Human Molecular Genetics Advance Access originally published online on August 11, 2008
Human Molecular Genetics 2008 17(22):3446-3458; doi:10.1093/hmg/ddn238
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A novel mechanistic spectrum underlies glaucoma-associated chromosome 6p25 copy number variation
1 Departments of Ophthalmology 2 Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada T6G 2H7, 3 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK 4 Department of Clinical Genetics, Leicester Royal Infirmary, Leicester, UK 5 Department of Human Genetics, University of Chicago, Chicago, IL, USA 6 Developmental Biology Unit, UCL Institute of Child Health, London, UK
* To whom correspondence should be addressed. Email: olehmann{at}ualberta.ca
Received May 27, 2008; Revised July 11, 2008; Accepted August 7, 2008
The factors that mediate chromosomal rearrangement remain incompletely defined. Among regions prone to structural variant formation, chromosome 6p25 is one of the few in which disease-associated segmental duplications and segmental deletions have been identified, primarily through gene dosage attributable ocular phenotypes. Using array comparative genome hybridization, we studied ten 6p25 duplication and deletion pedigrees and amplified junction fragments from each. Analysis of the breakpoint architecture revealed that all the rearrangements were non-recurrent, and in contrast to most previous examples the majority of the segmental duplications and deletions utilized coupled homologous and non-homologous recombination mechanisms. One junction fragment exhibited an unprecedented 367 bp insert derived from tandemly arranged breakpoint elements. While this accorded with a recently described replication-based mechanism, it differed from the previous example in being unassociated with template switching, and occurring in a segmental deletion. These results extend the mechanisms involved in structural variant formation, provide strong evidence that a spectrum of recombination, DNA repair and replication underlie 6p25 rearrangements, and have implications for genesis of copy number variations in other genomic regions. These findings highlight the benefits of undertaking the extensive studies necessary to characterize structural variants at the base pair level.