A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders

Cell. 2007 Dec 28;131(7):1235-47. doi: 10.1016/j.cell.2007.11.037.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Blotting, Southern
  • DNA Mutational Analysis
  • DNA Replication*
  • Gene Deletion*
  • Gene Dosage
  • Gene Duplication*
  • Gene Rearrangement*
  • Genetic Predisposition to Disease
  • Genomic Instability
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Models, Genetic
  • Molecular Sequence Data
  • Mutation
  • Myelin Proteolipid Protein / genetics*
  • Nucleic Acid Conformation
  • Nucleic Acid Hybridization
  • Oligonucleotide Array Sequence Analysis
  • Pelizaeus-Merzbacher Disease / genetics*
  • Polymerase Chain Reaction
  • Recombination, Genetic*
  • Tandem Repeat Sequences
  • Templates, Genetic


  • Membrane Proteins
  • Myelin Proteolipid Protein
  • PLP1 protein, human