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PLoS Genet. 2015 Mar 6;11(3):e1005050. doi: 10.1371/journal.pgen.1005050. eCollection 2015 Mar.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Centro de Pesquisas Rene Rachou- FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.
3
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America.
4
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America; Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
5
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University, Göttingen, Germany.
6
Department of Pediatric Neurology, DNA Laboratory, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic.
7
University of Rochester Medical Center, Rochester, New York, United States of America.
8
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America; Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America; University of Delaware, Department of Biological Sciences, Newark, Delaware, United States of America.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Department of Pediatrics and Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America; Texas Children's Hospital, Houston, Texas, United States of America.

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.

PMID:
25749076
PMCID:
PMC4352052
DOI:
10.1371/journal.pgen.1005050
[Indexed for MEDLINE]
Free PMC Article

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