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Structural variation in the human genome

Nature Reviews Genetics volume 7, pages 85–97 (2006)Cite this article

Key Points

  • Structural variants in the human genome include cytogenetically detectable and submicroscopic deletions, duplications, large-scale copy-number variants, inversions and translocations.

  • The ability to detect and characterize structural variants in the 1-kb to 3-Mb size range in a robust manner across the genome has not been possible until recently.

  • New developments in genome-scanning technologies and computational methodologies, and the availability of a reference sequence for comparison, have made possible the large-scale discovery of structural variants.

  • Many studies are revealing that the total content of structural variants in the human genome could equal or exceed that of SNPs.

  • Structural variants often coincide with low-copy repeat DNA (also called segmental duplications), as these highly related sequences are more likely to undergo non-allelic recombination and subsequent rearrangement.

  • Structural variation in the genome can directly or indirectly influence gene dosage through different mechanisms, and therefore influence phenotypic variation and disease.

  • The cataloguing of structural variants and their frequencies in populations will be important for disease-mapping studies and for proper interpretation of clinical diagnostic-testing data.

Abstract

The first wave of information from the analysis of the human genome revealed SNPs to be the main source of genetic and phenotypic human variation. However, the advent of genome-scanning technologies has now uncovered an unexpectedly large extent of what we term 'structural variation' in the human genome. This comprises microscopic and, more commonly, submicroscopic variants, which include deletions, duplications and large-scale copy-number variants — collectively termed copy-number variants or copy-number polymorphisms — as well as insertions, inversions and translocations. Rapidly accumulating evidence indicates that structural variants can comprise millions of nucleotides of heterogeneity within every genome, and are likely to make an important contribution to human diversity and disease susceptibility.

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Figure 1: Cytogenetic detection and confirmation of structural variants.
Figure 2: Array-based, genome-wide methods for the identification of copy-number variants.
Figure 3: Multiplex PCR-based methods for the identification of copy-number variants.
Figure 4: The complexity of segmental duplications and copy-number variants.
Figure 5: Influence of structural variants on phenotype.

References

  1. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

  2. Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 431, 931–945 (2004).

  4. Przeworski, M., Hudson, R. R. & Di Rienzo, A. Adjusting the focus on human variation. Trends Genet. 16, 296–302 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Reich, D. E. et al. Human genome sequence variation and the influence of gene history, mutation and recombination. Nature Genet. 32, 135–142 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Jacobs, P. A., Baikie, A. G., Court Brown, W. M. & Strong, J. A. The somatic chromosomes in mongolism. Lancet 1, 710 (1959).

    Article  CAS  PubMed  Google Scholar 

  7. Edwards, J. H., Harnden, D. G., Cameron, A. H., Crosse, V. M. & Wolff, O. H. A new trisomic syndrome. Lancet 1, 787–790 (1960).

    Article  CAS  PubMed  Google Scholar 

  8. Patau, K., Smith, D. W., Therman, E., Inhorn, S. L. & Wagner, H. P. Multiple congenital anomaly caused by an extra autosome. Lancet 1, 790–793 (1960).

    Article  CAS  PubMed  Google Scholar 

  9. Bobrow, M., Joness, L. F. & Clarke, G. A complex chromosomal rearrangement with formation of a ring 4. J. Med. Genet. 8, 235–239 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jacobs, P. A., Matsuura, J. S., Mayer, M. & Newlands, I. M. A cytogenetic survey of an institution for the mentally retarded: I. Chromosome abnormalities. Clin. Genet. 13, 37–60 (1978).

    Article  CAS  PubMed  Google Scholar 

  11. Coco, R. & Penchaszadeh, V. B. Cytogenetic findings in 200 children with mental retardation and multiple congenital anomalies of unknown cause. Am. J. Med. Genet. 12, 155–173 (1982).

    Article  CAS  PubMed  Google Scholar 

  12. Warburton, D. De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am. J. Hum. Genet. 49, 995–1013 (1991). A comprehensive survey that describes the prevalence of microscopic structural variants and their relevance to clinical diagnostics.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Jacobs, P. A., Browne, C., Gregson, N., Joyce, C. & White, H. Estimates of the frequency of chromosome abnormalities detectable in unselected newborns using moderate levels of banding. J. Med. Genet. 29, 103–108 (1992). A landmark study of the frequency of chromosomal abnormalities that affect newborns.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kim, S. S., Jung, S. C., Kim, H. J., Moon, H. R. & Lee, J. S. Chromosome abnormalities in a referred population for suspected chromosomal aberrations: a report of 4117 cases. J. Korean Med. Sci. 14, 373–376 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Benyush, V. A., Luckash, V. G. & Shtannikov, A. V. Quantitative analysis of C-bands based on optical density profiles in human chromosomes. Hum. Genet. 39, 169–175 (1977).

