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Non-Coding, 'Ultraconserved' DNA Rarely Lost from Mammalian Genome

NEW YORK (GenomeWeb News) – Non-coding stretches of DNA that are highly similar or identical across different mammalian species are rarely lost from the mammalian genome and appear to influence species fitness, according to new research.
Stanford University researchers Cory McLean and Gill Bejerano looked at how often highly conserved, non-protein-coding regions found in the human, macaque, dog, and ancestral rodent genomes were lost from the genomes of modern rats and mice. Their results, appearing online today in Genome Research, suggest that ultraconserved regions are some 300 times less likely to be lost from the genome than evolutionarily neutral stretches of DNA.
“As perhaps you’d imagine, these ultraconserved regions are almost never deleted in the context of a species,” senior author Bejerano, a developmental biologist at Stanford, told GenomeWeb Daily News.
Bejerano and his co-workers discovered ultraconserved elements about four years ago, when Bejerano was a post-doctoral researcher at the University of California at Santa Cruz. At the time, they uncovered nearly 500 ultraconserved elements with at least 200 bases of perfect conservation in the human, mouse, and rat genomes. These ultraconserved regions represent non-protein-coding DNA that does not appear to represent miRNA precursors or known non-coding RNA sequences.
But then, as now, researchers could only guess about their function. For his part, Bejerano believes the ultraconserved elements play a role in cis-regulation of the genome, perhaps acting to enhance or repress the transcription of certain genes. “I think we have yet to appreciate the depth of gene regulation,” he said.
Subsequent research suggested that ultra-conserved elements could act as enhancers at certain stages in development, Bejerano said. And, he added, based on the research so far, researchers have developed the idea that these elements are important in the function of species as a whole.
In contrast, though, a study published in PLoS Biology last year demonstrated that there was no discernable effect in laboratory mice when these regions were knocked out of the mouse genome — rather, mice lacking ultraconserved regions were viable and able to reproduce.
“We were interested in trying to reconcile these seemingly un-reconcilable observations,” Bejerano said.
Part of the explanation could lie in the fact that laboratory conditions are not the same as real life conditions, Bejerano said. For instance, mice lacking ultraconserved elements may have a small decrease in viability that can’t be detected in the lab. “If you put these animals out in the wild, you would see that they’re very rapidly removed from the population,” he said.
In an effort to understand these mysterious elements a bit better, McLean and Bejerano tested whether the likelihood that such highly conserved stretches of DNA were lost from the rodent genome. They looked for tell-tale signs of natural deletion events, looking at regions of the genome that were similar or identical in humans, macaques, dogs, and ancestral rodents and determining whether these were also present in modern mice and rats.
“While elements with complete functional redundancy may be dispensable, the loss of elements that provide unique functions may be deleterious and will not fix in natural populations,” the authors reasoned.
By determining the likelihood that rodents will lose pieces of DNA that are identical or nearly identical in primates and dogs over 100 base pairs, the researchers concluded that ultraconserved elements are resistant to natural deletion. And, they say, that suggests these bits of DNA do play an important, if unknown, part in species fitness. Whereas roughly a quarter of non-conserved DNA found in humans, macaques, and dogs was missing in mice and rats, less than a tenth of a percent of DNA that was identical or very similar was lost.
“The functional importance of ultraconserved elements is reinforced by the observation that the elements are rarely lost in any species,” McLean, a graduate student in Bejerano’s lab, said in a statement. “In fact, they are over 300-fold less likely to be lost than genomic loci which evolve neutrally in our genome.”
McLean and Bejerano also discovered that evolutionarily “older” sequences — those that were found in humans as well as animals that are only distantly related, such as the platypus — were least likely to be deleted. “Regions that have been there longer presumably play more basal roles,” Bejerano said. 
In the future, he said, as the genomes of more and more species are sequenced, it should be possible to determine which sequences are best conserved across a wide range of mammalian species. But he noted that it will also be useful to try to compare the effects that ultraconserved regions have on the individual level compared to the species level.
“The true function of these regions remains a mystery, but it’s clear that the genome really does need and use them,” Bejerano said in a statement.

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