Gene maps of simpler life forms point the way to human disease gene
In an experiment that demonstrates how maps of the genetic codes of simpler organisms can shed light on human disease, a computerized comparison of the complete genetic codes of a type of algae, a weed and humans has led medical researchers to a gene linked to a human illness.
The comparison allowed researchers at Washington University School of Medicine in St. Louis to locate human genes that code for proteins likely to become part of hair-like structures on cells known as cilia or flagella. Researchers at Johns Hopkins University used the findings to pin down the location of a gene that contributes to Bardet-Biedl Syndrome (BBS), a rare genetic condition that causes blindness, mental retardation, severe obesity and many other problems.
The genetic comparison was arranged by Susan Dutcher, Ph.D., professor of genetics and of cell biology and physiology at Washington University. Dutcher studies cilia in the green alga Chlamydomonas. The work will be published in the May 14 issue of Cell.
"Almost every cell in the human body has cilia," Dutcher says. "Cilia that are active early in development ensure that organs like the heart and stomach end up where they’re supposed to be. Cilia clear away dirt and bacteria in the respiratory tract, help sperm swim and help keep fluid flowing into and out of the brain, just to name a few examples."
Cilia and basal bodies, the structures that anchor them on the surfaces of cells, are complex. Scientists estimate that cells use at least 250 proteins to build cilia and an additional 150 for basal bodies.
Studying algae allows Dutcher’s group to isolate and manipulate cilia more easily. Simpler life forms like Chlamydomonas often have genes for many basic cellular structures and functions that were wholly or partially preserved through the evolutionary development of more complex life forms. This Dutcher means genes in the alga that help build cilia often have matches in the human genetic code that contribute to cilia construction.
Although evolution generally tends to preserve genes for basic functions that work well, exceptions have occurred during major environmental shifts. Dutcher took advantage of one of these exceptions to set up her comparison: Plants discarded their cilia when they left the ocean for land.
"That meant we could first have the computer look for all the gene matches between the algae and humans," Dutcher explains. "Next, we brought in the genetic code for Arabadopsis, a land plant, and eliminated any matches we found, assuming that those matches are genes for basic cell structures and functions that are not involved in the creation of cilia."
The comparison between genetic codes of the human and the alga produced 4,348 "fairly good" matches, according to Dutcher. In that pool of common genes, the genetic code of Arabidposis, sequenced by Washington University’s Genome Sequencing Center and Cold Spring Harbor Laboratory in 2000, has 3,660 matching genes. That left 688 genes. Comparisons with the genetic codes of the fruit fly, mouse and sea squirt, a small ocean-going animal, narrowed the results down to 200 to 300 genes.
Dutcher applied several tests to check the accuracy of the results.
"For example, we found the comparison had highlighted 92 percent of the 62 genes that we already knew were real components of flagella and basal bodies," Dutcher says. "This absolutely flabbergasted the computational biologists who helped us run the comparison. They thought we’d get more noise."
Dutcher also found that the comparison had singled out several genes already linked to polycystic kidney disease and other conditions that affect proteins in cilia. Intrigued by the possibility of using the results to identify new disease genes, she contacted Nicholas Katsanis, Ph.D., assistant professor in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University. Katsanis studies BBS, which is caused by problems in cilia. Mutations in six genes already had been shown to contribute to BBS or conditions like it; a seventh was thought to be in a region on chromosome number two, but the area was very large and contained nearly 230 genes.
Dutcher’s analysis had highlighted two genes in that region, and when Katsanis’ group sequenced the genes in families of patients with the condition, they found several families had abnormalities in one of the genes and named it BBS5.
Dutcher plans to study additional genes identified by the comparison.
"It’s amazing how many of these genes have completely unknown functions," says Dutcher.
She also plans further computerized comparisons of genetic codes.
"Humans have two kinds of cilia--motile cilia, which create motion, and non-motile cilia, which respond to motion," she says. "The microscopic worm C. elegans only has non-motile cilia, so if we were to take our results from this study and eliminate all the genes that have a match in the genetic code of C. elegans, that might let us highlight genes for proteins that create and control the movements of cilia."
The Washington University Genome Sequencing Center, working in collaboration with England’s Sanger Center, completed sequencing of the genetic code of C. elegans in 1998.
Li BJ, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque O, Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, Dutcher SK. Comparative Genomics Identifies a Flagellar and Basal Body Proteome that Includes the BBS5 Human Disease Gene. Cell, May 14, 2004.
Funding from the National Institutes of Health, the March of Dimes and Monsanto.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
Michael C. Purdy | WUSTL