Journal article
Heterogeneous Duplications in Patients with Pelizaeus-Merzbacher Disease Suggest a Mechanism of Coupled Homologous and Nonhomologous Recombination
American journal of human genetics, Vol.77(6), pp.966-987
2005
DOI: 10.1086/498048
PMCID: PMC1285180
PMID: 16380909
Abstract
We describe genomic structures of 59 X-chromosome segmental duplications that include the proteolipid protein 1 gene (
PLP1) in patients with Pelizaeus-Merzbacher disease. We provide the first report of 13 junction sequences, which gives insight into underlying mechanisms. Although proximal breakpoints were highly variable, distal breakpoints tended to cluster around low-copy repeats (LCRs) (50% of distal breakpoints), and each duplication event appeared to be unique (100 kb to 4.6 Mb in size). Sequence analysis of the junctions revealed no large homologous regions between proximal and distal breakpoints. Most junctions had microhomology of 1–6 bases, and one had a 2-base insertion. Boundaries between single-copy and duplicated DNA were identical to the reference genomic sequence in all patients investigated. Taken together, these data suggest that the tandem duplications are formed by a coupled homologous and nonhomologous recombination mechanism. We suggest repair of a double-stranded break (DSB) by one-sided homologous strand invasion of a sister chromatid, followed by DNA synthesis and nonhomologous end joining with the other end of the break. This is in contrast to other genomic disorders that have recurrent rearrangements formed by nonallelic homologous recombination between LCRs. Interspersed repetitive elements (
Alu elements, long interspersed nuclear elements, and long terminal repeats) were found at 18 of the 26 breakpoint sequences studied. No specific motif that may predispose to DSBs was revealed, but single or alternating tracts of purines and pyrimidines that may cause secondary structures were common. Analysis of the 2-Mb region susceptible to duplications identified proximal-specific repeats and distal LCRs in addition to the previously reported ones, suggesting that the unique genomic architecture may have a role in nonrecurrent rearrangements by promoting instability.
Details
- Title: Subtitle
- Heterogeneous Duplications in Patients with Pelizaeus-Merzbacher Disease Suggest a Mechanism of Coupled Homologous and Nonhomologous Recombination
- Creators
- Karen J Woodward - Clinical and Molecular Genetics, Institute of Child Health, LondonMaria Cundall - Clinical and Molecular Genetics, Institute of Child Health, LondonKaren Sperle - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Nemours Children's Clinic, Wilmington, DEErik A Sistermans - Department of Human Genetics, Radboud University, Nijmegen, The NetherlandsMark Ross - The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United KingdomGareth Howell - The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United KingdomSusan M Gribble - The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United KingdomDeborah C Burford - The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United KingdomNigel P Carter - The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United KingdomDonald L Hobson - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Nemours Children's Clinic, Wilmington, DEJames Y Garbern - Department of Neurology, Wayne State University, DetroitJohn Kamholz - Department of Neurology, Wayne State University, DetroitHenry Heng - Center for Molecular Medicine and Genetics, Wayne State University, DetroitM.E Hodes - Department of Medical & Molecular Genetics, Indiana University School of Medicine, IndianapolisSue Malcolm - Clinical and Molecular Genetics, Institute of Child Health, LondonGrace M Hobson - Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Nemours Children's Clinic, Wilmington, DE
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.77(6), pp.966-987
- Publisher
- Elsevier Inc
- DOI
- 10.1086/498048
- PMID
- 16380909
- PMCID
- PMC1285180
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Language
- English
- Date published
- 2005
- Academic Unit
- Neurology; Psychiatry
- Record Identifier
- 9984020795402771
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