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Unusual Mutation Leads to Extra Immune Genes

By Nancy Touchette

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Human Genome

Researchers plan to study whether patients with cystic fibrosis who have extra copies of defensin genes are resistant to infection by Pseudomonas aeruginosa (above).
The human genome is full of surprises. Researchers have found that some people have an unusually large block of DNA repeated in their genomes. But unlike many such structures, this extra hunk of DNA does not appear to cause disease. Instead, it contains a set of genes encoding proteins that kill microbes.

The researchers do not yet know how individuals with this mutation are affected.

“In terms of consequences, the truth is that we just don’t know yet,” says Edward J. Hollox of the University of Nottingham, United Kingdom, who led the study. “It’s possible that individuals with different numbers of repeats will have different responses to infection.”

This could be a double-edged sword, Hollox says. People with many copies of these genes, called defensins, may be more resistant to infection than other people. But they may also be sensitive to conditions such as asthma, in which the body's inflammatory response is triggered too easily.

The repeated stretch, on chromosome 8, contains 240,000 base pairs and at least three defensin genes. Defensins, which are produced by immune cells and cells that line the airways, can destroy invading pathogens such as bacteria and viruses.

Over 100 people tested so far have extra copies of defensin genes. Most have 4 or 5 copies of the repeated sequence, but individuals with 10 or 12 copies have been found.

The discovery is unusual because most large DNA repeats in the human genome are made up of short sequences repeated many times. Short repeats tend to disrupt genes and often contribute to disease. But individuals with the defensin repeats show no signs of disease.

Hollox is planning to study whether cystic fibrosis patients with extra copies of a defensin gene called DEFB4 are more resistant to lung infection by the bacterium Pseudomonas aeruginosas, a common cause of mortality.

Hollox, E.J. Extensive normal copy number variation of a ß-defensin antimicrobial-gene cluster. Am. J. Hum. Gen . 73 , 591-600 (2003).

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