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Cited by 1,140Genomic variations and chromosomal abnormalitiesGenome Rearrangement AlgorithmsGenomics and Rare Diseases

Mapping copy number variation by population-scale genome sequencing

Open access
1000 Genomes Project, Mills, Ryan E., Walter, Klaudia, Stewart, Chip, Handsaker, Robert E., Chen, Ken, Alkan, Can, Abyzov, Alexej +50 more·2011·Nature
DOI 10.1038/nature09708PMC PMC3077050
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Abstract

Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.

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Crossref · 10.1038/nature09708

Cites

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Claims the paper makes

0 of 36 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Fifty-three percent of structural variants were mapped to nucleotide resolution.

    “Most SVs (53%) were mapped to nucleotide resolution, which facilitated analyzing their origin and functional impact.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.
  • Findingown data

    Gene disruptions are depleted among high-frequency deletions.

    “observed a depletion of gene disruptions amongst high frequency deletions”
    • Also stated in: § Population genetic properties of deletions · plain
      “we observed a depletion of high frequency alleles among deletions intersecting with protein-coding sequence compared to other deletions (P=1.1×10−11; KS test)”
    Quote in the paperSubstantial claim
  • Findingown data

    The map contained 22,025 deletions and 6,000 additional structural variants, including insertions and tandem duplications.

    “Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.
  • Findingown data

    The authors constructed a map of structural-variant hotspots formed by common mechanisms.

    “constructed a map constructed a map of SV hotspots formed by common mechanisms”
    Quote in the paperSubstantial claim
  • Findingown data

    Structural variants originating from different formation mechanisms have different size spectra.

    “we observed differences in the size spectra of SVs originating from distinct formation mechanisms”
    Quote in the paperSubstantial claim
  • May combine two claims. 37
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    The authors built a copy-number-variant map from whole-genome sequencing of 185 human genomes, combining multiple discovery methods and experimental validation.

    “We constructed a map of unbalanced SVs (i.e., copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingcitation

    The median structural-variant size was 729 bp (mean 8 kb), about four times smaller than in a recent tiling CGH study.

    “The median SV size was 729 bp (mean=8 kb), approximately four times smaller than in a recent tiling CGH based study1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Conrad, D. F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010) source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    1,700 structural variants affected coding sequences, causing full gene overlaps or exon disruptions, many of which led to out-of-frame exons.

    “Seventeen hundred SVs affected coding sequences, resulting in full gene overlaps or exon disruptions (Table 2), many of which led to out-of-frame exons”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    70.8% of deletions and 89.6% of insertions exhibited breakpoint microhomology or homology ranging from 2 to 376 bp, with distribution modes at 2 bp and 15 bp.

    “70.8% of the deletions and 89.6% of the insertions exhibited breakpoint microhomology/homology ranging from 2-376 bp in size, with distribution modes of 2 bp (attributable to NH) and 15 bp (attributable to MEI), respectively”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    Non-homologous and non-allelic homologous recombination mechanisms occurred across a wide size range, whereas variable-number tandem-repeat expansion or shrinkage produced relatively small structural variants.

    “NH and NAHR based mechanisms occurred across a wide size-range, whereas VNTR expansion/shrinkage, consistent with earlier findings1, led to relatively small SV sizes”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Conrad, D. F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010) source

      Not checked in the free run.

    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    The map enabled examination of size spectra of structural-variant formation mechanisms and identification of genomic hotspots commonly dominated by a single formation mechanism.

    “Our map further enabled us to examine size spectra of SV formation mechanisms and led us to identify genomic SV hotspots that are commonly dominated by a single formation mechanism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Most hotspots corresponded to non-allelic homologous recombination hotspots, although hotspots dominated by non-homologous rearrangement and variable-number tandem repeats were also evident.

    “Most of these corresponded to NAHR hotspots, although hotspots dominated by NH and VNTR also were evident.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    Of the remaining structural variants, 60% were classified as deletions relative to ancestral sequence, and the ancestral state of 17% was undetermined.

    “Of the remaining SVs, 60% were classified as deletions relative to ancestral sequence, whereas the ancestral state of 17% was undetermined.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    15,556 structural variants in the set were classified as novel, with enrichment of low-frequency and small variants among the novel ones.

    “we classified 15,556 SVs in our set as novel, with an enrichment of low frequency SVs and small SVs amongst the novel variants”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Eight callsets met the pre-specified specificity threshold of FDR at or below 10%, while other callsets had FDRs between 13% and 89%.

