Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome

By Jan O. Korbel, A. E. Urban, J. Affourtit, B. Godwin, Fabian Grubert, J. Simons, Philip M. Kim, D. Palejev, N. Carriero, Lei Du and 14 more. Science, 2007

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Structural variation of the genome involves kilobase- to megabase-sized deletions, duplications, insertions, inversions, and complex combinations of rearrangements. We introduce high-throughput and massive paired-end mapping (PEM), a large-scale genome-sequencing method to identify structural variants (SVs) ∼3 kilobases (kb) or larger that combines the rescue and capture of paired ends of 3-kb fragments, massive 454 sequencing, and a computational approach to map DNA reads onto a reference genome. PEM was used to map SVs in an African and in a putatively European individual and identified shared and divergent SVs relative to the reference genome. Overall, we fine-mapped more than 1000 SVs and documented that the number of SVs among humans is much larger than initially hypothesized; many of the SVs potentially affect gene function. The breakpoint junction sequences of more than 200 SVs were determined with a novel pooling strategy and computational analysis. Our analysis provided insights into the mechanisms of SV formation in humans.

Subfields: Genetics, Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/4a7855dab20e157ba8f2cc620c46ae6c0159b161

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Citations in the corpus

Multi-platform discovery of haplotype-resolved structural variation in human genomes (2017, methodology): “To construct an integrated dataset, we merged (1) calls unique to each filtered dataset, (2) calls shared between pairs of datasets, and (3) calls shared across all three datasets.”
Natural genetic variation caused by small insertions and deletions in the human genome. (2011, background): “…2010), small insertions and deletions (INDELs) ranging from 1 bp to 10 kb in length (Weber et al. 2002; Bhangale et al. 2005; Mills et al. 2006; Korbel et al. 2007; Kidd et al. 2008; The 1000 Genomes Project Consortium 2010), and larger structural variants ranging from 10 kb to several…”
Applications of next-generation sequencing technologies in functional genomics. (2008, methodology): “More recently, a paired-end mapping (PEM) procedure has been developed for the 454 technology and used to map structural rearrangements in two previously studied human genomes [43].”
CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. (2011, methodology): “However, new sequencing-based approaches such as clone-based sequencing (Kidd et al. 2008), paired-end mapping (Korbel et al. 2007, 2009), split-read (SR) mapping (Mills et al. 2006), read-depth (RD) analysis (Bentley et al. 2008; Campbell et al. 2008; Alkan et al. 2009; Chiang et al. 2009; Yoon et…”
ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end tag sequencing (2010, background): “Further, certain binding sites in cancer genomes may be the results of genome amplifications [8,14], and should be flagged, such that caution can be exercised in using them.”
Next-generation sequencing platforms. (2013, background): “In mate-pair sequencing, the library is constructed of fragments longer than 1 kb, and instead of ligating two adapters at each fragment end, the fragment is circularized around a single adapter and both fragment ends ligate to the adapter ends (24).”
Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations (2012, positive): “PCR Validation PCR validations for breakpoint junctions were performed as previously described (Korbel et al., 2007).”