Journal Article

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 and Ordan J. Lehmann

in Human Molecular Genetics

Volume 17, issue 22, pages 3446-3458
Published in print November 2008 | ISSN: 0964-6906
Published online August 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn238
A novel mechanistic spectrum underlies glaucoma-associated chromosome 6p25 copy number variation

Show Summary Details

Preview

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.

Journal Article.  5723 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.