    “eight callsets (three deletion, four insertion, and one tandem duplication callset) met the pre-specified specificity threshold33 (FDR≤10%), whereas the other callsets yielded lower specificity (FDRs of 13%-89%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010) source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Of 160 nucleotide-resolution structural variants identified as tandem duplications relative to the reference, 91.6% were classified as duplications relative to the ancestral genome, and 8.4% had undetermined ancestral state.

    “out of 160 nucleotide-resolution SVs identified as tandem duplications relative to the reference genome, 91.6% were classified as duplications relative to the ancestral genome, whereas the ancestral state of 8.4% remained undetermined”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    Common polymorphisms with minor allele frequency above 5% were generally shared across populations, while rare alleles were frequently observed in only one population.

    “common polymorphisms (minor allele frequency (MAF) >5%) were generally shared across populations, while rare alleles were frequently observed in only one population”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 156 individuals genotyped are representative of the populations from which they were sampled, so allele-frequency patterns reflect population-level properties.

  • May combine two claims.

    Findingown data

    In low-coverage data, the individual method with the greatest accuracy (FDR=3.7%) was second most sensitive on the gold standard and most sensitive when the gold standard was expanded.

    “in the low-coverage data, the individual method with the greatest accuracy (FDR=3.7%) was the second most sensitive based on our gold standard (Fig. 2B), and the most sensitive when expanding the gold standard to a larger set of individuals”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Non-homologous rearrangement was inferred as the dominant deletion mechanism, and mobile element insertion as the dominant insertion mechanism.

    “we inferred NH as the dominating deletion mechanism, and MEI as the dominating insertion mechanism”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    Most structural variants intersecting genes were deletions, but several validated tandem duplications and mobile element insertions also intersected coding sequences.

    “While most SVs intersecting with genes were deletions, several validated tandem duplications and MEIs also intersected with coding sequences”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    Compared with a recent individual-genome survey, the set had a similar deletion size distribution but different size distributions for other structural-variant classes, reflecting ascertainment differences.

    “we also compared our set to a recent survey of SVs in an individual genome37 based on capillary sequencing and array-based analyses24, and observed a similar size distribution for deletions, but differences in the size distributions of other SV classes, reflecting underlying differences in SV ascertainment”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Hasin-Brumshtein, Y., Lancet, D. & Olender, T. Human olfaction: from genomic variation to phenotypic diversity. Trends Genet. 25, 178–184 (2009) source

      Not checked in the free run.

    • cites [24] Pang, A. W. et al. Towards a comprehensive structural variation map of an individual human genome. Genome Biol. 11, R52 (2010) source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Marked insertion peaks for mobile element insertions occurred at 300 bp, corresponding to Alu elements, and at 6 kb, corresponding to L1/LINEs.

    “we observed marked insertion peaks for MEIs at 300 bp, corresponding to Alu elements, and at 6 kb, corresponding to L1/LINEs”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    The genotypes showed 99.1% concordance with CGH array-based genotypes for 1,970 deletions, suggesting high genotyping accuracy.

    “The genotypes displayed 99.1% concordance with CGH array1 based genotypes (available for 1,970 of the deletions), suggesting high genotyping accuracy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Conrad, D. F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010) source

      Not checked in the free run.

    • Rests on an assumption: The 156 individuals genotyped are representative of the populations from which they were sampled, so allele-frequency patterns reflect population-level properties.

  • May combine two claims.

    Findingown data

    Non-allelic homologous recombination was significantly enriched near recombination hotspots (P=1.3e-15) and segmental duplications (P=3.1e-17), contributing to clustering.

    “A significant enrichment of NAHR near recombination hotspots (P=1.3e-15) and segmental duplications (P=3.1e-17) further contributed to the clustering”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    The release set contained 22,025 deletions, 501 tandem duplications, 5,371 mobile element insertions, and 128 non-reference insertions.

    “the release set comprised 22,025 deletions, 501 tandem duplications, 5,371 MEIs, and 128 non-reference insertions”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Most high-frequency coding deletions occurred in regions annotated as segmental duplications, consistent with lessened evolutionary constraint in functionally redundant gene categories.

    “Most of these occurred in regions annotated as segmental duplications, consistent with lessened evolutionary constraintin functionally redundant gene categories22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Kidd, J. M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008) source

      Not checked in the free run.

    • Rests on an assumption: The 156 individuals genotyped are representative of the populations from which they were sampled, so allele-frequency patterns reflect population-level properties.

  • May combine two claims.

    Findingreasoning

    Several candidate monomorphic deletions were observed, explainable by rare insertions in the reference genome or by remaining genotyping inaccuracies.

    “We observed several candidates for monomorphic deletions (i.e., genomic segments putatively deleted in all individuals), explainable by rare insertions present in the reference genome or by remaining genotyping inaccuracies”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 156 individuals genotyped are representative of the populations from which they were sampled, so allele-frequency patterns reflect population-level properties.

