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Am J Hum Genet. 2015 Apr 2;96(4):555-64. doi: 10.1016/j.ajhg.2015.01.021. Epub 2015 Mar 19.

Absence of heterozygosity due to template switching during replicative rearrangements.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Centro de Pesquisas René Rachou - FIOCRUZ, Belo Horizonte, MG 30190-002, Brazil.
2
Department of Human Genetics, Radboud University Medical Center Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, the Netherlands.
3
Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
5
Department of Clinical Genetics, Maastricht University Medical Center, 6202 AZ, Maastricht, the Netherlands.
6
Sheffield Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, UK.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
8
Department of Human Genetics, Radboud University Medical Center Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, 6202 AZ, Maastricht, the Netherlands.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: jlupski@bcm.tmc.edu.

Abstract

We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

PMID:
25799105
PMCID:
PMC4385179
DOI:
10.1016/j.ajhg.2015.01.021
[Indexed for MEDLINE]
Free PMC Article

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