Dec 28, 2007

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

Cell
Jennifer A LeeJames R Lupski

Abstract

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.

  • References47
  • Citations436

References

  • References47
  • Citations436

Citations

Mentioned in this Paper

Pelizaeus-Merzbacher Disease, Transitional
Non-Homologous DNA End-Joining
Low-Copy Repeats
Polymerase
DMD gene
RNA Conformation
Tissue Membrane
Gene Dosage
DNA Probes
PLP1 gene

Related Feeds

Cell eTOC

Cell is a scientific journal publishing research across a broad range of disciplines within the life sciences field. Discover the latest research from Cell here.