Title | Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Beck, CR, Carvalho, CMB, Banser, L, Gambin, T, Stubbolo, D, Yuan, B, Sperle, K, McCahan, SM, Henneke, M, Seeman, P, Garbern, JY, Hobson, GM, Lupski, JR |
Journal | PLoS Genet |
Volume | 11 |
Issue | 3 |
Pagination | e1005050 |
Date Published | 2015 Mar |
ISSN | 1553-7404 |
Keywords | Chromosome Breakpoints, Chromosome Inversion, Gene Dosage, Gene Duplication, Humans, Myelin Proteolipid Protein, Pelizaeus-Merzbacher Disease |
Abstract | 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. |
DOI | 10.1371/journal.pgen.1005050 |
Alternate Journal | PLoS Genet |
PubMed ID | 25749076 |
PubMed Central ID | PMC4352052 |
Grant List | R01 NS058978 / NS / NINDS NIH HHS / United States U54 HG006542 / HG / NHGRI NIH HHS / United States R01NS058529 / NS / NINDS NIH HHS / United States T32 NS043124 / NS / NINDS NIH HHS / United States P20GM103464 / GM / NIGMS NIH HHS / United States R01 NS058529 / NS / NINDS NIH HHS / United States U54HD006542 / HD / NICHD NIH HHS / United States R01NS058978 / NS / NINDS NIH HHS / United States P20 GM103464 / GM / NIGMS NIH HHS / United States T32NS043124-11 / NS / NINDS NIH HHS / United States U54 HD083092 / HD / NICHD NIH HHS / United States |
Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication.
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