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Missing DNA fails to kill mice

Of mice and men

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DNA sequences we share with mice might not be as important as researchers previously thought. A series of experiments on mice at Berkeley have cast doubt on the notion that these so-called ultraconserved elements of DNA are indispensable, after test mice with sequences snipped out managed to grow up just fine.

Ultraconserved elements are sections of DNA discovered three years ago, that we have in common with mice and rats. The sections are exactly alike, meaning that they are inherited from our last common ancestor over 85m years ago, and have been conserved since then without mutation.

Researchers speculate that they have stayed perfectly intact because they are vital to our function as living beings, possibly playing a key role in reproduction or fertility. But these findings, reported in the September, 2007 issue of PLoS Biology, undermine that hypothesis.

Nadav Ahituv of Berkeley Lab's Genomics Division, a human geneticist who led the experiment, said that the results were a complete surprise.

"We fully expected to demonstrate the vital role these ultraconserved elements play by showing what happens when they are missing. Instead, our knockout mice were not only viable and fertile but showed no critical abnormalities in growth, longevity, pathology, or metabolism," he said.

The researchers chose to delete sequences that are known as "enhancers". They do not directly encode proteins, but they are thought to play a key role in regulating the expression of nearby genes. (Taking out the genes themselves does muck up an organisms viability, so the team thought the DNA that regulated the genes might also have an effect.)

Study director Edward Rubin, head of the Joint Genome Institute and Berkeley Lab's Genomics Division, said that although no one could say the mice in the study were "normal", "we can confidently conclude that the presence of the ultraconserved elements are not required for the viability of the organism".

The biggest question the research raises is that of how these sections of DNA came to be perfectly preserved, if they are not vital to the viability of the animal? The researchers are not entirely sure.

Ahituv suggests the survival of the mice may lie in redundancy, explaining that for one of the elements the team chose to delete, there are other noncoding ultraconserved elements positioned near it in the genome that show similar enhancer activity.

But he acknowledges that this doesn't explain why the sequences are perfectly preserved. "It may be that we saw no deleterious effects in the knockouts because nature provides a backup for these ultraconserved elements. These may rescue the organism from the abnormalities we speculated would be caused by the missing ultraconserved sequences -- though this still does not explain why they are so ultimately conserved."

Len Pennacchio, a Berkeley Lab senior scientist and a primary author of the study, suggests that the deletion does make the mice less fit, but not in a way that we can observe on short time scales.

Suffice to say, more work is needed.

You can read the paper here. ®

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