Complex Genomic Rearrangements at the PLP1 Locus Include Triplication and Quadruplication

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​Complex Genomic Rearrangements at the PLP1 Locus Include Triplication and Quadruplication​
Beck, C. R.; Carvalho, C. M. B.; Banser, L.; Gambin, T.; Stubbolo, D.; Yuan, B. O. & Sperle, K. et al.​ (2015) 
PLoS Genetics11(3) art. e1005050​.​

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Beck, Christine R.
Carvalho, Claudia M. B.
Banser, Linda
Gambin, Tomasz
Stubbolo, Danielle
Yuan, B. O.
Sperle, Karen
McCahan, Suzanne M.
Henneke, Marco
Seeman, Pavel
Garbern, James Y.
Hobson, Grace M.
Lupski, James R.
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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Journal Article
Public Library Science
PLoS Genetics 
1553-7404; 1553-7390



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