  • May combine two claims.

    Findingown data

    Discovery methods differed in the genomic regions they ascertained, the structural-variant size range they accessed, and their breakpoint precision.

    “we observed notable differences between methods (Fig. 2ABC) in terms of genomic regions ascertained (Supplementary Fig. 1), accessible SV size-range (Fig. 2A), and breakpoint precision”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    Overall deletion discovery sensitivity was 82% in trios and 69% in low-coverage sequence using a 1 bp overlap criterion.

    “we estimated an overall sensitivity of deletion discovery of 82% in the trios, and 69% in low-coverage sequence (Fig. 2B) using a 1 bp overlap criterion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    About 15,000 structural variants were mapped at nucleotide resolution, and 48% of these were novel.

    “Altogether, we mapped ~15,000 SVs at nucleotide resolution, 48% of which were novel.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    In trios, the highest sensitivities were achieved by read-depth and read-pair methods, but these had FDR above 10%.

    “in the trios the highest sensitivities were achieved by RD and RP methods with FDR>10%”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of 11,254 nucleotide-resolution structural variants discovered as deletions relative to the human reference, 21% were insertions and 2% were tandem duplications relative to the putative ancestral genome.

    “of the 11,254 nucleotide-resolution SVs discovered as deletions relative to a human reference, 21% actually represented insertion and 2% represented tandem duplications relative to the putative ancestral genome.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingcitation

    Clustering was influenced by an abundance of variable-number tandem repeats near centromeres and non-allelic homologous recombination near telomeres.

    “The clustering was influenced by an abundance of VNTR near the centromeres43 and NAHR near the telomeres”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Lee, J. A., Carvalho, C. M. & Lupski, J. R. A. DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–1247 (2007) source

      Not checked in the free run.

    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • May combine two claims.

    Findingown data

    An algorithm-centric set had about 13% more high-specificity calls than the release set but fewer total calls because of lower sensitivity below 200 bp.

    “this alternative approach resulted in an increased number (by ~13%) of high-specificity (FDR<10%) calls compared to the release set (Supplementary Text), it overall resulted in fewer SV calls owing to its decreased sensitivity at the lower (<200bp) SV size range.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Structural variants have been associated with autism, schizophrenia, and Crohn's disease.

    “SVs have already been associated with diverse diseases, including autism2,3, schizophrenia4,5 and Crohn’s disease6,7.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [2] Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368–372 (2010) source

      Not checked in the free run.

    • cites [3] Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007) source

      Not checked in the free run.

    • cites [4] Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008) source

      Not checked in the free run.

    • cites [5] McCarthy, S. E. et al. Microduplications of 16p11.2 are associated with schizophrenia. Nature Genet. 41, 1223–1227 (2009) source

      Not checked in the free run.

    • cites [6] Craddock, N. et al. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464, 713–720 (2010) source

      Not checked in the free run.

    • cites [7] McCarroll, S. A. et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nature Genet. 40, 1107–1112 (2008) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Locus-specific studies suggest that diverse mechanisms form structural variants de novo, with some mechanisms involving complex rearrangements and multiple chromosomal breakpoints.

    “locus-specific studies suggest that diverse mechanisms may form SVs de novo, with some mechanisms involving complex rearrangements resulting in multiple chromosomal breakpoints8,9.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Hastings, P. J., Lupski, J. R., Rosenberg, S. M. & Ira, G. Mechanisms of change in gene copy number. Nature Rev. Genet. 10, 551–564 (2009) source

      Not checked in the free run.

    • cites [9] Stankiewicz, P. & Lupski, J. R. Structural variation in the human genome and its role in disease. Annu. Rev. Med. 61, 437–455 (2010) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Genome STRiP combined read-pair and read-depth features, implying that using different evidence types can improve structural-variant discovery.

    “This method, Genome STRiP (to be described elsewhere36), integrated both RP and RD features (PD), implying that considering different evidence types can improve SV discovery.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Levy, S. et al. The diploid genome sequence of an individual human. PLoS Biol. 5, e254 (2007) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    The linkage-disequilibrium properties of complex structural variants have not been fully ascertained because methods for genotyping them with similar accuracy are still being developed.

    “the LD properties of complex SVs (e.g., multiallelic SV) have not yet been fully ascertained as methods for genotyping such SVs with similar accuracy still being developed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Extensive validation included PCR for more than 3,000 candidate loci and microarray analyses for 50,000 candidate loci.