    Article  CAS  PubMed  Google Scholar 

  16. Maegenis, R. E., Donlon, T. A. & Wyandt, H. E. Giemsa-11 staining of chromosome 1: a newly described heteromorphism. Science 202, 64–65 (1978).

    Article  CAS  PubMed  Google Scholar 

  17. Verma, R. S., Rodriguez, J. & Dosik, H. The clinical significance of pericentric inversion of the human Y chromosome: a rare 'third' type of heteromorphism. J. Hered. 73, 236–238 (1982).

    Article  CAS  PubMed  Google Scholar 

  18. Hsu, L. Y., Benn, P. A., Tannenbaum, H. L., Perlis, T. E. & Carlson, A. D. Chromosomal polymorphisms of 1, 9, 16, and Y in 4 major ethnic groups: a large prenatal study. Am. J. Med. Genet. 26, 95–101 (1987).

    Article  CAS  PubMed  Google Scholar 

  19. Verma, R. S., Dosik, H. & Lubs, H. A. Size and pericentric inversion heteromorphisms of secondary constriction regions (h) of chromosomes 1, 9, and 16 as detected by CBG technique in Caucasians: classification, frequencies, and incidence. Am. J. Med. Genet. 2, 331–339 (1978).

    Article  CAS  PubMed  Google Scholar 

  20. Lubs, H. A. A marker X chromosome. Am. J. Hum. Genet. 21, 231–244 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wright, A. F. in Nature Encyclopedia of the Human Genome 2 959–968 (Nature Publishing Group, London, 2003).

    Google Scholar 

  22. Kruglyak, L. & Nickerson, D. A. Variation is the spice of life. Nature Genet. 27, 234–236 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Hinds, D. A. et al. Whole-genome patterns of common DNA variation in three human populations. Science 307, 1072–1079 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  25. Solinas-Toldo, S. et al. Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20, 399–407 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004). This and reference 27 were the first papers to describe the global presence and distribution of CNVs in the human genome.

    Article  CAS  PubMed  Google Scholar 

  27. Iafrate, A. J. et al. Detection of large-scale variation in the human genome. Nature Genet. 36, 949–951 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Tuzun, E. et al. Fine-scale structural variation of the human genome. Nature Genet 37, 727–732 (2005). The first description of a clone-end sequencing strategy to discover mainly intermediate-sized structural variants in the human genome.

    Article  CAS  PubMed  Google Scholar 

  29. Feuk, L. et al. Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies. PLoS Genet. 1, e56 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Dhami, P. et al. Exon array CGH: detection of copy-number changes at the resolution of individual exons in the human genome. Am. J. Hum. Genet. 76, 750–762 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sharp, A. J. et al. Segmental duplications and copy-number variation in the human genome. Am. J. Hum. Genet. 77, 78–88 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stefansson, H. et al. A common inversion under selection in Europeans. Nature Genet. 37, 129–137 (2005). This reports the discovery and characterization of a 900-kb inversion polymorphism on chromosome 17. This variant was found to be under positive selection in Europeans, as determined by population-based screening.

    Article  CAS  PubMed  Google Scholar 

  33. Visser, R. et al. Identification of a 3.0-kb major recombination hotspot in patients with sotos syndrome who carry a common 1.9-Mb microdeletion. Am. J. Hum. Genet. 76, 52–67 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Inoue, K. & Lupski, J. R. Molecular mechanisms for genomic disorders. Annu. Rev. Genomics Hum. Genet. 3, 199–242 (2002). An outstanding review of the mechanisms behind genomic disorders, including their association with segmental duplications, and non-allelic homologous recombination.

    Article  CAS  PubMed  Google Scholar 

  35. Gripenberg, U. Size variation and orientation of the human Y chromosome. Chromosoma 15, 618–629 (1964).

    Article  CAS  PubMed  Google Scholar 

  36. Nielsen, J. & Sillesen, I. Incidence of chromosome aberrations among 11148 newborn children. Humangenetik 30, 1–12 (1975).

