A novel mechanistic spectrum underlies glaucoma-associated chromosome 6p25 copy number variation

Bhaskar Chanda, Mika Asai-Coakwell, Ming Ye, Andrew J. Mungall, Margaret Barrow, William B. Dobyns, Hourinaz Behesti, Jane C. Sowden, Nigel P. Carter, Michael A. Walter, Ordan J. Lehmann

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3446-3458
Number of pages13
JournalHuman molecular genetics
Issue number22
StatePublished - 2008
Externally publishedYes

Bibliographical note

Funding Information:
This work was initially supported by the Birth Defects Foundation and the Wellcome Trust, and subsequently by the Canadian Institutes of Health Research, Alberta Heritage Foundation for Medical Research and Canada Research Chair program.


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