Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication.

TitleComplex genomic rearrangements at the PLP1 locus include triplication and quadruplication.
Publication TypeJournal Article
Year of Publication2015
AuthorsBeck, 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
JournalPLoS Genet
Volume11
Issue3
Paginatione1005050
Date Published2015 Mar
ISSN1553-7404
KeywordsChromosome 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.

DOI10.1371/journal.pgen.1005050
Alternate JournalPLoS Genet.
PubMed ID25749076
PubMed Central IDPMC4352052
Grant ListR01NS058529 / NS / NINDS NIH HHS / United States
T32NS043124-11 / NS / NINDS NIH HHS / United States
U54 HD083092 / HD / NICHD 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