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Cell. 2017 Feb 23;168(5):830-842.e7. doi: 10.1016/j.cell.2017.01.037.

An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA. Electronic address: pengfei.liu@bcm.edu.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
3
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
4
Collaborative Innovation Center of Genetics and Development, Institute of Reproduction and Development, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China.
5
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA; Texas Children's Hospital, Houston, TX 77030, USA.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
10
Medical Genetics Center, Bayerstrasse 3-5, 80335 Munich, Germany.
11
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; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.

Abstract

De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.

KEYWORDS:

CNV; DNA replication; cancer; de novo; duplication; genomic instability; germline; mutator

PMID:
28235197
PMCID:
PMC5407901
DOI:
10.1016/j.cell.2017.01.037
[Indexed for MEDLINE]
Free PMC Article

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