Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication

PLoS Genetics
Christine R BeckJames R Lupski

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.

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Citations

Mar 1, 2016·Nature Reviews. Genetics·Claudia M B Carvalho, James R Lupski
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Datasets Mentioned

BETA
NA10851
GSE64122

Methods Mentioned

BETA
genotyping
PCR
electrophoresis
Assay
Chip
chips

Software Mentioned

Peak Scanner
UCSC browser
Vector NTI
AlphaImager
Lasergene
GelAnalyzer
Kodak Gel Logic
custom scripts
R
GeneChip Command Console

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