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Study: Genome-wide scanning unravels complex birth defect

Johns Hopkins Medicine

Researchers from the McKusick-Nathans Institute for Genetic Medicine at Johns Hopkins have successfully used genome scanning technology to search through thousands of DNA bits, from every chromosome, to identify two genes that cause an inherited intestinal disorder by working together.

The work is believed to be the first published evidence that genome-wide scanning, using conventional genetic markers and so-called "gene chips," can, in one shot, reveal the underpinnings of diseases caused by multiple genes, according to Minerva Carrasquillo, Ph.D., who is scheduled to present the findings Oct. 18 at the annual meeting of the American Society for Human Genetics in Baltimore. The study results also appeared Sept. 23 in Nature Genetics.

Complex disorders probably result from genetic mutations that create only subtle changes in their proteins' functions. Individually, these changes don't cause symptoms, but in combination they could help explain the occurrence and variability of complex diseases, say the researchers.

Because of this subtlety, gene hunters have found it difficult to get a single "snapshot" of all the genes that may be involved in these diseases. In the last 10 years, it's been relatively easy only to find the genetic causes of single-gene diseases, such as cystic fibrosis, or one gene at a time for genetically complex diseases.

"In complex diseases like diabetes and heart disease, the genes involved are probably scattered throughout the genome, so you need to be able to look at the whole genome at once and process all that data," says Aravinda Chakravarti, Ph.D., director of the McKusick-Nathans Institute of Genetic Medicine. "Fortunately, the technology now exists to get this done."

Studying the inherited bowel disorder known as Hirschsprung disease, the Hopkins scientists began years ago by looking for single genes, but quickly realized that no one gene could explain the condition completely, says Carrasquillo, a postdoctoral fellow in the McKusick-Nathans Institute.

Now linked to mutations in eight genes, including two known as RET and EDNRB, Hirschsprung disease varies widely in severity, is more common in males than females, and frequently has a very complicated inheritance pattern. The disease's physical symptoms, primarily bowel obstruction, stem from the fact that nerves controlling the intestines are missing.

Using so-called "gene chips," or microarrays, made up of a tiny grid of more than 2,000 known DNA bits, some already linked to Hirschsprung, the Hopkins team probed the genomes of an affected child and both parents from 43 Old Order Mennonite families. Hirschsprung disease occurs in Mennonite communities in about 1 out of 500 births, a rate roughly 10 times higher than in the general population.

Using special computer software they developed, the scientists searched for sets of genetic changes that occurred with unexpected frequency in affected people. Variations in the RET and EDNRB genes had to co-exist to cause disease in these families, they discovered. An as yet unspecified gene or genes on chromosome 16 was also picked up by the computer analysis, the scientists report.

"By tracking thousands of genetic variations passed to affected children by their unaffected parents, we discovered which markers were important in the disease and which ones weren't," says Carrasquillo.

To bolster their findings, team member Andrew McCallion bred two sets of mice, one with RET disrupted and the other with EDNRB disrupted. While neither parental line of mice had intestinal symptoms, offspring exhibited conditions more similar to Hirschsprung than any previous attempt to model the disease, the researchers report.

The team's success lends some practical support for the creation of so-called "haplotype maps," says Chakravarti, who says their analyses provided a crude one. A haplotype is the collection of all the key genetic changes present in an individual, whereas a "genotype" is an individual's status at a single location in the DNA. Geneticists expect haplotypes to explain genetically complex diseases just as genotypes have in "simpler" diseases.

Exactly how abnormal RET and EDNRB genes coordinate to cause Hirschsprung disease isn't yet understood, adds Carrasquillo. The proteins encoded by the RET and EDNRB genes are involved in distinct pathways, although some evidence exists of indirect interaction between proteins related to RET and EDNRB. Both RET and EDNRB proteins are involved in connecting nerves to the digestive tract during embryo development.


The gene chips were made by Affymetrix, Inc. The studies were funded by the National Institute of Child Health and Development, one of the National Institutes of Health, and by The Johns Hopkins University School of Medicine. Authors on the paper are Carrasquillo, McCallion, Chakravarti and Carl Kashuk, all of Hopkins; Erik Puffenberger of the Clinic for Special Children in Strasburg, Pa.; and Nassim Nouri formerly of Affymetrix, now of NuGen Technologies, San Carlos, Calif.

Chakravarti is a paid member of the Affymetrix Scientific Advisory Board. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

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