Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication
| Autor: | Suzanne M McCahan, Pavel Seeman, Linda Banser, Marco Henneke, Karen Sperle, James Y. Garbern, Tomasz Gambin, Grace M. Hobson, Danielle Stubbolo, Christine R. Beck, Bo Yuan, James R. Lupski, Claudia M.B. Carvalho |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
congenital hereditary and neonatal diseases and abnormalities lcsh:QH426-470 Pelizaeus-Merzbacher Disease Inverted repeat Polymerase chain reaction Haplotypes Southern blot Human genomics Cloning Genomic libraries Genome complexity Genotyping Gene Dosage Locus (genetics) Biology Structural variation Chromosome Breakpoints Gene Duplication Gene duplication Genetics Humans Genomic library Myelin Proteolipid Protein Molecular Biology Genetics (clinical) Ecology Evolution Behavior and Systematics Chromosomal inversion Breakpoint lcsh:Genetics Rolling circle replication Chromosome Inversion Research Article |
| Zdroj: | PLoS Genetics, Vol 11, Iss 3, p e1005050 (2015) PLoS Genetics |
| Popis: | Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex duplication—inverted triplication—duplication (DUP-TRP/INV-DUP) rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals—16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homology—or homeology—driven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication and potentially higher order amplification of a genomic interval can occur in a manner consistent with rolling circle amplification as predicted by the microhomology-mediated break induced replication (MMBIR) model. Author Summary Genomic architecture, such as direct or inverted repeats, can facilitate structural variation (SV) of the human genome. SV can consist of deletion, duplication, or inversion of a genomic segment, or combinations thereof, the latter referred to as complex genomic rearrangements (CGR). CGR are defined as requiring two or more novel DNA breakpoint junctions. We described a CGR product at the MECP2 locus with an unusual pattern consisting of an inverted triplicated segment flanked by duplicated segments of the genome. This complex CGR is facilitated by inverted repeats in a process that mechanistically could occur by two template switches mediated by replicative DNA repair. We now investigate the PLP1 locus and demonstrate that 16/17 CGR independent events present with duplication—inverted triplication—duplication pattern facilitated by two inverted repeats, similar to events involving MECP2. We show that the same inverted repeats facilitating CGR formation are also responsible for an inversion polymorphism observed frequently in the normal population. Intriguingly, one CGR was found to have a quadruplication resulting in the presence of four copies of a genomic segment. Breakpoint studies suggest this quadruplication occurred in a manner consistent with rolling circle amplification as predicted by previously postulated models. |
| Databáze: | OpenAIRE |
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