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

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.

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    • "Another model achieves the same end point by template switching across two diverging replication forks (Brewer et al. 2011). The same structures can be explained by the microhomology-mediated break-induced replication (MMBIR) model described below (Hastings et al. 2009a) in which template switches are not restricted to replication fork regions. "
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    ABSTRACT: Changes in gene copy number are among the most frequent mutational events in all genomes and were among the mutations for which a physical basis was first known. Yet mechanisms of gene duplication remain uncertain because formation rates are difficult to measure and mechanisms may vary with position in a genome. Duplications are compared here to deletions, which seem formally similar but can arise at very different rates by distinct mechanisms. Methods of assessing duplication rates and dependencies are described with several proposed formation mechanisms. Emphasis is placed on duplications formed in extensively studied experimental situations. Duplications studied in microbes are compared with those observed in metazoan cells, specifically those in genomes of cancer cells. Duplications, and especially their derived amplifications, are suggested to form by multistep processes often under positive selection for increased copy number. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 02/2015; 7(2). DOI:10.1101/cshperspect.a016592 · 8.68 Impact Factor
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    • "These complex genomic rearrangements consist of more than one simple rearrangement, and have two or more breakpoint junctions. Rearrangements such as these have been suggested to occur by microhomology-mediated replication-dependent recombination (MMRDR); a replicationbased mechanism that requires microhomology and includes fork stalling and template switching (FoSTeS) (Lee et al. 2007), serial replication slippage (SRS) (Chen et al. 2010), and microhomology-mediated break-induced replication (MMBIR) (Hastings et al. 2009) models. These models suggest that during replication downstream fork switching results in a deletion, whereas switching to an upstream fork results in duplication and repeated switches back and forth result in complex rearrangements such as triplications and inversions. "
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    ABSTRACT: Genomic rearrangements such as intragenic deletions and duplications are the most prevalent type of mutations in the dystrophin gene resulting in Duchenne and Becker muscular dystrophy (D/BMD). These copy number variations (CNVs) are nonrecurrent and can result from either nonhomologous end joining (NHEJ) or microhomology-mediated replication-dependent recombination (MMRDR). We characterized five DMD patients with complex genomic rearrangements using a combination of MLPA/mRNA transcript analysis/custom array comparative hybridization arrays (CGH) and breakpoint sequence analysis to investigate the mechanisms for these rearrangements. Two patients had complex rearrangements that involved microhomologies at breakpoints. One patient had a noncontiguous insertion of 89.7 kb chromosome 4 into intron 43 of DMD involving three breakpoints with 2–5 bp microhomology at the junctions. A second patient had an inversion of exon 44 flanked by intronic deletions with two breakpoint junctions each showing 2 bp microhomology. The third patient was a female with an inherited deletion of exon 47 in DMD on the maternal allele and a de novo noncontiguous duplication of exons 45–49 in DMD and MID1 on the paternal allele. The other two patients harbored complex noncontiguous duplications within the dystrophin gene. We propose a replication-based mechanisms for all five complex DMD rearrangements. This study identifies additional underlying mechanisms in DMD, and provides insight into the molecular bases of these genomic rearrangements.
    11/2014; 2(6). DOI:10.1002/mgg3.108
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    • "Apart from the above well-defined classes of SVs, complex SVs which include combinations of two or more of these broad classes are not uncommon to observe in real-life situations (Hastings, et al., 2009). A number of studies have highlighted the molecular predispositions which enable SVs to occur. "
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    ABSTRACT: Structural variations (SVs) are genomic re-arrangements that affect fairly large fragments of DNA. Most of the SVs such as inversions, deletions and translocations have been largely studied in context of genetic diseases in eukaryotes. However, recent studies demonstrate that genome rearrangements can also have profound impact on prokaryotic genomes, leading to altered cell phenotype. In contrast to single nucleotide variations, SVs provide a much deeper insight into organization of bacterial genomes at a much better resolution. SVs can confer change in gene copy number, creation of new genes, altered gene expression and many other functional consequences. High-throughput technologies have now made it possible to explore SVs at a much refined resolution in bacterial genomes. Through this review, we aim to highlight the importance of the less explored field of SVs in prokaryotic genomes and their impact. We also discuss its potential applicability in the emerging fields of synthetic biology and genome engineering where targeted SVs could serve to create sophisticated and accurate genome editing.
    Bioinformatics 09/2014; 31(1). DOI:10.1093/bioinformatics/btu600 · 4.98 Impact Factor
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