The NHGRI study, which appears in the February, 1998, issue of Nature Genetics, marks the first time the chips have been used to sequence DNA from nonhuman primates. The tiny DNA chips-each the size of a postage stamp-represents a new way of analyzing genetic material that is expected to have a formidable impact on the future of both clinical and research genetics.
The study demonstrates, the scientists say, that chip technology can deduce with close to 100% accuracy the sequence of nucleotides in a particular ape gene if the analogous human sequence is known already. "Which is to say that you don't have to start analyzing those genomes from scratch, which would be much more time-consuming and expensive," said Francis S. Collins, the paper's corresponding author, who heads NHGRI and directs the Human Genome Project.
"This technology is a rapid and accurate way of obtaining information about these genomes," said NHGRI's Joseph G. Hacia, the paper's first author. "You have to make a big investment to get human sequences, but then you can use that investment to get the sequences of our closest relatives at a relatively cheap price."
The researchers believe their approach has a number of potential benefits. It will be valuable, they say, for determining not only gene structure, but also gene function, regulation, and evolution. And it could eventually make possible a fairly quick and relatively inexpensive Chimpanzee Genome Project--the mapping and sequencing of chimp DNA. Chimp and human DNA are believed to differ in only about 1.5% of their sequences. Identification and study of the small genetic variations between the two species could help explain why chimps and people are so different--why, for example, the human brain is so much larger, and possesses more complicated mental capacities.
"Eventually, the scientific community will determine what the small differences between human and ape genomes are, and then figure out how that makes us distinct on the biochemical level," said Dr. Hacia. "It will be really exciting to apply this DNA sequence-based approach toward understanding the evolution of higher cognitive functions."
The chip approach could also save time and perhaps money, Dr. Hacia said, if employed as a backup confirmation of gene sequences determined by the standard method, called dideoxy sequencing.
The chips in the study compared the structure of a 3.4 kilo base strand of BRCA1, a human gene that causes hereditary breast and ovarian cancer, with corresponding DNA regions from other animals, mostly nonhuman primates. The researchers used the BRCA1 chip because they have recently been employing it to look for disease-causing mutations in that gene, so it was readily available.
Their mutation research had demonstrated that the BRCA1 chip is good at finding subtle sequence changes in a large gene. "You can think of a chimp as a collection of sequence changes relative to humans, so if it worked for finding disease-causing mutations it ought to work pretty well at finding sequence differences between humans and other primates, as long as there are not too many of them," Dr. Collins said.
The chip was less accurate when the researchers analyzed DNA from other primates, including rhesus monkey, galago, and red howler monkey, and least accurate of all when they studied dog DNA. But even the distantly related genomes contained some identical blocks of nucleotides, apparently conserved in several species throughout their evolution.
"The chips work best when you're looking at very close relatives like chimps, gorillas, and orangutans. But in DNA regions that are strongly conserved, which is true of the coding regions of many genes, you might also be able to use the chip to look further away to other mammals,"
Dr. Collins suggested. "The regions of a gene that are most strongly conserved are often the parts that are most important functionally. With some more development, this might be a way of assessing what's the most functionally important part of a gene--not only its coding region, but also its regulatory regions, which is an area that we are really not that far
The NHGRI oversees the NIH's role in the Human Genome Project, an international research effort to develop tools for gene discovery.
To arrange an interview with Dr. Collins or Hacia, contact Jeff Witherly, 301-402-8564 or Galen Perry, 301-402- 3035.