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Hum Mol Genet. 2015 Jul 15;24(14):4061-77. doi: 10.1093/hmg/ddv146. Epub 2015 Apr 23.

Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3.

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Department of Molecular & Human Genetics.
Department of Molecular & Human Genetics, Texas Children's Hospital, Houston, TX 77030, USA and.
Department of Molecular & Human Genetics, Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
Department of Molecular & Human Genetics, Department of Pediatrics and Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA, Texas Children's Hospital, Houston, TX 77030, USA and


Alu repetitive elements are known to be major contributors to genome instability by generating Alu-mediated copy-number variants (CNVs). Most of the reported Alu-mediated CNVs are simple deletions and duplications, and the mechanism underlying Alu-Alu-mediated rearrangement has been attributed to non-allelic homologous recombination (NAHR). Chromosome 17 at the p13.3 genomic region lacks extensive low-copy repeat architecture; however, it is highly enriched for Alu repetitive elements, with a fraction of 30% of total sequence annotated in the human reference genome, compared with the 10% genome-wide and 18% on chromosome 17. We conducted mechanistic studies of the 17p13.3 CNVs by performing high-density oligonucleotide array comparative genomic hybridization, specifically interrogating the 17p13.3 region with ∼150 bp per probe density; CNV breakpoint junctions were mapped to nucleotide resolution by polymerase chain reaction and Sanger sequencing. Studied rearrangements include 5 interstitial deletions, 14 tandem duplications, 7 terminal deletions and 13 complex genomic rearrangements (CGRs). Within the 17p13.3 region, Alu-Alu-mediated rearrangements were identified in 80% of the interstitial deletions, 46% of the tandem duplications and 50% of the CGRs, indicating that this mechanism was a major contributor for formation of breakpoint junctions. Our studies suggest that Alu repetitive elements facilitate formation of non-recurrent CNVs, CGRs and other structural aberrations of chromosome 17 at p13.3. The common observation of Alu-mediated rearrangement in CGRs and breakpoint junction sequences analysis further demonstrates that this type of mechanism is unlikely attributed to NAHR, but rather may be due to a recombination-coupled DNA replicative repair process.

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