Jumbled DNA Separates Chimps and Humans

[编者的话]

我们知道人和猩猩的DNA组成有98.5是相同的，那么是什么使得人与猩猩的表现型如此不同呢？下面的短文来自science，文章通过大规模的DNA芯片分析，为这一问题的解答提供了一个可能的答案。

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); 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.