An Organismal CNV Mutator Phenotype Restricted to Early Human Development

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


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.

Publication types

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

MeSH terms

  • Chromosome Aberrations*
  • Chromosome Breakpoints
  • Chromosome Duplication
  • DNA Copy Number Variations*
  • DNA Replication
  • Embryonic Development
  • Female
  • Gametogenesis
  • Genetic Diseases, Inborn / embryology*
  • Genetic Diseases, Inborn / genetics*
  • Genomic Instability*
  • Humans
  • Male
  • Mutation*