STANFORD, Calif. — Small stretches of seemingly useless DNA harbor a bigsecret, say researchers at the Stanford University School of Medicine.There's one problem: We don't know what it is. Although individuallaboratory animals appear to live happily when these genetic ciphers aredeleted, these snippets have been highly conserved throughout evolution.
"The true function of these regions remains a mystery, but it's clearthat the genome really does need and use them," said Gill Bejerano, PhD,assistant professor of developmental biology and of computer science. Infact, these so-called "ultraconserved" regions are about 300 times lesslikely than other regions of the genome to be lost during mammalianevolution, according to research from Bejerano and graduate student CoryMcLean to be published in the Oct. 2 issue of Genome Research.
Although some of the ultraconserved regions, which were first identifiedby Bejerano in 2004, are involved in the regulation of the expression ofneighboring genes, previous research has shown that mice missing each offour regions seem perfectly normal.
"It's very surprising that none of the four has any observablephenotype," said Bejerano. "In some ways it just doesn't make sense."
This lack of effect is usually taken as a strong argument against animportant functional role for the missing segments of DNA — eitherbecause they don't do much or because other bits of DNA serve asunderstudies when the primary actors are missing. But in this mostrecent study, evolution roars over the squeak of the seemingly contentedmice.
"When we tried to determine whether similar deletions occur in thewild," said Bejerano, "we found that this is almost never seen in nature."
McLean and Bejerano compared the likelihood that ultraconserved elementsof at least 100 base pairs shared by humans, macaques and dogs wouldhave been deleted in rats and mice, with the likelihood of a similarpattern in non-conserved DNA. Less than one-tenth of 1 percent ofsegments completely identical among the primates and dog were missing inthe rodents. In contrast, about 25 percent of non-conserved segmentswere absent in the mice and rats.
It's not that these regions are somehow protected against change: theyare mutated in about one in 200 healthy humans. Rather, these changesseem to be swept away over time by the tides of evolution in a processcalled "purifying selection." Bejerano and McLean believe that somethingsimilar may be happening in the laboratory mice on a scale too subtle tobe seen under carefully controlled experimental conditions.
After establishing how infrequently the ultraconserved segments aredeleted, the researchers investigated whether the degree of homology(the percent of nucleotides shared between species) or the extent ofconservation (the evolutionary distance between species that share aversion of the sequence) correlated most closely with the likelihoodthat it would be lost in primates or rodents. Sequences shared amongmany distantly related species are likely to be older than sequencesfound only in closely related species. The researchers found thatless-highly conserved sequences shared among several distantly relatedspecies — including opossum, platypus, chicken, frog and fish — are morelikely to also occur in humans than are more-homologous sequences thatoccur in only a few closely related species. The likelihood that asequence will be found in humans increases as the evolutionary age ofthe sequence increases.
"Interestingly," said Bejerano, "the longer the sequence has been in us,the less likely it is to be lost. It's almost like the bricks in thefoundation of a building, which hold up the rest of the structure."
Clearly there remains a lot to be discovered. The upcoming availabilityof several additional well-sequenced mammalian genomes will give theresearchers even more data with which to work. And subjecting thelaboratory mice missing the ultraconserved regions to a variety ofconditions, such as changes in diet or living conditions, may make morenoticeable any differences between them and the mice without changes.
"Evolution is a lot of fun," said Bejerano, who plans to continue theinvestigation into what the ultraconserved segments might be doing. "Youanswer one question, and five others pop up. But one of the mostrewarding things to me is the fact that we're developing a growingappreciation for how much these regions actually matter."