
for understanding the underlying molecular defects that cause cystic fibrosis,
appear in the Feb. 19 issue of the Proceedings of the National Academy of
Additional research is needed to determine whether the newly discovered
beta-defensin genes actually code for antimicrobial peptides, said Paul McCray,
M.D., UI professor of pediatrics and the study's corresponding author and
principal investigator. He and co-principal investigator, Brian Schutte, Ph.D.,
UI assistant professor of pediatrics, will want to learn where the peptides
are made in the body and what organisms they kill.
"Our main goal now is to figure out which members in this new set of
beta-defensin family members are important for protecting the lungs against
infection," McCray said. "Then we can think about how that protection
process might be altered in cystic fibrosis and consider interventions."
The possibility of additional infection-fighters in the lungs might add
to understanding of the chronic lung infections in people with cystic fibrosis.
The disease alters the normal defenses of the lung-lining surface. One way
this happens is by making antimicrobials less effective. The resulting bacterial
infections cause an overactive immune response that leads to inflammation
and tissue damage.
While additional research lies ahead, the path to finding the beta-defensin
genes required an interdisciplinary effort involving the UI College of Medicine
and the UI College of Engineering. The team used an innovative combination
of two computer search programs, BLAST and HMMER.
When the research team started their project two years ago, only five beta-defensin
genes were known. "We thought there were more," Schutte said. "These
beta-defensin genes are very small and hard to find using a single search
method. We hypothesized that if we could get more of the sequence from the
human genome and scan it in new ways, we would find additional beta-defensin
With that idea, the researchers turned to Thomas Casavant, Ph.D., UI professor
of electrical and computer engineering. He suggested they use the HMMER software
(based on a mathematical technique employing Hidden Markov models), along
with the more traditional BLAST software, and apply the tool to the entire
genome -- some three billion base pairs of DNA.
Using HMMER to scan the entire genome normally requires 48 hours of processing
time on a single high-performance computer workstation. However, by using
a technique that employs 32 processors in a "cluster" computer,
this time was reduced to about three hours.
"Each time we did these reiterations with HMMER and BLAST, we refined
the model," Casavant said.
Casavant explained that BLAST uses one model sequence to look for similarities,
whereas HMMER takes all the sequences already documented and uses them to
find comparable sequences. He compared the use of the two tools to a complimentary
search for members of the Osmond family, as an example.
"Using BLAST is like taking a picture of just one of the Osmonds and
then looking for other people who look like that individual," Casavant
said. "Using HMMER is like taking a family portrait of the Osmonds and
using the ensemble to look for people who look similar."
"Using BLAST and HMMER together turns out to be much better than using
either one of them alone," added McCray.
Several UI students played essential roles in the time-intensive programming
and analysis, including Jesse Walters, an undergraduate in electrical and
computer engineering; Joseph Mitros, who initially participated in the research
through the Interdisciplinary Summer Undergraduate Research Program and now
is a research assistant in pediatrics; and Jennifer Bartlett, a student in
the Genetics Ph.D. Program.
"The students were key," McCray said. "Their seats were firmly
attached to the chairs in front of their computers."
Other UI contributors included Hong Peng Jia, M.D., a research scientist
in pediatrics; and Michael J. Welsh, M.D., the Roy J. Carver Chair in Physiology
and Biophysics, UI professor of internal medicine and physiology and biophysics,
and a Howard Hughes Medical Institute investigator.
The study was funded in part by grants from the National Heart, Lung, and
Blood Institute and the National Institute of Child Health and Human Development,
both part of the National Institutes of Health, and from the Howard Hughes
Medical Institute. Casavant also received a Cystic Fibrosis Genome Analysis
Information about McCray's and Casavant's laboratories is available online
at, respectively: http://mccraylab.genetics.uiowa.edu/ and http://genome.uiowa.edu/.
In addition, information about
Welsh's cystic fibrosis research is at the following Howard Hughes Medical
Institute Web site: http://www.hhmi.org/research/investigators/welsh.html.
For information about cystic fibrosis, visit the Cystic Fibrosis Foundation
online at http://www.cff.org/
University of Iowa Health Care describes the partnership between the
UI College of Medicine and the UI Hospitals and Clinics and the patient care,
medical education and research programs and services they provide. Visit UI
Health Care online at http://www.uihealthcare.com/.