Dataset Information

An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

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.

SUBMITTER: Liu P

PROVIDER: S-EPMC5407901 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

Liu Pengfei P Yuan Bo B Carvalho Claudia M B CMB Wuster Arthur A Walter Klaudia K Zhang Ling L Gambin Tomasz T Chong Zechen Z Campbell Ian M IM Coban Akdemir Zeynep Z Gelowani Violet V Writzl Karin K Bacino Carlos A CA Lindsay Sarah J SJ Withers Marjorie M Gonzaga-Jauregui Claudia C Wiszniewska Joanna J Scull Jennifer J Stankiewicz Paweł P Jhangiani Shalini N SN Muzny Donna M DM Zhang Feng F Chen Ken K Gibbs Richard A RA Rautenstrauss Bernd B Cheung Sau Wai SW Smith Janice J Breman Amy A Shaw Chad A CA Patel Ankita A Hurles Matthew E ME Lupski James R JR

Cell 20170201 5

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 increas ...[more]

PMID: 28235197

Similar Datasets

Project description:UnlabelledLactobacillus rhamnosus GG is a lactic acid bacterium widely marketed by the food industry. Its genomic analysis led to the identification of a gene cluster encoding mucus-binding SpaCBA pili, which is located in a genomic island enriched in insertion sequence (IS) elements. In the present study, we analyzed by genome-wide resequencing the genomic integrity of L. rhamnosus GG in four distinct evolutionary experiments conducted for approximately 1,000 generations under conditions of no stress or salt, bile, and repetitive-shearing stress. Under both stress-free and salt-induced stress conditions, the GG population (excluding the mutator lineage in the stress-free series [see below]) accumulated only a few single nucleotide polymorphisms (SNPs) and no frequent chromosomal rearrangements. In contrast, in the presence of bile salts or repetitive shearing stress, some IS elements were found to be activated, resulting in the deletion of large chromosomal segments that include the spaCBA-srtC1 pilus gene cluster. Remarkably, a high number of SNPs were found in three strains obtained after 900 generations of stress-free growth. Detailed analysis showed that these three strains derived from a founder mutant with an altered DNA polymerase subunit that resulted in a mutator phenotype. The present work confirms the stability of the pilus production phenotype in L. rhamnosus GG under stress-free conditions, highlights the possible evolutionary scenarios that may occur when this probiotic strain is extensively cultured, and identifies external factors that affect the chromosomal integrity of GG. The results provide mechanistic insights into the stability of GG in regard to its extensive use in probiotic and other functional food products.ImportanceLactobacillus rhamnosus GG is a widely marketed probiotic strain that has been used in numerous clinical studies to assess its health-promoting properties. Hence, the stability of the probiotic functions of L. rhamnosus GG is of importance, and here we studied the impact of external stresses on the genomic integrity of L. rhamnosus GG. We studied three different stresses that are relevant for understanding its robustness and integrity under both ex vivo conditions, i.e., industrial manufacturing conditions, and in vivo conditions, i.e., intestinal tract-associated stress. Overall, our findings contribute to predicting the genomic stability of L. rhamnosus GG and its ecological performance.

Dataset Information

An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

Publications

An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets