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

Abstract

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.

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

“…DNA sequencing of these three fragments showed no sequence differences, indicating that this ancestral complex duplication is identical by descent and likely arose several generations ago as a result of DNA template switching replication error. 38 Alternatively, the 64 kb deletion between the HERV elements might have arisen owing to polymerase slippage error during or following the formation of CDKL5 duplication.…”

Large duplications at reciprocal translocation breakpoints that might be the counterpart of large deletions and could arise from stalled replication bubbles

“…2B; Howarth et al 2008). The cloned junctions were at 10,438,664 bp and 9,108,545 bp (Table 1 Table 3), 80 kb away from the breakpoint, typical of the small fragments of distant sequence that are often found inserted in junctions, named ''genomic shards'' (Bignell et al 2007;Hastings et al 2009a). The resulting loss was clear in the SNP6 array-CGH data from Bignell et al (2010) (Supplemental Fig.…”

Genomic profile of copy number variants on the short arm of human chromosome 8

“…[52][53][54][55][56] However, none of the proposed mechanisms can fully explain the occurrence of some deletion-or duplication-specific start or stop breakpoints of CNVs and some deletion-or duplicationspecific CNVs observed in this study (Figure 2; Supplementary Tables S2-S5). The actual mechanisms leading to this phenomenon remain unknown, and it is possible that yet-to-be discovered mechanisms prohibit the formation of certain deletions or duplications.…”