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

By P. Hastings, G. Ira, J. R. Lupski. PLoS Genetics, 2009

800 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/020f93156c8356647489685bd4fdd07dd4a3f1cc

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In Genetics

1. M. Lieber
2. G. Ira

In Molecular Biology

1. M. Lieber
2. G. Ira

In Plant Science

1. M. Lieber
2. G. Ira

Citations in the corpus

• Patterns of somatic structural variation in human cancer genomes (2020, neutral): “Liver−HCC (312) Lymph−BNHL (107) Kidney−ChRCC (43) Panc−Endocrine (81) Biliary−AdenoCA (33) SoftTissue−Leiomyo (15) Lung−AdenoCA (37) Skin−Melanoma (106) Uterus−AdenoCA (42) Panc−AdenoCA (230) Breast−AdenoCA (192) Cervix−SCC (18) Lung−SCC (47) Head−SCC (56) Bone−Osteosarc (34) Ovary−AdenoCA (109) Es”
• Mechanisms of change in gene copy number (2009, background): “By bringing together the findings from model organisms with the characteristics of copy number variation in human and primate genomes, we can begin to work towards an understanding of the processes that lead to chromosomal structural change, and thus gain insights into a major driving force of human”
• The Mechanism of Double-Strand DNA Break Repair by the Nonhomologous DNA End Joining Pathway (2010, background): “Replication-based mechanisms are also likely to be very important for major genomic rearrangements (151, 152).”
• Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations (2012, neutral): “NHEJ-mediated repair of shattered DNA fragments appears more likely to be involved in this context, as it is difficult to reconcile the model of MMBIR with the massive rearrangements (including complex double-minute chromosomes) we detected in association with chromothripsis.”