An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

TitleAn Organismal CNV Mutator Phenotype Restricted to Early Human Development.
Publication TypeJournal Article
Year of Publication2017
AuthorsLiu, P, Yuan, B, Carvalho, CMB, Wuster, A, Walter, K, Zhang, L, Gambin, T, Chong, Z, Campbell, IM, Akdemir, ZCoban, Gelowani, V, Writzl, K, Bacino, CA, Lindsay, SJ, Withers, M, Gonzaga-Jauregui, C, Wiszniewska, J, Scull, J, Stankiewicz, P, Jhangiani, SN, Muzny, DM, Zhang, F, Chen, K, Gibbs, RA, Rautenstrauss, B, Cheung, SWai, Smith, J, Breman, A, Shaw, CA, Patel, A, Hurles, ME, Lupski, JR
Date Published2017 Feb 23
KeywordsChromosome Aberrations, Chromosome Breakpoints, Chromosome Duplication, DNA Copy Number Variations, DNA Replication, Embryonic Development, Female, Gametogenesis, Genetic Diseases, Inborn, Genomic Instability, Humans, Male, Mutation

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.

Alternate JournalCell
PubMed ID28235197
PubMed Central IDPMC5407901
Grant ListR01 CA172652 / CA / NCI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
P30 HD024064 / HD / NICHD NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom

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