By Karen Pihl-Carey

A month after the Sanger Centre announced the completion of the chromosome 22 DNA sequence, it is forging ahead in a collaboration with Third Wave Technologies to build the first high-density single nucleotide polymorphism (SNP) map of the chromosome.

Sanger will use Third Wave's Invader technology to construct the map and a corresponding SNP test panel.

Third Wave intends to introduce the Invader technology today at the 18th annual Chase H&Q Healthcare Conference in San Francisco, which will run through Thursday. More than 230 companies will present at the conference, and more than 4,000 people are expected to attend.

Using the Invader technology, Sanger researchers will analyze chromosome 22's genetic variations within a large population. Third Wave will develop and supply Invader assays for about 2,000 unique SNPs positioned at 40 Kb intervals along the chromosome. Sanger will use this panel to type unamplified genomic DNA from several hundred individuals.

"This is a really big deal. This may be the first major step in making large-scale genomics a reality," said Lance Fors, CEO of Third Wave, of Madison, Wis. The completed sequence of chromosome 22 was a huge milestone, Fors said. And now, less than six weeks later, he said, there's an effort to put new pieces in the human jigsaw puzzle. "So it sort of gives you the sense that you're going to get there, and you're going to get there a lot quicker than you thought you were."

The Sanger Centre said it chose the Invader technology because it is more accurate than polymerase chain reaction (PCR) technology. Many approaches rely on PCR primers to hybridize DNA and RNA to generate specificity. The Invader technology relies on a simple enzyme-substrate reaction and uses two nucleic acid probes to identify a specific sequence of DNA or RNA. One probe is recognized and cleaved by an enzyme. The presence of the released cleaved probe can be measured using microtiter plate readers, mass spectrometry and DNA chips.

Fors said researchers will take the raw sequence of chromosome 22, use the Invader technology to develop a panel, "and then start to look at how common diseases are impacted by genetic variations here."

Fors compared the technology to Microsoft's Windows. "We're viewing this technology as a potential operating system to enable large-scale genomics," he told BioWorld Today. While the technology will provide Sanger with assays for about 2,000 SNPs, "we're preparing to take on projects that could be 10 times or more that size," he said.

He said the foundation work with Sanger should be done in four months. Then, researchers can look at specific disease studies. And the Invader technology will be available to help in the construction of more SNP maps of additional chromosomes, once sequenced.

In the disease studies, for instance, Fors said researchers would ask questions like, "How is chromosome 22 playing a role in diabetes or in hypertension or in Alzheimer's?"

"You develop the basic diagnostic, and then you look at the various treatments today that are available or under development," he said. "And then you see if people with this genetic disposition respond to one treatment more than another."

The Sanger Centre, located in Cambridge, UK, is funded by the Wellcome Trust, which financially supports one-third of Sanger's work on the Human Genome Project. The total sequencing of the project is expected to be completed by 2003. The sequencing of chromosome 22, the second smallest chromosome, was reported in the Dec. 2 issue of Nature. (See BioWorld Today, Dec. 13, 1999, p. 1.)

Aside from the project with Sanger, privately held Third Wave is working with other institutions using its Invader technology. In October, the company entered into research collaborations with the University of Guelph in Guelph, Ontario, and Stanford University, of Stanford, Calif. The company also signed an agreement in September to provide Warner-Lambert Co., of Morris Plains, N.J., with a portfolio of Invader assays for evaluation in genotyping and gene expression applications.