    “we carried out extensive validations (Methods), including PCRs for over 3,000 candidate loci, and microarray data analyses for 50,000 candidate loci”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The fine-scale map enabled examination of functional impact, exemplified by gene disruption variants, and will be valuable for genome and exome sequencing studies.

    “Our fine-scale map enabled us to examine the functional impact of SVs, as exemplified by our analysis of gene disruption variants, which will be of value for genome and exome sequencing studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Sequence-based structural-variant discovery had been applied to fewer than 20 genomes, leaving the fine-scale architecture of most common structural variants unknown.

    “Sequence-based SV discovery approaches have thus far been applied to a limited (<20) number of genomes, leaving the fine-scale architecture of most common SVs unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Nucleotide-resolution data allow construction of reference datasets and make structural variants readily assessable across different experimental platforms using genotyping approaches.

    “Nucleotide resolution data allow the construction of reference datasets and make SVs readily assessable across different experimental platforms using genotyping approaches.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    High levels of structural variation, including copy-number variation, had previously been described for cell defense and sensory perception.

    “High levels of structural variation, including copy-number variation, were previously described for both processes15,22,39.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Korbel, J. O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–426 (2007) source

      Not checked in the free run.

    • cites [22] Kidd, J. M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008) source

      Not checked in the free run.

    • cites [39] Altshuler, D. M. et al. Integrating common and rare genetic variation in diverse human populations. Nature 467, 52–58 (2010) source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Detailed structural-variant characterization, including analyses of origin and impact, requires precise structural-variant sequences.

    “a detailed SV characterization, including analyses of SV origin and impact, requires knowledge of precise SV sequences.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The 1000 Genomes Project generated 4.1 terabases of raw sequence in pilot projects targeting whole human genomes.

    “The 1000GP recently generated 4.1 Terabases of raw sequence in pilot projects targeting whole human genomes33”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recurrent rearrangements implicated in genomic disorders are hypothesized to be associated with local genome architecture, such as segmental duplications that facilitate non-allelic homologous recombination.

    “Recurrent rearrangements, implicated in genomic disorders, are hypothesized to be associated with local genome architecture44, e.g., with segmental duplications that facilitate NAHR.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Harrow, J. et al. GENCODE: producing a reference annotation for ENCODE. Genome Biol. 7, (suppl. 1)S4 (2006) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DNA rearrangement in the absence of homology, namely microhomology-mediated break-induced replication, has been implicated in recurrent structural-variant formation.

    “DNA rearrangement in the absence of homology, i.e., MMBIR, has been implicated in recurrent SV formation8,45.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Hastings, P. J., Lupski, J. R., Rosenberg, S. M. & Ira, G. Mechanisms of change in gene copy number. Nature Rev. Genet. 10, 551–564 (2009) source

      Not checked in the free run.

    • cites [45]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The study focused on characterizing deletions, which are often associated with disease.

    “Our study focused on characterizing deletions, which are often associated with disease9.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Stankiewicz, P. & Lupski, J. R. Structural variation in the human genome and its role in disease. Annu. Rev. Med. 61, 437–455 (2010) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The analysis revealed a map of structural-variant hotspots that may constitute local centers of de novo structural-variant formation, consistent with local genome architecture contributing to genomic instability.

    “our analysis revealed a map of SV hotspots that may constitute local centers of de novo SV formation, consistent with the concept that local genome architecture contributes to genomic instability44.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Harrow, J. et al. GENCODE: producing a reference annotation for ENCODE. Genome Biol. 7, (suppl. 1)S4 (2006) source

      Not checked in the free run.

    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Systematic characterization of structural variants in future genomes will benefit from the concepts and datasets presented.

    “Systematic characterization of SVs in these genomes will benefit from the concepts and datasets presented here.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Most structural-variant discovery methods depend on mapping reads to their genomic locus of origin, the accessible fraction of the genome, which is reduced in segmental duplications.

    “most SV discovery methods depend on mapping reads onto their genomic locus of origin, i.e., the ‘accessible’ fraction of the genome, a fraction lessened in segmental duplications”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.
46 of 46

  • The paper relies on this without support.

    The 156 individuals genotyped are representative of the populations from which they were sampled, so allele-frequency patterns reflect population-level properties.

    “we generated genotypes for 13,826 autosomal deletions in 156 individuals”

  • The paper relies on this without support.

    The human reference genome assembly is a valid representation of the reference sequence for identifying structural variants.

    “identifying SVs as genomic differences relative to a human reference”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Human genomes carry on average more than 1,000 CNVs, amounting to about 4 million base pairs of difference.

    “On average, there are >1000 CNVs in the genome, accounting for ~4 million base pairs of genomic difference (Conrad et al., 2010; Mills et al., 2011).”