    Article  CAS  PubMed  Google Scholar 

  37. Nussbaum, R. L., McInnes, R. R. & Willard, H. F. Thompson & Thompson Genetics in Medicine (W.B. Saunders, 2004).

    Google Scholar 

  38. McKinlay Gardner, R. J. & Sutherland, G. R. Chromosome Abnormalities and Genetic Counseling (Oxford Univ. Press, USA, 2003).

    Google Scholar 

  39. Barber, J. C. et al. Duplication of 8p23.1: a cytogenetic anomaly with no established clinical significance. J. Med. Genet. 35, 491–496 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Babu, A. & Verma, R. S. Heteromorphic variants of human chromosome 4. Cytogenet. Cell Genet. 41, 60–61 (1986).

    Article  CAS  PubMed  Google Scholar 

  41. Verma, R. S. Heterochromatin: Molecular and Structural Aspects (Cambridge Univ. Press, New York, 1988).

    Google Scholar 

  42. Starke, H. et al. Homologous sequences at human chromosome 9 bands p12 and q13–21.1 are involved in different patterns of pericentric rearrangements. Eur. J. Hum. Genet. 10, 790–800 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Wyandt, H. E. & Tonk, V. S. Atlas of Human Chromosome Heteromorphisms (Kluwer Academic, Netherlands, 2004).

    Book  Google Scholar 

  44. Barber, J. C. Directly transmitted unbalanced chromosome abnormalities and euchromatic variants. J. Med. Genet. 42, 609–629 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Speicher, M. R. & Carter, N. P. The new cytogenetics: blurring the boundaries with molecular biology. Nature Rev. Genet. 6, 782–792 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Locke, D. P. et al. BAC microarray analysis of 15q11–q13 rearrangements and the impact of segmental duplications. J. Med. Genet. 41, 175–182 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Vissers, L. E., Veltman, J. A., van Kessel, A. G. & Brunner, H. G. Identification of disease genes by whole genome CGH arrays. Hum. Mol. Genet. 14 (Suppl. 2), R215–R223 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Mantripragada, K. K. et al. DNA copy-number analysis of the 22q11 deletion-syndrome region using array-CGH with genomic and PCR-based targets. Int. J. Mol. Med. 13, 273–279 (2004).

    CAS  PubMed  Google Scholar 

  49. Lucito, R. et al. Representational oligonucleotide microarray analysis: a high-resolution method to detect genome copy number variation. Genome Res. 13, 2291–2305 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pollack, J. R. et al. Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nature Genet. 23, 41–46 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Barrett, M. T. et al. Comparative genomic hybridization using oligonucleotide microarrays and total genomic DNA. Proc. Natl Acad. Sci. USA 101, 17765–17770 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Brennan, C. et al. High-resolution global profiling of genomic alterations with long oligonucleotide microarray. Cancer Res. 64, 4744–4748 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Zhao, X. et al. An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. Cancer Res. 64, 3060–3071 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Heid, C. A., Stevens, J., Livak, K. J. & Williams, P. M. Real time quantitative PCR. Genome Res. 6, 986–994 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Bieche, I. et al. Novel approach to quantitative polymerase chain reaction using real-time detection: application to the detection of gene amplification in breast cancer. Int. J. Cancer 78, 661–666 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Charbonnier, F. et al. Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments. Cancer Res. 60, 2760–2763 (2000).

    CAS  PubMed  Google Scholar 

  57. Armour, J. A., Sismani, C., Patsalis, P. C. & Cross, G. Measurement of locus copy number by hybridisation with amplifiable probes. Nucleic Acids Res. 28, 605–609 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hollox, E. J., Akrami, S. M. & Armour, J. A. DNA copy number analysis by MAPH: molecular diagnostic applications. Expert Rev. Mol. Diagn. 2, 370–378 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Schouten, J. P. et al. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 30, e57 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  60. White, S. J. et al. Two-color multiplex ligation-dependent probe amplification: detecting genomic rearrangements in hereditary multiple exostoses. Hum. Mutat. 24, 86–92 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Pinkel, D. et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nature Genet. 20, 207–211 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Kennedy, G. C. et al. Large-scale genotyping of complex DNA. Nature Biotechnol. 21, 1233–1237 (2003).

    Article  CAS  Google Scholar 

  63. Slater, S. R. et al. High-resolution identification of chromosomal abnormalities using oligonucleotide arrays containing 116,204 SNPs. Am. J. Hum. Genet. 77, 709–726 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Huang, J. et al. Whole genome DNA copy number changes identified by high density oligonucleotide arrays. Hum. Genomics 1, 287–299 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bignell, G. R. et al. High-resolution analysis of DNA copy number using oligonucleotide microarrays. Genome Res. 14, 287–295 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lindblad-Toh, K. et al. Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays. Nature Biotechnol. 18, 1001–1005 (2000).

