The 22q11 low copy repeats are characterized by unprecedented size and structural variability
- Wolfram Demaerel1,10,
- Yulia Mostovoy2,10,
- Feyza Yilmaz3,4,10,
- Lisanne Vervoort1,
- Steven Pastor5,
- Matthew S. Hestand1,6,7,
- Ann Swillen1,
- Elfi Vergaelen1,
- Elizabeth A. Geiger4,
- Curtis R. Coughlin4,
- Stephen K. Chow2,
- Donna McDonald-McGinn5,
- Bernice Morrow8,
- Pui-Yan Kwok2,
- Ming Xiao9,
- Beverly S. Emanuel5,
- Tamim H. Shaikh4 and
- Joris R. Vermeesch1
- 1Departement of Human Genetics, KU Leuven, Leuven, 3000 Belgium;
- 2Cardiovascular Research Institute, UCSF School of Medicine, San Francisco, California 94158, USA;
- 3Department of Integrative Biology, University of Colorado Denver, Denver, Colorado 80204, USA;
- 4Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado Denver, Aurora, Colorado 80045, USA;
- 5Division of Human Genetics, Children's Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 6Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA;
- 7Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45221, USA;
- 8Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA;
- 9School of Biomedical Engineering, Drexel University, Philadelphia, Pennsylvania 19104, USA
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↵10 These authors contributed equally to this work.
Abstract
Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.
Footnotes
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[Supplemental material is available for this article.]
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Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.248682.119.
- Received January 27, 2019.
- Accepted July 24, 2019.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
