What good is the cystic fibrosis gene?

A significant puzzle surrounding cystic fibrosis is its prevalence. The fatal respiratory disease results when a person has mutations in both of the body's copies of a gene called cftr. Yet even though in the past the disease killed people before they had reproduced and passed on their genes, about 1 in 20 white people of European descent are carriers of a mutant cftr.

Researchers have suggested that the mutant cftr gene persists so widely because of a heterozygote advantage. That is, having one mutant copy of cftr and one normal copy is somehow beneficial. For example, having two mutant copies of a certain hemoglobin gene results in sickle-cell anemia, but possessing one mutant and one normal gene bestows resistance to malaria.

What might the heterozygote advantage of cystic fibrosis be? In recent years, some investigators have proposed that it offers protection against the bacteria causing cholera or similar diarrheal diseases. Other scientists have poked holes in that theory. Cholera does not seem to have reached Europe until the 1800s, too late to explain the high frequency of the mutant cftr gene, say population geneticists.

Gerald B. Pier of Harvard Medical School in Boston and his colleagues now suggest that cftr mutations protect people from typhoid fever. Earlier work by this group indicated that the cell surface protein encoded by cftr helps lung cells eliminate Pseudomonas aeruginosa by latching onto these bacteria and internalizing them. The lungs of cystic fibrosis patients, in contrast, are almost always flooded with P. aeruginosa.

The group has now found evidence that Salmonella typhi, the bacterium that causes typhoid fever, depends upon the cftr protein to invade cells of the gastrointestinal tract, normally the first step in its journey into the bloodstream. Compounds that bind to the cftr protein, for example, block the bacterium's entrance into those cells. Moreover, the protein from the most common mutant form of cftr is unusable by S. typhi, the researchers found.

Such data argue that the apparently widespread incidence of typhoid fever throughout European history may explain why so many people of European descent harbor one mutant cftr gene, says Pier. Before antibiotics, the disease killed up to 15 percent of those infected. Mutations in cftr that repel S. typhi could offer people protection, thereby improving the survival odds of their genes, he says.

While "fascinating," the typhoid fever hypothesis is far from proven, says Michael Swift of the New York Medical Center in Hawthorne, who in 1995 proposed that cystic fibrosis heterozygotes are more resistant to asthma than other people. The most persuasive evidence, he says, would be a study showing that people with one cftr mutation are more likely to survive typhoid fever than those with none.