NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits
- Piotr Dittwald1,
- Tomasz Gambin2,
- Przemyslaw Szafranski3,
- Jian Li3,
- Stephen Amato4,
- Michael Y. Divon5,
- Lisa Ximena Rodriguez Rojas6,
- Lindsay E. Elton7,
- Daryl A. Scott3,
- Christian P. Schaaf3,
- Wilfredo Torres-Martinez8,
- Abby K. Stevens8,
- Jill A. Rosenfeld9,
- Satish Agadi3,
- David Francis10,
- Sung-Hae L. Kang3,
- Amy Breman3,
- Seema R. Lalani3,
- Carlos A. Bacino3,
- Weimin Bi3,
- Aleksandar Milosavljevic3,
- Arthur L. Beaudet3,
- Ankita Patel3,
- James R. Lupski3,
- Chad A. Shaw3,
- Anna Gambin1,
- Sau Wai Cheung3 and
- Pawel Stankiewicz3,11
- 1 University of Warsaw;
- 2 Warsaw University of Technology;
- 3 Baylor College of Medicine;
- 4 Phoenix Children's Hospital;
- 5 Lenox Hill Hospital;
- 6 Instituto de Referencia Andino;
- 7 Pediatric Specialty Services;
- 8 Indiana University School of Medicine;
- 9 Signature Genomic Laboratories, PerkinElmer, Inc.;
- 10 Murdoch Children's Research Institute
- ↵* Corresponding author; email: pawels{at}bcm.tmc.edu
Abstract
We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our Chromosomal Microarray Analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically-derived large dataset allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/Velocardiofacial syndrome, 166). In the ~ 25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5'-CCNCCNTNNCCNC-3' correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13 were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR mediated genomic instability and further elucidates the role of NAHR in human disease.
- Received November 26, 2012.
- Accepted April 30, 2013.
- © 2013, Published by Cold Spring Harbor Laboratory Press
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