News: Mysterious Snippets Of DNA Withstand Eons Of Evolution

Mysterious Snippets Of DNA Withstand Eons Of Evolution
ScienceDaily (Oct. 7, 2008) - Small stretches of seemingly useless DNA
harbor a big secret, say researchers at the Stanford University School of
Medicine. There's one problem: We don't know what it is. Although individual
laboratory animals appear to live happily when these genetic ciphers are
deleted, these snippets have been highly conserved throughout evolution.

"The true function of these regions remains a mystery, but it's clear that
the genome really does need and use them," said Gill Bejerano, PhD,
assistant professor of developmental biology and of computer science. In
fact, these so-called "ultraconserved" regions are about 300 times less
likely than other regions of the genome to be lost during mammalian
evolution, according to research from Bejerano and graduate student Cory
McLean.

Although some of the ultraconserved regions, which were first identified by
Bejerano in 2004, are involved in the regulation of the expression of
neighboring genes, previous research has shown that mice missing each of
four regions seem perfectly normal.

"It's very surprising that none of the four has any observable phenotype,"
said Bejerano. "In some ways it just doesn't make sense."

This lack of effect is usually taken as a strong argument against an
important functional role for the missing segments of DNA - either because
they don't do much or because other bits of DNA serve as understudies when
the primary actors are missing. But in this most recent study, evolution
roars over the squeak of the seemingly contented mice.

"When we tried to determine whether similar deletions occur in the wild,"
said Bejerano, "we found that this is almost never seen in nature."

McLean and Bejerano compared the likelihood that ultraconserved elements of
at least 100 base pairs shared by humans, macaques and dogs would have been
deleted in rats and mice, with the likelihood of a similar pattern in
non-conserved DNA. Less than one-tenth of 1 percent of segments completely
identical among the primates and dog were missing in the rodents. In
contrast, about 25 percent of non-conserved segments were absent in the mice
and rats.

It's not that these regions are somehow protected against change: they are
mutated in about one in 200 healthy humans. Rather, these changes seem to be
swept away over time by the tides of evolution in a process called
"purifying selection." Bejerano and McLean believe that something similar
may be happening in the laboratory mice on a scale too subtle to be seen
under carefully controlled experimental conditions.

After establishing how infrequently the ultraconserved segments are deleted,
the researchers investigated whether the degree of homology (the percent of
nucleotides shared between species) or the extent of conservation (the
evolutionary distance between species that share a version of the sequence)
correlated most closely with the likelihood that it would be lost in
primates or rodents.

Sequences shared among many distantly related species are likely to be older
than sequences found only in closely related species. The researchers found
that less-highly conserved sequences shared among several distantly related
species - including opossum, platypus, chicken, frog and fish - are more
likely to also occur in humans than are more-homologous sequences that occur
in only a few closely related species. The likelihood that a sequence will
be found in humans increases as the evolutionary age of the 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 the foundation
of a building, which hold up the rest of the structure."

Clearly there remains a lot to be discovered. The upcoming availability of
several additional well-sequenced mammalian genomes will give the
researchers even more data with which to work. And subjecting the laboratory
mice missing the ultraconserved regions to a variety of conditions, such as
changes in diet or living conditions, may make more noticeable any
differences between them and the mice without changes.

"Evolution is a lot of fun," said Bejerano, who plans to continue the
investigation into what the ultraconserved segments might be doing. "You
answer one question, and five others pop up. But one of the most rewarding
things to me is the fact that we're developing a growing appreciation for
how much these regions actually matter."

The research was supported by a Stanford Bio-X graduate fellowship to McLean
and an Edward Mallinckrodt, Jr. Foundation junior faculty grant. Bejerano is
a Sloan research fellow and a Searle scholar.


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Journal reference:

1.. McLean, C., and Bejerano, G. Dispensability of mammalian DNA. Genome
Res., (in press) DOI: 10.1101/gr.080184.108
Adapted from materials provided by Stanford University Medical Center.
Stanford University Medical Center (2008, October 7). Mysterious Snippets Of
DNA Withstand Eons Of Evolution. ScienceDaily. Retrieved October 8, 2008,
from http://www.sciencedaily.com/releases/2008/10/081001181306.htm

Posted by
Robert Karl Stonjek


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