Chromosome Catastrophes Involve Replication Mechanisms Generating Complex Genomic Rearrangements

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell (Impact Factor: 32.24). 09/2011; 146(6):889-903. DOI: 10.1016/j.cell.2011.07.042
Source: PubMed


Complex genomic rearrangements (CGRs) consisting of two or more breakpoint junctions have been observed in genomic disorders. Recently, a chromosome catastrophe phenomenon termed chromothripsis, in which numerous genomic rearrangements are apparently acquired in one single catastrophic event, was described in multiple cancers. Here, we show that constitutionally acquired CGRs share similarities with cancer chromothripsis. In the 17 CGR cases investigated, we observed localization and multiple copy number changes including deletions, duplications, and/or triplications, as well as extensive translocations and inversions. Genomic rearrangements involved varied in size and complexities; in one case, array comparative genomic hybridization revealed 18 copy number changes. Breakpoint sequencing identified characteristic features, including small templated insertions at breakpoints and microhomology at breakpoint junctions, which have been attributed to replicative processes. The resemblance between CGR and chromothripsis suggests similar mechanistic underpinnings. Such chromosome catastrophic events appear to reflect basic DNA metabolism operative throughout an organism's life cycle.

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    • "The first, chromothripsis acting through breakage and ligation (Stephens et al., 2011; Korbel and Campbell, 2013). The second, chromoanasynthesis, via replication fork collapse and template switching (Hastings et al., 2009; Liu et al., 2011; Kloosterman and Cuppen, 2013). Our in silico reconstruction suggests that NHEJ is involved in repairing breaks that occurred on the shattered chromosomes. "
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    • "Even when strand exchange does occur this may have no genetic consequences if it occurs between identical regions on the sister duplexes generated by the original fork. Conversely, strand exchange between homologous chromosomes can lead to loss of heterozygosity in eukaryotes (St Charles and Petes 2013), whereas nonallelic exchange within the same, or between different, chromosomes can cause gross chromosomal rearrangements (Lambert et al. 2005; Liu et al. 2011; Mizuno et al. 2012). "
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