    Article  CAS  Google Scholar 

  67. Mei, R. et al. Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays. Genome Res. 10, 1126–1137 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Altug-Teber, O. et al. A rapid microarray based whole genome analysis for detection of uniparental disomy. Hum. Mutat. 26, 153–159 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Raghavan, M. et al. Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias. Cancer Res. 65, 375–378 (2005).

    CAS  PubMed  Google Scholar 

  70. Bruce, S. K. et al. Global analysis of uniparental disomy using high-density genotyping arrays. J. Med. Genet. 42, 847–851 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ponchel, F. et al. Real-time PCR based on SYBR-Green I fluorescence: An alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions. BMC Biotechnol 3, 18 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Fredman, D. et al. Complex SNP-related sequence variation in segmental genome duplications. Nature Genet. 36, 861–866 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Estivill, X. et al. Chromosomal regions containing high-density and ambiguously mapped putative single nucleotide polymorphisms (SNPs) correlate with segmental duplications in the human genome. Hum. Mol. Genet. 11, 1987–1995 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Istrail, S. et al. Whole-genome shotgun assembly and comparison of human genome assemblies. Proc. Natl Acad. Sci. USA 101, 1916–1921 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Scherer, S. W. et al. Human chromosome 7: DNA sequence and biology. Science 300, 767–772 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Scherer, S. W. & Green, E. D. Human chromosome 7 circa 2004: a model for structural and functional studies of the human genome. Hum. Mol. Genet. 13 (Spec. No. 2), R303–R313 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Hillier, L. W. et al. The DNA sequence of human chromosome 7. Nature 424, 157–164 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Beck, S. & Trowsdale, J. The human major histocompatability complex: lessons from the DNA sequence. Annu. Rev. Genomics Hum. Genet. 1, 117–137 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Bailey, J. A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002). The first global map of segmental duplications in the human genome, including an analysis of their relationship to genes and genetic diseases.

    Article  CAS  PubMed  Google Scholar 

  80. An International System for Human Cytogenetic Nomenclature ISCN 1985. Report of the Standing Committee on Human Cytogenetic Nomenclature. Birth Defects Orig. Artic. Ser. 21, 1–117 (1985).

  81. Shaw-Smith, C. et al. Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. J. Med. Genet. 41, 241–248 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cheung, J. et al. Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence. Genome Biol. 4, R25 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Eichler, E. E., Clark, R. A. & She, X. An assessment of the sequence gaps: unfinished business in a finished human genome. Nature Rev. Genet. 5, 345–354 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Robledo, R. et al. A 9.1-kb gap in the genome reference map is shown to be a stable deletion/insertion polymorphism of ancestral origin. Genomics 80, 585–592 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Ghanem, N. et al. Polymorphism of MHC class III genes: definition of restriction fragment linkage groups and evidence for frequent deletions and duplications. Hum. Genet. 79, 209–218 (1988).

    Article  CAS  PubMed  Google Scholar 

  86. Groot, P. C., Mager, W. H. & Frants, R. R. Interpretation of polymorphic DNA patterns in the human α-amylase multigene family. Genomics 10, 779–785 (1991).

    Article  CAS  PubMed  Google Scholar 

  87. Buckland, P. R. Polymorphically duplicated genes: their relevance to phenotypic variation in humans. Ann. Med. 35, 308–315 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Hollox, E. J., Armour, J. A. & Barber, J. C. Extensive normal copy number variation of a β-defensin antimicrobial-gene cluster. Am. J. Hum. Genet. 73, 591–600 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Knight, S. J. & Flint, J. Perfect endings: a review of subtelomeric probes and their use in clinical diagnosis. J. Med. Genet. 37, 401–409 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Barber, J. C. et al. Duplications and copy number variants of 8p23.1 are cytogenetically indistinguishable but distinct at the molecular level. Eur. J. Hum. Genet. 13, 1131–1136 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Lakich, D., Kazazian, H. H. Jr, Antonarakis, S. E. & Gitschier, J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nature Genet. 5, 236–41 (1993).

