December 21, 2006

Silent mutations speak up

Overlooked genetic changes could impact on disease.

by Helen Pearson
Nature News

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Biologists have realized that the genetic code harbours a layer of information that they have largely ignored. Again.

This time, the focus is on 'silent' mutations, single letter changes that were, as their name suggests, generally thought to have little impact on that gene's instructions for making protein.

But a study published in Science this week shows that two silent mutations are nothing of the sort. They seem to change the rate at which a drug-pumping protein folds and may help decide whether certain cancers become drug resistant.

Silent also called synonymous mutations arise because of the rules of the genetic code. Three chemical letters of DNA, called a codon, instruct the cell to insert a particular amino acid into the string that makes up a protein. But often several different codons code for the same amino acid.

A silent mutation is one that changes the triplet, but leaves the amino acid unchanged. "We were all educated that silent mutations should be ignored, and people really don't pay attention to them," says Chava Kimchi-Sarfaty at the National Cancer Institute in Bethesda, Maryland. But it is becoming clear that proteins made of identical amino acids can nevertheless behave differently.

Toxin pump

Kimchi-Sarfaty and her colleagues studied three mutations, of which two are silent, which crop up frequently in a human protein that pumps toxins out of cells. Some versions of this protein make cancer cells resistant to chemotherapy by ridding cells of the drug; there have been hints that silent mutations might be involved.

The team showed that proteins containing at least one of the silent mutations have a subtly different shape compared with normal proteins. In tests on cells in the lab dish, those with mutations were not blocked by drugs that normally inhibit the toxin pump.

The two silent mutations Kimchi-Sarfaty's team studied turned out to replace common triplets with much rarer ones. The body's machinery isn't as quick and adept at translating the less common bits of code. This pause in protein production could allow the protein to fold slightly differently, Kimchi-Sarfaty suggests, so that it works in a different way.

Quiet killer

Some researchers proposed nearly 20 years ago that silent mutations could fine-tune protein folding and function. And studies have shown how artificially engineering silent mutations into a protein can affect its folding. But "nobody was paying attention", says Anton Komar who studies the phenomenon at Cleveland State University, Ohio. The new study confirms that naturally occurring silent mutations can also have such an effect.

Silent mutations are known to have other effects. For example, they can change the way that RNA, the molecule that bridges DNA to protein production, is cut and spliced together. A team led by Francisco Baralle at the International Centre for Genetic Engineering and Biotechnology in Trieste, Italy, last year showed that many silent mutations in the gene responsible for the lung disease cystic fibrosis can cause splicing changes that inactivate the protein.

Baralle says that geneticists who screen people for mutations in disease-causing genes are discounting these and similar mutations. "Many patients might be misdiagnosed because of this problem," he says.

Silent mutations with important functions could be scattered across the human genome, Komar says. Researchers now need to re-examine mutations in numerous genes that were previously brushed aside, he says. Understanding these mutations could one day help doctors to personalize medicines to match a patient's genetic profile.

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