In this newer report, Lupski and colleagues describe how this process - called fork stalling and template switching (FoSTeS) in humans or microhomology-mediated break-induced replication (MMBIR) in simpler models - generated genomic rearrangements ranging in size from several megabases to a few hundred base pair during normal cell division, resulting in the duplication or even triplications of individual genes or the rearrangements of single exons (the coding region of genes).

"This phenomenon occurs throughout the genome," said Dr. Feng Zhang, a postdoctoral associate in Lupski's laboratory and the first author of the report.

In studies of subjects with abnormalities in the gene associated with Charcot-Marie Tooth type 1A (PMP22), the researchers found that the fork stalling, template switching phenomenon explained the changes, from those that involved triplication of a gene to others that resulted from shuffling within an exon.

Studies of one family - two children and a mother - demonstrated that the event occurred during mitosis or cell division, a significant finding that further confirms the significance of the event.

The researchers noted that finding this mitotic rearrangement of the gene in the mother, who did not have the disorder, of two children with a neuropathy suggests that the mechanism might be considered in genetic counseling about the risk of having another child with the disorder.

The scientists wrote, "We propose that FoSTeS/MMBIR may be a key mechanism for generating structural variation, particularly nonrecurrent CNV (copy number variation), of the human genome. "

The observation of mosaicism for an apparent mitotically generated, FoSTeS/MMBIR-mediated complex PMP22 rearrangement in the unaffected mother of two children with neuropathy suggests this mechanism can have implications for genetic counseling regarding recurrence risk.

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