    Article  CAS  PubMed  Google Scholar 

  92. Bondeson, M. L. et al. Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome. Hum. Mol. Genet. 4, 615–621 (1995).

    Article  CAS  PubMed  Google Scholar 

  93. Small, K., Iber, J. & Warren, S. T. Emerin deletion reveals a common X-chromosome inversion mediated by inverted repeats. Nature Genet. 16, 96–99 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Osborne, L. R. et al. A 1.5 million-base pair inversion polymorphism in families with Williams–Beuren syndrome. Nature Genet. 29, 321–5 (2001). A study of structural variants at the Williams–Beuren locus, describing a 1.5-Mb polymorphic micro-inversion that predisposes to subsequent disease-causing deletions.

    Article  CAS  PubMed  Google Scholar 

  95. Gimelli, G. et al. Genomic inversions of human chromosome 15q11–q13 in mothers of Angelman syndrome patients with class II (BP2/3) deletions. Hum. Mol. Genet. 12, 849–858 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Kurotaki, N. et al. Fifty microdeletions among 112 cases of Sotos syndrome: low copy repeats possibly mediate the common deletion. Hum. Mutat. 22, 378–387 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Giglio, S. et al. Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am. J. Hum. Genet. 68, 874–883 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Giglio, S. et al. Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation. Am. J. Hum. Genet. 71, 276–285 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Nobrega, M. A., Zhu, Y., Plajzer-Frick, I., Afzal, V. & Rubin, E. M. Megabase deletions of gene deserts result in viable mice. Nature 431, 988–993 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Ravnan, J. B. et al. Subtelomere FISH analysis of 11,688 cases: An evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities. J. Med. Genet. 30 September 2005 (10.1136/jmg.2005.036350).

  101. Yu, C. E. et al. Presence of large deletions in kindreds with autism. Am. J. Hum. Genet. 71, 100–115 (2002). A thorough analysis of microsatellite markers behaving in a non-Mendelian manner in autism kindreds, which led to the discovery of novel microdeletions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Gribble, S. M. et al. The complex nature of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes. J. Med. Genet. 42, 8–16 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gonzalez, E. et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307, 1434–1440 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005).

  105. Cheng, Z. et al. A genome-wide comparison of recent chimpanzee and human segmental duplications. Nature 437, 88–93 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Aston, C., Mishra, B. & Schwartz, D. C. Optical mapping and its potential for large-scale sequencing projects. Trends Biotechnol. 17, 297–302 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Hinds, D. A., Kloek, A. P., Jen, M., Chen, X. & Frazer, K. A. Common deletions and SNPs are in linkage disequilibrium in the human genome. Nature Genet. 38, 82–85 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Conrad, D. F., Andrews, T. D., Carter, N. P., Hurles, M. E. & Pritchard, J. K. A high-resolution survey of deletion polymorphism in the human genome. Nature Genet. 38, 75–81 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. McCarroll, S. A. et al. Common deletion polymorphisms in the human genome. Nature. Genet. 38, 86–92 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Le Caignec, C. et al. Detection of genomic imbalances by array based comparative genomic hybridisation in fetuses with multiple malformations. J. Med. Genet. 42, 121–128 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jobanputra, V. et al. Application of ROMA (representational oligonucleotide microarray analysis) to patients with cytogenetic rearrangements. Genet. Med. 7, 111–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Bejjani, B. A. et al. Use of targeted array-based CGH for the clinical diagnosis of chromosomal imbalance: is less more? Am. J. Med. Genet. A 134, 259–267 (2005).

    Article  PubMed  Google Scholar 

  113. van Ommen, G. J. Frequency of new copy number variation in humans. Nature Genet. 37, 333–334 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank R. Khaja, J. MacDonald, J. Zhang and M. Shago (from The Centre for Applied Genomics, Hospital for Sick Children), N. Carter and M. Hurles (Wellcome Trust Sanger Institute), K. Jones (Affymetrix), and C. Lee (Brigham and Woman's Hospital, Harvard Medical School) for discussions. The work was supported from grants from Genome Canada/Ontario Genomics Institute, the Canadian Institutes of Health Research (CIHR), and the McLaughlin Centre for Molecular Medicine. A.R.C. is supported by the Natural Science and Engineering Research Council and L.F. is supported by the Swedish Medical Research Council. S.W.S. is an Investigator of CIHR and International Scholar of the Howard Hughes Medical Institute.

