Silent mutations speak up

news@nature.com ^ | 21 December 2006 | Helen Pearson

[neverdem]

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Published online: 21 December 2006; | doi:10.1038/

Silent mutations speak up

Overlooked genetic changes could impact on disease.

Helen Pearson

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 sort¹. 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 protein².

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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References

1. Kimchi-Sarfaty C., et al. Science, doi:10.1126/science.1135308 (2006).
2. Pagani F., et al. Proc. Natl Acad. Sci. USA, 102. 6368 - 6372 (2005).

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[NonValueAdded]

Perhaps this is the article I've been waiting for. My concern about genetic engineering has always been that we're messing with the elemental forces of nature without really knowing what we're doing. It seemed to be like that scene in Fat Man and Little Boy where they are using that screwdriver to move the sphere of uranium (or was it plutonium?). But only one person was killed in that experiment.

I've heard the argument that taking a segment of DNA and splicing it onto another is little different than selective breeding or plant grafting. But I thought the difference was in bypassing whatever safeguards Mother Nature has in place. We have been told that we understand what the segment did but that understanding ignored the possibility that the same segment participated in other processes. (Does God not reuse code??? I thought he'd be at least SEI level 20 or something). Now we find out that a single letter can make a potentially fatal difference. Time for the Butlerian Jihad?

[patton]

SEI Level 20....LOLOLOLOL

[Hacksaw]

Interesting! There is also a lot of research lately about how many cancers may actually be caused by viral DNA becoming integrating into cells.

[NonValueAdded]

Imagine His ISO certifications!

[neverdem]

My concern about genetic engineering has always been that we're messing with the elemental forces of nature without really knowing what we're doing.

It's more interesting that way, but we don't know what we don't know.

[SunkenCiv]

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.