A novel mechanistic spectrum underlies glaucoma-associated chromosome 6p25 copy number variation
Open Access
- 11 August 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 17 (22), 3446-3458
- https://doi.org/10.1093/hmg/ddn238
Abstract
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.This publication has 71 references indexed in Scilit:
- Psoriasis is associated with increased β-defensin genomic copy numberNature Genetics, 2007
- Contribution of SHANK3 Mutations to Autism Spectrum DisorderAmerican Journal of Human Genetics, 2007
- Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogsNature Genetics, 2007
- Diet and the evolution of human amylase gene copy number variationNature Genetics, 2007
- Challenges and standards in integrating surveys of structural variationNature Genetics, 2007
- GDF6, a Novel Locus for a Spectrum of Ocular Developmental AnomaliesAmerican Journal of Human Genetics, 2007
- Global variation in copy number in the human genomeNature, 2006
- Processes of copy-number change in human DNA: The dynamics of α-globin gene deletionProceedings of the National Academy of Sciences of the United States of America, 2006
- Fine-scale structural variation of the human genomeNature Genetics, 2005
- Mechanism and regulation of human non-homologous DNA end-joiningNature Reviews Molecular Cell Biology, 2003