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The 22q11 low copy repeats are characterized by unprecedented size and structure variability

Wolfram Demaerel, Yulia Mostovoy, Feyza Yilmaz, Lisanne Vervoort, Steven Pastor, Matthew S Hestand, Ann Swillen, Elfi Vergaelen, Elizabeth A. Geiger, Curtis R. Coughlin, Stephen K. Chow, Donna McDonald-McGinn, Bernice Morrow, Pui-Yan Kwok, Ming Xiao, Beverly S. Emanuel, Tamim H. Shaikh, Joris R Vermeesch
doi: https://doi.org/10.1101/403873
Wolfram Demaerel
1Departement of Human Genetics, KU Leuven, Leuven, Belgium
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Yulia Mostovoy
2Cardiovascular Research Institute, UCSF School of Medicine, San Francisco, California 94158, USA
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Feyza Yilmaz
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
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  • For correspondence: joris.vermeesch@uzleuven.be
Lisanne Vervoort
1Departement of Human Genetics, KU Leuven, Leuven, Belgium
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Steven Pastor
5School of Biomedical Engineering, Drexel University, Philadelphia, Pennsylvania 19104, USA
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Matthew S Hestand
1Departement of Human Genetics, KU Leuven, Leuven, Belgium
6Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
7Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA
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Ann Swillen
1Departement of Human Genetics, KU Leuven, Leuven, Belgium
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Elfi Vergaelen
1Departement of Human Genetics, KU Leuven, Leuven, Belgium
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Elizabeth A. Geiger
4Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado Denver, Aurora, Colorado 80045, USA
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Curtis R. Coughlin
4Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado Denver, Aurora, Colorado 80045, USA
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Stephen K. Chow
2Cardiovascular Research Institute, UCSF School of Medicine, San Francisco, California 94158, USA
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Donna McDonald-McGinn
8Division of Human Genetics, Children’s Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
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Bernice Morrow
9Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
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Pui-Yan Kwok
2Cardiovascular Research Institute, UCSF School of Medicine, San Francisco, California 94158, USA
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Ming Xiao
5School of Biomedical Engineering, Drexel University, Philadelphia, Pennsylvania 19104, USA
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Beverly S. Emanuel
8Division of Human Genetics, Children’s Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
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Tamim H. Shaikh
4Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado Denver, Aurora, Colorado 80045, USA
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Joris R Vermeesch
1Departement of Human Genetics, KU Leuven, Leuven, Belgium
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  • For correspondence: joris.vermeesch@uzleuven.be
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Abstract:

Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The chromosome 22 LCRs (LCR22s) are amongst the most complex regions in the genome and their structure remains unresolved. These LCR22s mediate non-allelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS), causing the most frequent genomic disorder. Using fiber FISH optical mapping, we have de novo assembled the LCR22s in 33 cell lines. We observed a high level of variation in LCR22 structures, including 26 different haplotypes of LCR22A with alleles ranging from 250 Kb to over 2,000 Kb. An additional four haplotypes were detected using Bionano mapping. Further, Bionano maps generated from 154 individuals from different populations suggested significantly different LCR22 haplotype frequencies between populations. Furthermore, haplotype analysis in nine 22q11DS patients resulted in the localization of the NAHR site to a 160 Kb paralog between LCR22A and –D in seven patients and to a 31 Kb region in two individuals with a rearrangement between LCR22A and –B.. This 31 Kb region contains a palindromic AT-rich repeat known to be a driver of chromosomal rearrangements. Our study highlights an unprecedented level of polymorphism in the structure of LCR22s, which are likely still evolving. We present the most comprehensive map of LCR22 variation to date, paving the way towards investigating the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability in 22q11DS patients as well as in the general population.

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Posted September 12, 2018.
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The 22q11 low copy repeats are characterized by unprecedented size and structure variability
Wolfram Demaerel, Yulia Mostovoy, Feyza Yilmaz, Lisanne Vervoort, Steven Pastor, Matthew S Hestand, Ann Swillen, Elfi Vergaelen, Elizabeth A. Geiger, Curtis R. Coughlin, Stephen K. Chow, Donna McDonald-McGinn, Bernice Morrow, Pui-Yan Kwok, Ming Xiao, Beverly S. Emanuel, Tamim H. Shaikh, Joris R Vermeesch
bioRxiv 403873; doi: https://doi.org/10.1101/403873
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The 22q11 low copy repeats are characterized by unprecedented size and structure variability
Wolfram Demaerel, Yulia Mostovoy, Feyza Yilmaz, Lisanne Vervoort, Steven Pastor, Matthew S Hestand, Ann Swillen, Elfi Vergaelen, Elizabeth A. Geiger, Curtis R. Coughlin, Stephen K. Chow, Donna McDonald-McGinn, Bernice Morrow, Pui-Yan Kwok, Ming Xiao, Beverly S. Emanuel, Tamim H. Shaikh, Joris R Vermeesch
bioRxiv 403873; doi: https://doi.org/10.1101/403873

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