title: Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3.
abstract: 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.
authors.affiliation: Department of Molecular & Human Genetics.
authors.forename: Shen
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Molecular & Human Genetics.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Molecular & Human Genetics.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.affiliation: Department of Molecular & Human Genetics.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Beck
authors.affiliation: Department of Molecular & Human Genetics.
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.affiliation: Department of Molecular & Human Genetics, Texas Children's Hospital, Houston, TX 77030, USA and.
authors.forename: Sandesh C S
authors.initials: SC
authors.lastname: Nagamani
authors.affiliation: Department of Molecular & Human Genetics, Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Erez
authors.affiliation: Department of Molecular & Human Genetics.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Molecular & Human Genetics, Texas Children's Hospital, Houston, TX 77030, USA and.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.affiliation: Department of Molecular & Human Genetics.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.affiliation: Department of Molecular & Human Genetics.
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
authors.affiliation: Department of Molecular & Human Genetics.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: Department of Molecular & Human Genetics.
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.affiliation: 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 jlupski@bcm.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000483:Alleles; D020087:Alu Elements / Q000235:genetics*; D001483:Base Sequence; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D020440:Gene Duplication; D015321:Gene Rearrangement; D015894:Genome, Human; D042822:Genomic Instability; D023281:Genomics; D059765:Homologous Recombination; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D056916:Segmental Duplications, Genomic; D017384:Sequence Deletion