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Orion Licenses CSHL Technology to Target Plant Genomics Community

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COLD SPRING HARBOR, NY--Cold Spring Harbor Laboratory and Orion Genomics of St. Louis have announced a deal that could have important implications for the application of bioinformatics to plant genomics. Orion has signed an exclusive license for new gene discovery technology invented at the laboratory. The technology, called methyl filtration, is a biological method that sifts out noncoding DNA for faster and more cost-effective sequencing of large, complex plant genomes, such as those of maize and wheat.

According to John McPherson, Orion's chief scientific officer, the technology reduces the amount of data to be analyzed and puts it into a form that's easier to manage. "Bioinformatics is really all about discovering genes and discovering what they do based on the sequence," he said. McPherson added that this method, which eliminates the DNA repeats that could complicate analysis, "produces the raw materials for bioinformatics."

The methyl filtration technology, which will be marketed as GeneThresher, will enable Orion to directly sequence and find genes in major plant species much faster and at a much lower cost than other available technologies permit, the lab and company claimed. In fact, tests have shown that GeneThresher can cut the time and cost of sequencing required to find genes by a factor of 5-20, depending on the species being investigated.

GeneThresher works by separating plant genes from repetitive, noncoding DNA in the genome. The technology is better suited to plants' repeat DNA structures, which have methyl groups (one carbon and three hydrogen atoms) attached to them. These methyl groups tend to appear only in filler DNA and not where genes are located, enabling researchers to divide the two by filter cloning genomic libraries in a series of engineered bacterial strains, McPherson explained. Antibiotics are then used to kill off unwanted clones--those with methylated, noncoding DNA. "You can take advantage of the fact that the repeats look different than the genes in plants due to this methylation, so you can trick bugs into essentially eliminating the repeats," McPherson said. The procedure would not work as well in animals because their methylated regions are not largely restricted to repeats, he noted.

Once the repeat DNA has been removed, Orion can sequence the desired clones. Each sequencing breed produced is much more likely to contain a gene and not a repeat, McPherson said.

Excluding junk DNA is a primary concern when sequencing plant genomes, especially those that are extremely large with sizable amounts of noncoding genetic material. While humans, maize, rice, and wheat have similar numbers of genes, the sizes of their genomes vary widely: the human genome has about 3.5 gigabases, maize has 2.5 gigabases, wheat is about five times the size of the human genome, and rice has only some 450 megabases.

Due to its enormous size, sequencing the wheat genome with existing technology would be difficult and expensive, McPherson noted. A researcher using modern equipment and methodology would likely end up with many repeats and poor gene discovery results. Furthermore, McPherson said, the operation could not be done in less than 10 years. Cold Spring Harbor's procedure, he added, will make it possible to discover most wheat genes within a year, he claimed.

To get an idea of how the new method stacks up, the laboratory here compared its technology to the expressed sequence tag sequencing technique, which avoids the intergenic and noncoding DNA but is limited in that the cDNA libraries it uses leave out or under-represent many potentially important genes. Experiments showed that the technology produced filtered libraries with unique sequences not found in EST databases.

Orion plans to use methyl filtration to provide sequencing services to its research and business partners and expects demand to come from large agricultural companies such as DuPont. The company contended that GeneThresher has great potential to benefit the study of the three major US crops--barley, maize, and wheat. McPherson said Orion has not yet determined what it will charge for access to the technology.

Founded last year, Orion already had links to Cold Spring Harbor: Two of the company's founders, Robert Martienssen and Richard McCombie, work at the laboratory and helped invent the technology. The other two founders, McPherson and Richard Wilson, Orion's president and CEO, are assistant director and codirector, respectively, of the Genome Sequencing Center at the Washington University School of Medicine in St. Louis. All four of the scientists have worked on the Human Genome Project.

--Matthew Dougherty

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