Absence of heterozygosity due to template switching during replicative rearrangements

Claudia M B Carvalho; Rolph Pfundt; Daniel A King; Sarah J Lindsay; Luciana W Zuccherato; Merryn V E Macville; Pengfei Liu; Diana Johnson; Pawel Stankiewicz; Chester W Brown; DDD Study; Chad A Shaw; Matthew E Hurles; Grzegorz Ira; P J Hastings; Han G Brunner; James R Lupski

doi:10.1016/j.ajhg.2015.01.021

Absence of heterozygosity due to template switching during replicative rearrangements

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

Authors

Claudia M B Carvalho¹, Rolph Pfundt², Daniel A King³, Sarah J Lindsay³, Luciana W Zuccherato⁴, Merryn V E Macville⁵, Pengfei Liu⁴, Diana Johnson⁶, Pawel Stankiewicz⁴, Chester W Brown⁷; DDD Study; Chad A Shaw⁴, Matthew E Hurles³, Grzegorz Ira⁴, P J Hastings⁴, Han G Brunner⁸, James R Lupski⁹

Affiliations

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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
DNA Copy Number Variations / genetics*
DNA Repair / genetics*
DNA Replication / genetics*
Gene Rearrangement / genetics*
Humans
In Situ Hybridization, Fluorescence
Loss of Heterozygosity / genetics*
Models, Genetic*
Molecular Sequence Data
Netherlands
Polymerase Chain Reaction
Polymorphism, Single Nucleotide / genetics
Sequence Analysis, DNA
Uniparental Disomy / genetics*

Associated data

GEO/GSE65113
GEO/GSE65379

Abstract

Publication types

MeSH terms

Associated data

Grants and funding