Agilent Aids Discovery Of DNA Mutation Mechanism

When Baylor College of Medicine (BCM) researcher Jennifer Lee was studying the mechanisms of Pelizaeus-Merzbacher disease (PMD), she expected to find DNA additions or deletions in the wrong place on patients’ chromosomes. After all, PMD – a progressive degenerative disorder of the central nervous system – occurs when DNA gets shuffled around incorrectly during replication. She did observe these expected mutations, but she also encountered some spots in which genetic material was found in the middle of other duplications. Previous theories of DNA recombination couldn’t explain that. So Lee, senior investigator James Lupski, and a team of researchers at BCM decided to investigate – with the help of Agilent’s DNA microarrays. These oligonucleotide probes enable scientists to analyze DNA samples to detect subtle yet significant biological changes. With the results from the microarrays, Lee and colleagues were able to describe a new mechanism for human genomic disorders: replication Fork Stalling and Template Switching (FoSTeS). Sometimes, when the DNA replication process stalls, it will switch to a different “template” rather than restarting in the same place. That’s why Lee observed segments of DNA in the middle of other duplications when studying PMD patients. The mechanism explains similar types of “errors” that have been associated with Alzheimer’s, Parkinson’s, Potocki-Lupski Syndrome, and other developmental and neurological disorders. In addition to disease research, Lupski says the FoSTeS mechanism could also play an important role in studies probing human evolution. “The Agilent microarrays were essential in enabling us to elucidate this novel mechanism,” Lupski, professor of molecular and human genetics at BCM, said in a statement. The paper, “A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders,” was published in the December 28, 2007 issue of the journal Cell. Agilent’s marketing manager Condie Carmack said the company was pleased that its custom DNA microarrays enabled the team to discover the mechanism. Agilent offers DNA analysis products ranging from whole-genome to zoom-in 60-mer oligo CGH microarrays for human, mouse, and rat genomes. “The Baylor team needed total control over the sequences on their microarrays as well as very high sensitivity and precision to make this research work,” Carmack said. “Our SurePrint in-situ synthesis platform is particularly well-suited for this type of work.”