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Why do Some Carry the Cystic Fibrosis Mutation?

DAVID WAHLBERG
Wisconsin State Journal
608-252-6125
September 14, 2007

Why do 10 million Americans carry the genetic mutation that causes cystic fibrosis, even though they don't have the frequently fatal lung disease?

The answer could lie in 2,500-year-old bones from Europe being tested at the State Laboratory of Hygiene.

An international effort, led by Dr. Phil Farrell, a pediatric pulmonologist from UW-Madison, is analyzing bones from ancient Celtic people.

Some of the people are thought to have been metal workers. Their exposure to lead, arsenic and cadmium may have disseminated a genetic mutation that protected them from metal toxicity — but also spread cystic fibrosis.

Cystic fibrosis is caused by a recessive gene, meaning that children must inherit two copies of the defective gene to have the disease. Even if both parents are carriers, each child faces only a one-in-four chance of developing cystic fibrosis.

About 30,000 Americans have the disease. Another 10 million are carriers.

According to evolutionary biology, there must be a reason — a "selective advantage" — that so many people carry the mutation.

Scientists have discovered such an advantage for the mutation responsible for another disease caused by a recessive gene: sickle cell anemia, a blood disorder. That defect protects against malaria.

Farrell and his colleagues believe the cystic fibrosis mutation may make people less susceptible to toxicity from lead and other metals. They're evaluating the theory and hope to publish some of their findings soon.

"We want to determine what the selective advantage is," said Farrell, former dean of the UW School of Medicine and Public Health.

Sickle cell, the most common childhood-onset inherited disorder in the United States, almost exclusively affects African-Americans. Cystic fibrosis, the second most common such disorder, occurs mostly in people of central and western European descent.

Scientists at the state lab's Environmental Health Division have analyzed 75 femurs from graveyards in central Europe, mostly in Austria. They are now studying 40 femurs from England.

Using ceramic tools, the scientists slice away small pieces of bone. They put diluted acid on the pieces to leech away the outer layer and remove contaminants. Then they use a microwave system to digest the bone into a solution. Inside a special clean room, they place the solution in a mass spectrometer, which can detect traces of metals.

"We're looking for signatures that could tell us about their exposure to these elements due to metal working," said Martin Shafer, a research scientist at the state lab, which is part of UW-Madison.

Other researchers on the team are studying DNA from molars from the same graves, to see if there's an association between the metals found and genetic changes related to cystic fibrosis.

Part of the challenge is making sure the metals found are from long ago and not from more recent exposure, Shafer said.

One technique is to study ratios of lead isotopes. The ratios can help identify whether lead was deposited in the bones while the people were alive — or if water or soil contaminated the graves.

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Please Note: This article and the accompanying photos are an electronic clipping from the Wisconsin State Journal from September 14, 2007.

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