Trends in Genetics
ReviewCharacterizing complex structural variation in germline and somatic genomes
Section snippets
The genomic landscape of structural variation
Structural variation (SV) is defined as differences in the copy number, orientation or location of relatively large genomic segments (typically >100 bp). The canonical forms include deletions, tandem duplications, insertions, inversions and translocations. Large-scale, microscopically visible genomic rearrangements have long been recognized for their role in evolution and disease, but the remarkable prevalence of submicroscopic SVs only became apparent during the past decade, with the
Complex SV defined
Structural variants are defined by their breakpoints, which are the novel sequence junctions generated by structural mutation (Figure 1a–c). Structural variants arise through four general mechanisms (reviewed in [21]): (i) ligation of double-strand DNA breaks (DSBs) through non-homologous end-joining (NHEJ) or microhomology-mediated end-joining (MMEJ); (ii) exchange between sequences sharing significant stretches of homology, as can occur either by non-allelic homologous recombination (NAHR)
Complex SV in the germline
The observation of complex structural mutation is not new. Using standard cytogenetic methods, such as G-banded karyotyping and fluorescent in situ hybridization (FISH), numerous complex chromosome rearrangements (CCRs) have been identified in patients suffering from sporadic disorders or infertility (reviewed in 24, 40). CCRs involve at least three breakpoints from two or more chromosomes (Figure 1a), and are estimated to comprise approximately 3% of spontaneous rearrangements detected in
Complex SV in tumor genomes
The architecture of a somatic genome is less constrained than that of a germline genome, which must complete meiosis and development to survive, and tumors evolve under diverse selective pressures and mutational forces. As a result, the types and numbers of de novo SV in different tumors vary widely, and diverse karyotypic configurations have been observed. Many tumors show complex patterns of gene amplification [55], presumably owing to repeated mutation and strong selection. In some breast
Identification and interpretation of complex variation
Advances in DNA sequencing technologies have enabled the exploration of genome structure with exquisite detail. Unlike conventional cytogenetic methods or array-CGH, sequencing permits genome-wide characterization of breakpoints from all classes of SV with high precision. The general algorithmic approaches and available tools for detecting SV breakpoints from DNA sequence data have been reviewed elsewhere 57, 58. In essence, the identification and interpretation of complex SV involves three
Concluding remarks
Studies of complex SV have provided new insights into the processes that generate genome variation, and this has clear implications for conventional models of species and cancer evolution that generally assume progressive, step-wise mutations. In both contexts, complex mutations represent a form of punctuated genome evolution. Resulting variants may have more subtle, unpredictable and multi-faceted phenotypic impacts compared with simple variants. For example, complex mutations can rearrange
Acknowledgments
Our work has been sponsored by the National Institutes of Health (DP2OD006493-01 to IMH; 1F32HG005197-01 to ARQ), the Burroughs Wellcome Fund (IMH) and the March of Dimes (IMH). We thank R.A. Clark for implementing our SV visualization pipeline.
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