TY - JOUR AU - AU - Beck, Christine R. AU - Carvalho, Claudia M. B. AU - Banser, Linda AU - Gambin, Tomasz AU - Stubbolo, Danielle AU - Yuan, B. O. AU - Sperle, Karen AU - McCahan, Suzanne M. AU - Henneke, Marco AU - Seeman, Pavel AU - Garbern, James Y. AU - Hobson, Grace M. AU - Lupski, James R. T1 - Complex Genomic Rearrangements at the PLP1 Locus Include Triplication and Quadruplication PY - 2015 PB - Public Library Science N2 - 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. DO - doi:10.1371/journal.pgen.1005050 ER -