A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders
Open accessAbstract
The prevailing mechanism for recurrent and some nonrecurrent rearrangements causing genomic disorders is nonallelic homologous recombination (NAHR) between region-specific low-copy repeats (LCRs). For other nonrecurrent rearrangements, nonhomologous end joining (NHEJ) is implicated. Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder caused most frequently (60%-70%) by nonrecurrent duplication of the dosage-sensitive proteolipid protein 1 (PLP1) gene but also by nonrecurrent deletion or point mutations. Many PLP1 duplication junctions are refractory to breakpoint sequence analysis, an observation inconsistent with a simple recombination mechanism. Our current analysis of junction sequences in PMD patients confirms the occurrence of simple tandem PLP1 duplications but also uncovers evidence for sequence complexity at some junctions. These data are consistent with a replication-based mechanism that we term FoSTeS, for replication Fork Stalling and Template Switching. We propose that complex duplication and deletion rearrangements associated with PMD, and potentially other nonrecurrent rearrangements, may be explained by this replication-based mechanism.
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FoSTeS is a replication-based rearrangement mechanism triggered by single-strand breaks during DNA replication.
“FoSTeS is a replication-based genomic rearrangement mechanism that is induced by errors (single strand breaks) during DNA replication process (Lee et al., 2007).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Lee et al., 2007
Clustering was influenced by an abundance of variable-number tandem repeats near centromeres and non-allelic homologous recombination near telomeres.
“The clustering was influenced by an abundance of VNTR near the centromeres43 and NAHR near the telomeres”
From Mapping copy number variation by population-scale genome sequencing (2011) · cites this paper as [43]
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References 52 · Cited by 914
- Authors
- Lee, J. A., Carvalho, C. M. B., & Lupski, J. R.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Lupski, James R.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2007-12
- Volume
- 131
- Issue
- 7
- Pages
- 1235-1247
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2147429782
- Cited by
- 914
- References
- 52
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 30 · 2023: 31 · 2022: 32 · 2021: 35 · 2020: 45 · 2019: 40 · 2018: 26 · 2017: 41 · 2016: 46 · 2015: 59 · 2014: 62 · 2013: 58 · 2012: 72
- FWCI
- 33.16
- Type
- journal article
- Language
- en
- Update notices
- erratum (2008-06-27)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 024064, P01 HD39422, P30HD024064)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- genomic disorders, Pelizaeus-Merzbacher disease, replication fork stalling, template switching, non-homologous end joining, non-allelic homologous recombination, segmental duplication
- MeSH terms
- Base Sequence, DNA Mutational Analysis, DNA Replication, Humans, Male, Membrane Proteins, Models, Genetic, Molecular Sequence Data, Mutation, Nucleic Acid Conformation, Nucleic Acid Hybridization, Recombination, Genetic, Templates, Genetic, Blotting, Southern, Gene Rearrangement, Polymerase Chain Reaction, Gene Deletion, Gene Dosage, Myelin Proteolipid Protein, Genetic Predisposition to Disease, Tandem Repeat Sequences, Pelizaeus-Merzbacher Disease, Oligonucleotide Array Sequence Analysis, Gene Duplication, Genomic Instability
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