Complex Inheritance Pattern Linked to Gene Changes

Three separate genetic regions, parts of chromosomes 3, 10, and 19, are crucial for causing Hirschsprung disease and together explain its complicated inheritance pattern. These findings, reported in the April 15, 2002, online edition of Nature Genetics, show that it is important to consider all parts of a gene, not just those that carry instructions for a protein, when looking for contributors to disease.

"Just because coding sequences are not changed does not mean a gene is not involved,” explains Dr. Aravinda Chakravarti of Johns Hopkins University (Baltimore, MD, USA). "Many diseases likely have genetics similar to Hirschsprung disease, and we have shown that such complex genetic contributors can be discovered with a carefully designed study.”

Hirschsprung disease is a hereditary disorder, occurring in about one in 5,000 births, in which nerves that normally control the bowel are missing. Since the inheritance pattern is complex, researchers collected and analyzed samples from parents and children in 49 families, each with at least two affected siblings.

Each participant's genome was scanned and analyzed to find changes that might explain how Hirschsprung is passed from generation to generation. In particular, the scientists looked for "overshared” genetic regions in siblings with the disease, reasoning that these regions would be present more often than could be expected by chance alone. Of the many genetic differences found, computer analysis revealed that the changes within particular regions of chromosomes 3, 10, and 19 could explain both familial and non-familial cases of short-segment Hirschsprung disease. The short-segment form of Hirschsprung disease is both more common and more genetically complex than the long-segment form.

Gene mapping showed that there were no changes in protein-encoding areas of chromosome 10. "Mapping gives you an independent way of saying that this gene is involved in a disease, even if there are no changes in the coding sequence,” says Dr. Chakravarti. "This disease and many others are complex not just because they involve more than one gene, but because the molecular mechanisms behind the genes' involvement are unusual.” Changes in noncoding sequences can affect sites for regulation, carry instructions for alternative ways to read the gene, or otherwise alter gene function and expression.



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