Genetic sequences preserved through evolutionary selection might not be functional.
“We were expecting to see either fertility problems or a lethal phenotype.”
A colony of mice whose very existence defies logic could rewrite our understanding of human evolution, health and disease, researchers say.
The laboratory mice lack stretches of DNA that scientists believed were essential for survival. And yet they eat, grow and reproduce normally. There seems to be nothing wrong with them despite their genetic deficiencies, says Nadav Ahituv, a human geneticist at the University of California, San Francisco, who created them through two painstaking years of breeding experiments. “We were expecting to see either fertility problems or a lethal phenotype” — the mice being affected so severely that they die in the womb. But neither happened. “I was very surprised,” says Ahituv, who published his results this week1.
Ahituv made four mouse 'knock-outs', each one lacking a stretch of DNA between 222 and 731 base pairs long. These same stretches of DNA exist in human genomes, base pair for base pair. This 'ultraconserved' DNA is exactly the same across the long evolutionary distance between humans and mice and rats. So why the mice lived could answer fundamental questions about evolution.
Ultraconserved DNA was first described in May 2004, when a group led by David Haussler at the University of California, Santa Cruz, reported the existence of 481 stretches of DNA more than 200 base pairs long with completely identical sequences in mice, rats and humans2. Of these stretches, 256 were found in non-coding DNA, often far away from genes. Those found close to genes were often near developmental regulators, which hinted that the ultraconserved DNA might act as a switch in the cascade of events that shapes an embryo into a fully formed mouse or human. Beyond that, it wasn't clear what this class of DNA did, and so such regions have been called 'junk' DNA.
But the fact that it was preserved through evolution led people to believe it was important. Haussler's group calculated that the probability of just one of these elements popping up at random in the human genome was less than 10−22. And on 17 August, Haussler's group reported in Science that natural selection processes are actively preventing ultraconserved DNA from changing. Haussler's group sequenced hundreds of pieces of ultraconserved DNA from 72 people and statistically analysed the pattern of variations in the ultraconserved regions. The pattern was consistent with that expected if natural selection was discriminating against mutations in ultraconserved regions3. “This means there is a force preventing mutations in the ultraconserved regions from spreading throughout the general population,” Haussler says. “What surprised me was the strength of the selection” — about three times as strong as selection on protein-coding regions.
However, although ultraconserved DNA seems crucial, scientists still aren't sure what it does or where it comes from. Ahituv was part of one group, headed up by Edward Rubin and based at Lawrence Berkeley National Laboratory, California, that found that 45% of 167 ultraconserved elements tested in developing mice acted as enhancers — regulators that tune up gene activity4. Scientists led by Steven Brenner at the University of California, Berkeley, have found another regulatory role for ultraconserved elements in a family of human genes that regulate themselves by destroying their own messenger RNA templates5.
Only a single ultraconserved element has so far revealed its origins. By scanning genome data, Haussler's group found that one human ultraconserved element is 80% similar to a piece of DNA found in a 400-million-year-old class of ancient fish that includes the coelacanth6. The element had been shuttled into the fish genome by a genetic invader called a retroposon, but mammals have now co-opted it to boost expression of a brain-development gene called ISL1.
Although little is known about the history of ultraconserved DNA, it should still be possible to determine what makes it so important that it has been kept unchanged for millions of years. “The ultraconserved region could play a role in human diseases and we are now deciphering this unexpected involvement,” says George Calin at the University of Texas MD Anderson Cancer Center in Houston. Ultraconserved DNA expression may be different in cancer cells and healthy cells, for example. Calin's findings are due to be published next week.
Ahituv's new results seem to contradict the little that is known about ultraconserved DNA, says Haussler. He thinks that the knock-outs may have produced effects so small that they weren't obvious in controlled laboratory conditions. “Evolution has performed vastly more trials than can ever be performed in a laboratory,” Haussler says. “It's possible that there's a pretty small effect that is difficult to measure in the lab, but is significant in the long run.”
Ahituv, N. et al. PLoS Biol. 5, e234 (2007).
Bejerano, G. et al. Science 304, 1321–1325 (2004).
Katzman, S. et al. Science 317, 915 (2007).
Pennacchio, L. A. et al. Nature 444, 499–502 (2006).
Lareau, L. F. et al. Nature 446, 926–929 (2007).
Bejerano, G. et al. Nature 441, 87–90 (2006).
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Small activating mRNA (samRNA): A hypothesis for a specific positive feedback regulation of gene expression
Bioscience Hypotheses (2008)