A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders

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.

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

“…Although the vast majority of WBS deletions result by nonallelic homologous recombination between large regions of very high identity, the nonrecurrent deletions are likely random events that could be facilitated by other repetitive elements flanking the deleted intervals. However, the location of the breakpoints in nonhomologous or with low similarity sequences suggests that the most likely mechanism leading to this atypical rearrangements may be nonhomologous end joining or other processes that do not required high homology at the breakpoint, and support the proposal that other mechanisms predisposes to genomic instability of the WBS region 31 This study underscores the importance to map precisely the WBS deletion boundaries to revaluate the significance of the WBS genes hemizygosity in the pathogenesis of epilepsy, facial features, and neurological phenotypes. [32][33][34][35][36][37][38][39][40] CONFLICT OF INTEREST All patients and/or their parents gave written consent for the study, for genetic testing some gave consent for publication of photos.…”

Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis

“…In addition, broken forks are the precursor lesions directly processed into segmental duplications in yeast 34 and Fork Stalling and Template Switching (FoSTeS) has been proposed as a replication-based mechanism that produces nonrecurrent rearrangements potentially facilitated by the presence of segmental duplications. 35 Thus, the del(X)(p11.22) containing SHROOM4 might occur through a segmental duplicationdependent manner.…”

Recent advance in our understanding of the molecular nature of chromosomal abnormalities

“…21 This observation suggests that a unique mechanism related to DNA replication-stalling that might cause non-random DSB formation and might potentially be another source of recurrent GCRs.…”