title: Absence of heterozygosity due to template switching during replicative rearrangements.
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.
authors: 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.
authors: Claudia M B
authors: CM
authors: Carvalho
authors: Department of Human Genetics, Radboud University Medical Center Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, the Netherlands.
authors: Rolph
authors: R
authors: Pfundt
authors: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors: Daniel A
authors: DA
authors: King
authors: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors: Sarah J
authors: SJ
authors: Lindsay
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Luciana W
authors: LW
authors: Zuccherato
authors: Department of Clinical Genetics, Maastricht University Medical Center, 6202 AZ, Maastricht, the Netherlands.
authors: Merryn V E
authors: MV
authors: Macville
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Pengfei
authors: P
authors: Liu
authors: Sheffield Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, UK.
authors: Diana
authors: D
authors: Johnson
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Pawel
authors: P
authors: Stankiewicz
authors: 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.
authors: Chester W
authors: CW
authors: Brown
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Chad A
authors: CA
authors: Shaw
authors: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors: Matthew E
authors: ME
authors: Hurles
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Grzegorz
authors: G
authors: Ira
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: P J
authors: PJ
authors: Hastings
authors: 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.
authors: Han G
authors: HG
authors: Brunner
authors: 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.
authors: James R
authors: JR
authors: Lupski
mesh_terms: D001483:Base Sequence; D056915:DNA Copy Number Variations / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D015321:Gene Rearrangement / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009426:Netherlands; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D024182:Uniparental Disomy / Q000235:genetics*