A Microhomology-Mediated Break-Induced Replication Model for the Origin of Human Copy Number Variation

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS Genetics (Impact Factor: 7.53). 02/2009; 5(1):e1000327. DOI: 10.1371/journal.pgen.1000327
Source: PubMed


Chromosome structural changes with nonrecurrent endpoints associated with genomic disorders offer windows into the mechanism of origin of copy number variation (CNV). A recent report of nonrecurrent duplications associated with Pelizaeus-Merzbacher disease identified three distinctive characteristics. First, the majority of events can be seen to be complex, showing discontinuous duplications mixed with deletions, inverted duplications, and triplications. Second, junctions at endpoints show microhomology of 2-5 base pairs (bp). Third, endpoints occur near pre-existing low copy repeats (LCRs). Using these observations and evidence from DNA repair in other organisms, we derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs. We propose that breakage of replication forks in stressed cells that are deficient in homologous recombination induces an aberrant repair process with features of break-induced replication (BIR). Under these circumstances, single-strand 3' tails from broken replication forks will anneal with microhomology on any single-stranded DNA nearby, priming low-processivity polymerization with multiple template switches generating complex rearrangements, and eventual re-establishment of processive replication.

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    • "b The father exhibited a recent onset of central serous chorioretinopathy in the left eye with fluid and pigment epithelial detachment over the fovea in the left eye. Pigmentary changes noted in the macula are likely attributed to early, dry age-related macular degeneration These suggest fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/ MMBIR) as the potential CNV generating mechanism via three template switches (Hastings et al. 2009; Lee et al. 2007; Zhang et al. 2009). The deletion/insertion spanned from the intron upstream of exon 45 to exon 48. "
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