Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication

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 (MI...

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Published in:PLoS genetics 2015-03, Vol.11 (3), p.e1005050
Main Authors: Beck, Christine R, Carvalho, Claudia M B, Banser, Linda, Gambin, Tomasz, Stubbolo, Danielle, Yuan, Bo, Sperle, Karen, McCahan, Suzanne M, Henneke, Marco, Seeman, Pavel, Garbern, James Y, Hobson, Grace M, Lupski, James R
Format: Article
Language:English
Subjects:
Bacteriology
Biomedical research
Chromosome Breakpoints
Chromosome Inversion
Deoxyribonucleic acid
DNA
DNA repair
DNA replication
Females
Gene Dosage
Gene Duplication
Genetic aspects
Genomes
Genomics
Homology (Biology)
Hospitals
Humans
Identification and classification
Laboratories
Medical research
Myelin Proteolipid Protein - genetics
Patients
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher Disease - genetics
Ratios
Software
Studies
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1005050