STANFORD--Researchers at the Stanford Human Genome Center have developed
a powerful new computer program that can map thousands of genetic markers
at once. Using this program, called Mapper, scientists have obtained one
of the most accurate views yet of the human genome as a whole.
"These maps have better resolution in local areas than the other available whole genome maps," said Dr. David Cox, professor of genetics and co-director of the Stanford Human Genome Center. "The others can tell you what block the house is on, but we can give the exact address."
Mapper produces high-quality genetic maps that will dramatically advance the efforts of the Human Genome Project, whose goal is to map and sequence the genetic blueprint that contains all of the instructions about how to make a human body, said Richard Myers, professor of genetics and director of the Stanford Human Genome Center.
"Previously, it would take months for us to build a map," said Myers. "Now we can rebuild it every day, including new information as it is gathered. Our maps are now much more accurate because we can map everything at once."
The Stanford team that developed Mapper will present the new method, this week, along with the maps it has generated, at the Genome Mapping and Sequencing meeting at Cold Spring Harbor, N.Y., May 8-12.
To get an idea of the challenge confronting gene mappers, imagine constructing a map of the world knowing only that Palo Alto is close to San Francisco, Paris and Frankfurt are both in Europe, and Johannesburg and Nairobi are on the same continent.
Gene mappers use short, distinctive genetic markers found in DNA as signposts in the human genome. Markers that are close together remain on the same piece of DNA when scientists cut the long strands into small pieces. Using statistics to count how often particular pairs of markers remain together, computers can measure the distances between them and can determine their order on the DNA.
Until now, generally available computer programs have had to test every possible combination of locations for each set of these DNA signposts to figure out which one was correct. This method takes a large computer a relatively short amount of time if processing only 15 or 20 markers. However, each of the human chromosomes contains 500 to 1,000 of these markers -- far too many to map all at once using available computer programs.
To solve this problem, computer scientists at the Stanford Human Genome Center applied a well-known computer trick: They instructed the computer to ignore some unlikely possibilities instead of demanding that every possibility be checked.
"This technique is not exact or exhaustive -- and that's why it works. The computers don't try everything -- that would take forever -- but they come up with pretty good answers," said Kathleen McKusick, computer scientist at the Stanford Human Genome Center. She and Cox played the major roles in developing the new computer program.
To create Mapper, the scientists started with a very thorough program developed by Michael Boehnke at the University of Michigan. But that program eventually fell by the wayside.
"We built a car around an engine, and then changed the engine," said McKusick.
McKusick and colleagues modified the original program in steps, gradually replacing the very precise, but time-consuming and expensive parts. At every point, they evaluated its success to make sure they were not sacrificing accuracy.
"We started out using the off-the-shelf thing, then tried to scale it up. We found that we were bumping up against its limitations -- then we'd change it. Eventually, the original program just dropped out of the picture," said McKusick.
So far Mapper is performing well, she said. The researchers have tested Mapper's accuracy by comparing its results with genetic maps obtained by other scientific methods.
The Stanford team believes that Mapper will be invaluable as scientists continue toward their goal of determining the entire sequence of genetic letters that make up the human genome.
"The maps we've made using this program are among the highest-resolution maps that have been made to date, but they're not detailed enough to allow sequencing the whole genome. Next, we'll do more of the same but with five times the number of markers so that we can use the maps for sequencing," said Myers.
The coming maps will also help researchers find the particular DNA markers that are used to diagnose disease. "The more detailed maps are essential in identifying disease genes, especially for diseases that are inherited in a complex manner and aren't due to a defect in a single gene," said Myers.