    From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Mills et al., 2011

  • Most variants present in an individual human genome are common alleles.

    “In truth, structural variants come in many shapes, sizes and allele frequencies, and a majority of variants present in an individual genome are common alleles (Conrad et al., 2010; McCarroll et al., 2008; Mills et al., 2011; Sudmant et al., 2010).”

    From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Mills et al., 2011

  • Large deletions and duplications in the 1000 Genomes Project had breakpoints with >95% sequence identity, suggesting NAHR.

    “Large deletions or duplications showed extensive stretches of sequence of >95% identity at breakpoints, suggesting that they were generated by NAHR.”

    From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Mills et al., 2011

  • In the 1000 Genomes Project, about 70.8% of deletions were attributed to NHEJ or MMBIR.

    “Approximately 70.8% of the deletions were attributed to either a non homology based mechanism (i.e., NHEJ) or MMBIR.”

    From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Mills et al., 2011

  • Most tandem duplications in the 1000 Genomes Project had 2-17 bp of microhomology at breakpoints, suggesting formation by FoSTeS/MMBIR.

    “Most tandem duplications displayed microhomology of 2–17 basepairs at breakpoints, indicating that they are likely formed by FoSTeS/MMBIR.”

    From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Mills et al., 2011

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Authors
1000 Genomes Project, Mills, R. E., Walter, K., Stewart, C., Handsaker, R. E., Chen, K., Alkan, C., Abyzov, A., Yoon, S. C., Ye, K., Cheetham, R. K., Chinwalla, A., Conrad, D. F., Fu, Y., Grubert, F., Hajirasouliha, I., Hormozdiari, F., Iakoucheva, L. M., Iqbal, Z., Kang, S., Kidd, J. M., Konkel, M. K., Korn, J., Khurana, E., Kural, D., Lam, H. Y. K., Leng, J., Li, R., Li, Y., Lin, C.-Y., Luo, R., Mu, X. J., Nemesh, J., Peckham, H. E., Rausch, T., Scally, A., Shi, X., Stromberg, M. P., Stütz, A. M., Urban, A. E., Walker, J. A., Wu, J., Zhang, Y., Zhang, Z. D., Batzer, M. A., Ding, L., Marth, G. T., McVean, G., Sebat, J., Snyder, M., Wang, J., Ye, K., Eichler, E. E., Gerstein, M. B., Hurles, M. E., Lee, C., McCarroll, S. A., & Korbel, J. O.
Affiliations
  • Brigham and Women's Hospital (US)
  • Boston College (US)
  • Broad Institute (US)
  • University of Washington (US)
  • Howard Hughes Medical Institute (US)
  • Yale University (US)
  • Leiden University Medical Center (NL)
  • Washington University in St. Louis (US)
  • Wellcome Sanger Institute (GB)
  • Stanford University (US)
  • Simon Fraser University (CA)
  • Centre for Human Genetics (GB)
  • Louisiana State University (US)
  • BGI Group (China) (CN)
  • European Molecular Biology Laboratory (DE)
  • University of California San Diego (US)
Corresponding author
Korbel, Jan O.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2011-02
Volume
470
Issue
7332
Pages
59-65
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature09708
PMC
PMC3077050
OpenAlex
W2116126626
Cited by
1,140
References
49
Citations by year
2026: 14 · 2025: 37 · 2024: 54 · 2023: 33 · 2022: 41 · 2021: 62 · 2020: 61 · 2019: 68 · 2018: 55 · 2017: 70 · 2016: 81 · 2015: 113 · 2014: 117 · 2013: 117 · 2012: 128
FWCI
88.14
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • Civil War Book Review (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
  • PMC
Funders
  • Wellcome Trust (085532, 062023, 077009, 077192, 077014)
  • National Institute for Health and Care Research (NF-SI-0508-10212)
  • National Institutes of Health (5p41hg004221-03)
  • National Institute on Alcohol Abuse and Alcoholism (R21AA022707)
  • National Institute of Mental Health (R01MH091350)
  • National Human Genome Research Institute (U54HG003067, U54HG003273, R01HG004719, U01HG005209, RC2HG005552, P41-HG004221)
  • National Institute of General Medical Sciences (R01GM059290, R01GM081533)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
copy number variation, structural variants, deletion mapping, tandem duplication, insertion, gene deletion, human genetic variation
MeSH terms
Genetics, Population, Genotype, Humans, Reproducibility of Results, Genome, Human, Mutagenesis, Insertional, Sequence Deletion, Sequence Analysis, DNA, Genetic Predisposition to Disease, Gene Duplication, Genomics, DNA Copy Number Variations

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