Microarrays Uncover Connection Between Genomic Errors and Neurologic Disorders

When the DNA addition or deletion occurs in the wrong place, another genomic-based disorder such as Pelizaeus-Merzbacher disease (PMD) can occur. PMD is a progressive degenerative disorder of the central nervous system in which motor abilities and intellectual function deteriorate. This X-chromosome-linked neurodevelopment disorder affects males and can have particularly devastating consequences.

Scientists at Baylor College of Medicine (BCM; Houston, TX, USA), used their own SurePrint in situ synthesis platform together with Agilent (Santa Clara, CA, USA) microarrays to observe the unique way that DNA additions or deletions introduced in genes during cell division were associated the diseases. The mechanism for human genomic disorders in which segments of DNA are added or deleted during replication is called replication Fork Stalling and Template Switching (FoSTes).

Jennifer Lee, Ph.D., a member of the Baylor team, was studying PMD and found genomic changes that previous theory about DNA recombination did not explain. In some places, extra genetic material was found in the middle of a different duplication.

"The Agilent microarrays were essential in enabling us to elucidate this novel mechanism,” said BCM's James R. Lupski, M.D., Ph.D., professor of molecular and human genetics, and senior investigator in this project. Prof. Lupski pioneered the emerging field of copy number variation (CNV) in the early 1990s in the quest to understand genetic variation and the multiple molecular mechanisms for disease. Now, he and his colleagues have discovered that the DNA replication process can stall, and sometimes, switch to a different "template” rather than restarting in the same place. In addition to disease research, according to Dr. Lupski, the FoSTeS mechanism could also play an important role in studies investigating human evolution.

The findings were published in the January 2007 issue of the journal Cell.


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