"Science" October 25, 2002 vol. 298, p. 719.721
Jumbled DNA Separates Chimps and Humans
Elizabeth Pennisi
BALTIMORE, MARYLAND--For almost 30 years, researchers have asserted that
the DNA of humans and chimps is at least 98.5% identical. Now research
reported here last week at the American Society for Human Genetics meeting
suggests that the two primate genomes might not be quite as similar after all. A
closer look has uncovered nips and tucks in homologous sections of DNA
that weren't noticed in previous studies.
The results are quite exciting, says Michael Conneally, a human
geneticist at Indiana University Medical Center in Indianapolis. With this
research, "we can really find out so much more about evolution," he predicts.
In the past 3 decades, biologists have used all sorts of biochemical
methods to assess differences between genomes, particularly those of humans and
chimps. As more DNA sequence became available over that time, many
researchers began to look at short stretches of DNA and count the number
of single bases that didn't match the equivalent bases in another species--
known as single-nucleotide polymorphisms. In contrast, some
cytogeneticists have taken a more global view of the genomic landscape, mapping out
differences in how chromosomes appear under the microscope.
Now two research teams have spotlighted the middle ground, using
so-called gene chips to evaluate millions of bases of DNA in a single experiment.
The chips--some of the most powerful to date--carry snippets of known
genetic material that, when paired up with DNA in a test sample, tell
researchers what genetic code is present.
With this wide-ranging view, genomicists Kelly Frazer, David Cox, and
their colleagues at Perlegen Sciences in Mountain View, California, have
detected insertions and deletions ranging from 200 bases to 10,000 bases in
length that differ between chimps and humans, each of which has a genome of
about 3 billion bases. Evan Eichler and Devin Locke, geneticists at Case Western
Reserve University in Cleveland, Ohio, have studied changes extending
about 150,000 bases. "A significant fraction of the variation [between chimps
and humans] is present in these [two types of] rearrangements," Frazer
reports.
The Perlegen team used chips densely packed with small pieces of DNA,
each 25 bases long. The chip is studded with "13 billion unique [pieces],"
Cox points out. The researchers assessed the resemblance between the chimp's
chromosome 22 and the equivalent human chromosome, 21. They compared 27
million bases, and "much to our surprise, we found around 57 areas of
rearrangement between the human and the chimp," says Cox.
There seemed to be no rhyme or reason to the changes; they occurred just
as frequently outside coding regions as within. The density of these
differences is "a little bit higher than anyone would have predicted,"
says Eichler. "The implications could be profound," he adds, because such
genetic hiccups could disable entire genes, possibly explaining why our closest
cousins seem so distant.
Instead of using small bits of DNA, Locke, Eichler, and their colleagues
deposited on a chip a series of bacterial artificial chromosomes, each
of which contained about 150,000 bases of human DNA. The chip sported
almost 2500 sequences covering 360 million bases in all. They compared this DNA
to DNA from Asian and African great apes and found 63 chunks that were
missing or added. The deletions and insertions they uncovered, which were larger
than those picked up by the Perlegen team, tended to be close to large
duplicated regions, Locke reported at the meeting, although the
researchers aren't sure how to interpret this finding. The frequency of such genetic
differences suggests, Frazer says, that "these rearrangements are
playing a much bigger role [in evolution] than we expected."
Locke's and Frazer's results come as no surprise to Roy Britten of the
California Institute of Technology in Pasadena, who has analyzed the
chimp and human genomes using a customized computer program. He compared
779,000 bases of chimp DNA with the sequence of the human genome, both found in
the public repository GenBank. Single-base changes accounted for 1.4% of the
differences between the human and chimp genomes, and insertions and
deletions ranging up to 31 bases long accounted for an additional 3.4%,
he reported in the 15 October Proceedings of the National Academy of
Sciences. Locke's and Frazer's groups didn't commit to new estimates of the
similarity between the species, but both agree that the previously accepted 98.5%
mark is too high.
Such findings leave researchers eager to scrutinize the full chimp
sequence. Japanese, German, South Korean, Taiwanese, and Chinese researchers
formalized a chimp genome project in 2001 (Science, 23 March 2001, p.
2297 <http://www.sciencemag.org/cgi/content/short/291/5512/2297b>); that
program recently got a boost when the National Human Genome Research Institute
in Bethesda, Maryland, listed the chimp as a high priority for sequencing
by its high-throughput centers. The sequence should be ready in mid-2003.
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