Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence

Cheung, Joseph; Estivill, Xavier; Khaja, Razi; MacDonald, Jeffrey R.; Lau, Ken S.; Tsui, Lap‐Chee; Scherer, Stephen W.

doi:10.1186/gb-2003-4-4-r25

Cited by 210 publications

(80 citation statements)

References 28 publications

(37 reference statements)

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“…Approximately 5% of the genome is low-copy-number repeat (LCR), also known as segmental duplications (15). An association between the locations of LCRs and constitutional copy-number polymorphisms is noted in refs.…”

Section: Resultsmentioning

confidence: 99%

A survey of homozygous deletions in human cancer genomes

Cox

Bignell

Greenman

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Homozygous deletions of recessive cancer genes and fragile sites are known to occur in human cancers. We identified 281 homozygous deletions in 636 cancer cell lines. Of these deletions, 86 were homozygous deletions of known recessive cancer genes, 17 were of sequenced common fragile sites, and 178 were in genomic regions that do not overlap known recessive oncogenes or fragile sites (''unexplained'' homozygous deletions). Some cancer cell lines have multiple homozygous deletions whereas others have none, suggesting intrinsic variation in the tendency to develop this type of genetic abnormality (P < 0.001). The 178 unexplained homozygous deletions clustered into 131 genomic regions, 27 of which exhibit homozygous deletions in more than one cancer cell line. This degree of clustering indicates that the genomic positions of the unexplained homozygous deletions are not randomly determined (P < 0.001). Many homozygous deletions, including those that are in multiple clusters, do not overlap known genes and appear to be in intergenic DNA. Therefore, to elucidate further the pathogenesis of homozygous deletions in cancer, we investigated the genome landscape within unexplained homozygous deletions. The gene count within homozygous deletions is low compared with the rest of the genome. There are also fewer short interspersed nuclear elements (SINEs), long interspersed nuclear elements (LINEs), and low-copy-number repeats (LCRs). However, DNA within homozygous deletions has higher flexibility. These features may signal the presence of currently unrecognized zones of susceptibility to DNA rearrangement. They may also reflect a tendency to reduce the adverse effects of homozygous deletions by minimizing the number of genes removed.

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Section: Resultsmentioning

confidence: 99%

A survey of homozygous deletions in human cancer genomes

Cox

Bignell

Greenman

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…The Human Genome Segmental Duplication Database (Cheung et al 2003) (http://projects.tcag.ca/humandup/) was used to check KIAA1549, BRAF, SRGAP3, and RAF1 for segmental duplications. The search for large regions of homology was conducted using BLASTN 2.2.22+ (Altschul et al 1997) (http://blast.ncbi.…”

Section: Bioinformatics Analysesmentioning

confidence: 99%

RAFgene fusion breakpoints in pediatric brain tumors are characterized by significant enrichment of sequence microhomology

Lawson

Hindley²,

Forshew³

et al. 2011

Genome Res.

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Gene fusions involving members of the RAF family of protein kinases have recently been identified as characteristic aberrations of low-grade astrocytomas, the most common tumors of the central nervous system in children. While it has been shown that these fusions cause constitutive activation of the ERK/MAPK pathway, very little is known about their formation. Here, we present a detailed analysis of RAF gene fusion breakpoints from a well-characterized cohort of 43 lowgrade astrocytomas. Our findings show that the rearrangements that generate these RAF gene fusions may be simple or complex and that both inserted nucleotides and microhomology are common at the DNA breakpoints. Furthermore, we identify novel enrichment of microhomologous sequences in the regions immediately flanking the breakpoints. We thus provide evidence that the tandem duplications responsible for these fusions are generated by microhomology-mediated break-induced replication (MMBIR). Although MMBIR has previously been implicated in the pathogenesis of other diseases and the evolution of eukaryotic genomes, we demonstrate here that the proposed details of MMBIR are consistent with a recurrent rearrangement in cancer. Our analysis of repetitive elements, Z-DNA and sequence motifs in the fusion partners identified significant enrichment of the human minisatellite conserved sequence/x-like element at one side of the breakpoint. Therefore, in addition to furthering our understanding of low-grade astrocytomas, this study provides insights into the molecular mechanistic details of MMBIR and the sequence of events that occur in the formation of genomic rearrangements.

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“…Moreover, our analysis of the entire human genome (using NCBI Build 31) revealed that chromosome 7 contained the largest amount of intrachromosomal duplication (23), which suggests that there could be other disease associations. To complete a more refined analysis of chromosome 7, we compared the CRA_TCAGchr7.v1 assembly with itself to search for all recent (>90% sequence identity) and large (>5 kb) intrachromosomal duplications.…”

Section: Chromosome 7 Functional and Structural Featuresmentioning

confidence: 99%

Human Chromosome 7: DNA Sequence and Biology

Scherer

Cheung

MacDonald

et al. 2003

Science

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189

133

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DNA sequence and annotation of the entire human chromosome 7, encompassing nearly 158 million nucleotides of DNA and 1917 gene structures, are presented. To generate a higher order description, additional structural features such as imprinted genes, fragile sites, and segmental duplications were integrated at the level of the DNA sequence with medical genetic data, including 440 chromosome rearrangement breakpoints associated with disease. This approach enabled the discovery of candidate genes for developmental diseases including autism.

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Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence

Cited by 210 publications

References 28 publications

A survey of homozygous deletions in human cancer genomes

A survey of homozygous deletions in human cancer genomes

RAFgene fusion breakpoints in pediatric brain tumors are characterized by significant enrichment of sequence microhomology

Human Chromosome 7: DNA Sequence and Biology

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