From Algae, Weeds And People: New Genetic Clues To Complex Obesity Syndrome

"Finding this gene underscores the power of comparing organisms' complete genetic information," says Nicholas Katsanis, Ph.D., an assistant professor in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. "We can use this technique to look for new genes and proteins involved in specific cellular structures and their roles in health and disease."

That's because even very distantly related organisms -- the alga and humans, for example -- may share genes and proteins for common cellular structures that have been conserved by nature.

The genetic comparisons, done by researchers at Washington University in St. Louis, revealed 688 genes in humans and the alga that are involved in building cells' hair-like projections called cilia, the team reports in the May 14 issue of Cell.

In people, cilia help push fluid and molecules around outside certain cells, including some in the lung, eye, brain and kidney. Hopkins researchers and their colleagues have reported that genetic mutations in BBS cause problems at least in part by rendering cilia and related structures useless.

Two of the identified genes turned out to be located in a region of human chromosome 2 that already had been linked to BBS. Stimulated by the St. Louis researchers, the international BBS team sequenced the two genes in families with BBS and discovered mutations in one of the two genes.

"There were 230 possible genes in the region of chromosome 2 linked to BBS, and this genomic comparison immediately narrowed down the most likely possibilities to just two," says Katsanis, also an assistant professor of ophthalmology. "Using comparative genomics in this way is a big, big deal. It would have been nearly impossible to find this gene in any other way."

He adds, "This study should be a massive springboard for using comparative genomics, and it proves without a doubt the value of sequencing the genomes of a wide variety of species."

The Washington University researchers, led by Susan Dutcher, Ph.D., a professor of genetics, study cilia in an alga called Chlamydomonas. The alga provides easier access than other organisms to examine cilia and related structures called flagella, which also help with cells' own movement.

To find new genes and proteins involved in cilia, Dutcher and her team compared all the proteins predicted by the alga's and human's genomes, and then compared those matches to a weed -- the laboratory plant Arabidopsis. The alga and humans both have cilia, but the weed doesn't, so the researchers could eliminate genes and proteins that aren't involved in cilia, says Dutcher.

The alga and humans shared 4,348 "fairly good" matches. Subtracting those also found in the weed cut the number of likely cilia-related proteins and genes to just 688.

To see if these data might help the hunt for disease genes, Dutcher contacted Katsanis. In 1999, a Canadian team of researchers had determined that BBS5 was in a particular region of chromosome 2. In 2003 and 2004, Katsanis, the Canadians and their colleagues presented evidence that faulty cilia and related structures were likely to be the direct cause of problems seen in people with BBS.

Including BBS5, seven BBS genes now have been isolated and "cloned," and another is known to be on chromosome 3. Katsanis fully expects that many more genes are involved in the syndrome.

"The list of cilia-related genes is likely to be invaluable in identifying additional BBS genes, and it likely includes genes already tied to other diseases and conditions whose traits overlap BBS," says Katsanis.

The cellular problems behind BBS, a rare condition, may also be involved in some "regular" or non-syndromic instances of BBS traits, such as specific learning disabilities, uncontrolled appetite, obesity and diabetes, retinal degeneration and some kidney problems, says Katsanis.

Authors on the paper are Jin Billy Li, Linya Li, Gary Stormo and Dutcher of Washington University in St. Louis; Jantje Gerdes, Tanya Teslovich, Carmen Leitch and Katsanis of Johns Hopkins; Courtney Haycraft, Haitao Li, Lisa Guay-Woodford and Bradley Yoder of the University of Alabama at Birmingham; Yanli Fan, Oliver Blacque, Michel Leroux and William Davidson of Simon Fraser University, Canada; Helen May-Simera and Philip Beales of University College London; Richard Lewis of Baylor College of Medicine; and Jane Green and Patrick Parfrey of Memorial University, St. John's, Canada. The Hopkins researchers were funded by the National Institutes of Health, the March of Dimes, and the German Academic Exchange Service.

On the Web:

http://www.cell.com

http://medschool.wustl.edu/

Faulty Cilia Identified as Primary Cause of BBS Problems:http://www.hopkinsmedicine.org/Press_releases/2003/09_21_03.html

BBS Gene Mutations Disrupt Cells' Highway, the Microtubules:http://www.hopkinsmedicine.org/Press_releases/2004/04_25_04.html