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Baylor Researchers Uncover New Mechanism Behind Genomic Disease Using CGH Array

NEW YORK (GenomeWeb News) - Agilent Technologies announced today that its custom microarray technology contributed to research revealing a new mechanism by which human genetic disorders may arise.
 
Using breakpoint sequence analyses in conjunction with Agilent’s oligonucleotide comparative genomic hybridization custom microarrays, a group of Texas-based researchers discovered that genomic-based disease can arise when sections of DNA are added or deleted during replication in a process they call “replication fork stalling and template switching.” Their research, motivated by an interest in understanding the non-recurrent DNA rearrangements associated with the rare genomic condition Pelizaeus-Merzbacher disease, appeared in the journal Cell on Dec. 28, 2007.
 
“The Agilent microarrays were essential in enabling us to elucidate this novel mechanism,” Baylor College of Medicine geneticist and pediatrician James Lupski, senior author on the paper, said in a statement issued today.
 
Most DNA rearrangements involved in genomic diseases are attributed to mechanisms such as non-allelic homologous recombination or non-homologous end joining. But these are insufficient to explain the non-recurrent DNA rearrangements associated with some syndromes.
 
The new study suggests genomic disruptions can also occur when DNA replication falters — in some cases jumping from one template to another midway through. Small, single-stranded DNA breaks apparently play a role in tripping up replication. 
 
Researchers at Baylor College of Medicine and the Texas Children’s Hospital discovered the new genetic foible — which appears to involve stalling and slippage at the replication fork — while studying Pelizaeus-Merzbacher, a neurodegenerative disease affecting the growth of the fatty myelin sheath that surrounds and protects nerves.
 
Because it is X-linked, Pelizaeus-Merzbacher primarily affects males. It is most often caused by non-recurrent duplication of a dose-sensitive gene known as proteolipid protein 1, though deletions and mutations of the gene may also occur. The condition is characterized by progressive central nervous system deterioration leading to decreased coordination, motor, and intellectual function.
 
The researchers used the CGH arrays to achieve better resolution of duplication breakpoint junctions while analyzing DNA samples taken from 17 males with Pelizaeus-Merzbacher. The patterns they found, including interrupted duplications “in which stretches of duplicated DNA were punctuated by stretches of DNA with no copy-number alteration,” argued against simple tandem duplications.
 
“Our model of replication fork stalling and template switching can explain the complex duplication and deletion rearrangements associated with PMD and potentially other non-recurrent rearrangements of the human genome,” the authors wrote in the paper. “The concept of a replication-based as opposed to a recombination-based mechanism revolutionizes our thinking about non-recurrent DNA rearrangements and how they may physically occur.”
 
In a commentary in the same issue of Cell, Italian researchers Dana Branzei and Marco Foiani, of the University of Milan, noted that similar replication fork slippage, “could be responsible for other non-recurrent disease-causing genomic rearrangements.”
 
Indeed, the Baylor researchers propose that their model may explain other conditions caused by non-recurrent rearrangements, such as duplications associated with some forms of Alzheimer’s and Parkinson’s disease.
 

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