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PMID: 16380909 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination.

American journal of human genetics ·Vol. 77 ·No. 6 ·2005-12-00 ·Pages 966-87

Woodward KJ, Cundall M, Sperle K, Sistermans EA, Ross M, Howell G, Gribble SM, Burford DC, Carter NP, Hobson DL, Garbern JY, Kamholz J, Heng H, Hodes ME, Malcolm S, Hobson GM

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.

MeSH Terms
Base Sequence Chromosome Breakage Chromosome Mapping Chromosomes, Human, X Cohort Studies Computational Biology Dosage Compensation, Genetic Gene Duplication Genetic Heterogeneity Humans In Situ Hybridization, Fluorescence Membrane Proteins/genetics Molecular Sequence Data Myelin Proteolipid Protein/genetics Pelizaeus-Merzbacher Disease/genetics Polymerase Chain Reaction Recombination, Genetic Sequence Analysis, DNA Sequence Homology, Nucleic Acid Tandem Repeat Sequences
Chemicals
Membrane Proteins Myelin Proteolipid Protein PLP1 protein, human
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Woodward Karen J
Clinical and Molecular Genetics, Institute of Child Health, London.
Cundall Maria
Sperle Karen
Sistermans Erik A
Ross Mark
Howell Gareth
Gribble Susan M
Burford Deborah C
Carter Nigel P
Hobson Donald L
Garbern James Y
Kamholz John
Heng Henry
Hodes M E
Malcolm Sue
Hobson Grace M
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/498048
Published
2005-12-00
Epub
2005-00-19
Pages
966-87
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1285180
Subset
IM
Grants
NINDS NIH HHS · R01 NS043783 · United States
NCRR NIH HHS · P20 RR-020173-01 · United States
NCRR NIH HHS · P20 RR020173 · United States
NINDS NIH HHS · NS043783 · United States
Wellcome Trust · United Kingdom
Databases
GENBANK
BC018033
External Links
PubMed source DOI: 10.1086/498048 PMC Full Text View journal details
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