Copy number variation at the breakpoint region of isochromosome 17q
- 19 August 2008
- journal article
- Published by Cold Spring Harbor Laboratory in Genome Research
- Vol. 18 (11) , 1724-1732
- https://doi.org/10.1101/gr.080697.108
Abstract
Isochromosome 17q, or i(17q), is one of the most frequent nonrandom changes occurring in human neoplasia. Most of the i(17q) breakpoints cluster within a ∼240-kb interval located in the Smith-Magenis syndrome common deletion region in 17p11.2. The breakpoint cluster region is characterized by a complex architecture with large (∼38–49 kb), inverted and directly oriented, low-copy repeats (LCRs), known as REPA and REPB that apparently lead to genomic instability and facilitate somatic genetic rearrangements. Through the analysis of bacterial artificial chromosome (BAC) clones, pulsed-field gel electrophoresis (PFGE), and public array comparative genomic hybridization (array CGH) data, we show that the REPA/B structure is also susceptible to frequent meiotic rearrangements. It is a highly dynamic genomic region undergoing deletions, inversions, and duplications likely produced by non-allelic homologous recombination (NAHR) mediated by the highly identical SNORD3@, also known as U3, gene cluster present therein. We detected at least seven different REPA/B structures in samples from 29 individuals of which six represented potentially novel structures. Two polymorphic copy-number variation (CNV) variants, detected in 20% of samples, could be structurally described along with the likely underlying molecular mechanism for formation. Our data show the high susceptibility to rearrangements at the i(17q) breakpoint cluster region in the general population and exemplifies how large genomic regions laden with LCRs still represent a technical challenge for both determining specific structure and assaying population variation. The variant REPA/B structures identified may have different susceptibilities for inducing i(17q), thus potentially representing important risk alleles for tumor progression.Keywords
This publication has 30 references indexed in Scilit:
- Phenotypically Concordant and Discordant Monozygotic Twins Display Different DNA Copy-Number-Variation ProfilesAmerican Journal of Human Genetics, 2008
- Psoriasis is associated with increased β-defensin genomic copy numberNature Genetics, 2007
- Recurrent DNA inversion rearrangements in the human genomeProceedings of the National Academy of Sciences, 2007
- Characterization of Potocki-Lupski Syndrome (dup(17)(p11.2p11.2)) and Delineation of a Dosage-Sensitive Critical Interval That Can Convey an Autism PhenotypeAmerican Journal of Human Genetics, 2007
- Two classes of low-copy repeats comediate a new recurrent rearrangement consisting of duplication at 8p23.1 and triplication at 8p23.2Human Mutation, 2007
- Global variation in copy number in the human genomeNature, 2006
- Genome structural variation and sporadic disease traitsNature Genetics, 2006
- A 1.5 million–base pair inversion polymorphism in families with Williams-Beuren syndromeNature Genetics, 2001
- A Bacterial Artificial Chromosome Library for Sequencing the Complete Human GenomeGenome Research, 2001
- Molecular mechanism for duplication 17p11.2— the homologous recombination reciprocal of the Smith-Magenis microdeletionNature Genetics, 2000