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  1. The Hospital for Sick Children and Department of Molecular and Medical Genetics, The Centre for Applied Genomics and Program in Genetics and Genomic Biology, University of Toronto, MaRS Centre — East Tower, 101 College Street, Room 14-701, Ontario, M5G 1L7, Canada

    Lars Feuk, Andrew R. Carson & Stephen W. Scherer

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DATABASES

OMIM

Angelman syndrome

Hunter syndrome

Sotos syndrome

Williams–Beuren syndrome

Wolf–Hirschhorn syndrome

FURTHER INFORMATION

Affymetrix

Agilent Technologies

Celera Genomics

Chromosome Abnormality Database

Database of Chromosomal Imbalance and Phenotypes in Humans using Ensembl Resources (DECIPHER)

Database of Genomic Variants

Human Genome Segmental Duplication Database

Human Structural Variation Database

Mendelian Cytogenetics Network Online Database

Mitelman Database of Chromosome Aberrations in Cancer

NIGMS Human Genetic Cell Repository

NimbleGen

The European Collection of Cell Cultures (ECACC)

The International HapMap Project

Nature Genetics

Glossary

Aneuploidy

The presence of an abnormal number of chromosomes within a cell.

Heteromorphism

A microscopically visible region of a chromosome that varies in size, morphology or staining properties. They include euchromatic and non-euchromatic variation, such as satellite–satellite stalk variation and heterochromatic variation (centromeres and other C-band positive regions).

Fragile site

A small break or a constriction of a chromosome that can be visualized under special cell-culture conditions. Some fragile sites are universal, others are normal structural variants, and two are associated with mental retardation syndromes (FRAXA and FRAXE).

Isochromosome

A chromosome that has two genetically and morphologically identical arms.

Double minute

Acentric, extra-chromosomally amplified chromatin, which usually contains a particular chromosomal segment or gene; common in cancer cells.

Marker chromosome

(Also known as an extra-structurally abnormal chromosome or 'supernumerary' chromosome.) Chromosomes that are seen in addition to the normal chromosome complement in fluorescence in situ hybridization experiments.

Secondary constriction

A thin chromatic filament that connects a chromosomal satellite with the rest of the chromosome.

Acrocentric chromosome

A chromosome that has a centromere at or close to one end. Human acrocentric chromosomes are 13, 14, 15, 21 and 22.

Chromosome banding

A method of defining chromosome structure by staining with Giemsa and looking at the banding pattern in the heterochromatin of the centromeric regions.

Fluorescence in situ hybridization

A technique in which fluorescently labelled DNA probes are hybridized to interphase cells, metaphase chromosome preparations or DNA fibres, as a means to determine the presence and relative location of target sequences.

Unbalanced rearrangement

A genomic variant that involves gain or loss of DNA, such as deletion and duplication.

Euchromatic variant

A subset of cytogenetic heteromorphisms that involve microscopically visible variations of the euchromatic regions of chromosomes.

Derivative chromosome

An abnormal chromosome consisting of segments of two or more chromosomes joined together as a result of a translocation of other rearrangement.

Segmental duplications

Segments of chromosomal DNA that are >1 kb in size and have >90% inter-copy sequence identity (also called low-copy repeats or duplicons). They have been shown to constitute ∼5% of the reference sequence of the human genome, where they are thought to have arisen over the past 35 million years of primate evolution.

Balanced variant

A genomic variant that involves no net loss or gain of genetic material. They include perfect inversions and translocations.

COT-1 DNA

DNA that is mainly composed of repetitive sequences. It is produced when short fragments of denatured genomic DNA are re-annealed.

Fosmid

A bacterially propagated phagemid vector system that is suitable for cloning genomic inserts of approximately 40 kb in size.

Cryptic translocation

A translocation, particularly one that involves DNA near telomeres, that is too small to be detectable by traditional chromosome-banding analysis.

Gene conversion

A process in which one sequence directs the sequence conversion of a partner allele or paralogous sequence into its own form.

Constitutional translocations

Chromosome abnormalities that occur before fertilization (during meiosis) or early in embryogenesis (during mitosis), such that essentially all cells in the individual harbour the same abnormality.

Position effect

A change in the expression of a gene that is produced by changing its location within a genome.

Genomic disorders

A group of human diseases that are caused by recurrent genomic rearrangements of unstable genomic regions. These give rise to phenotypes as a result of abnormal gene dosage within the rearranged genomic region. Segmental duplications are often involved in the rearrangement event.

Haplotype

A tightly linked group of genetic markers, which tend to be inherited as a unit because of their close proximity.

Gene Ontology

A project that provides sets of controlled vocabularies that have been developed to help describe and categorize genes. They describe the molecular function, biological process and cellular localization of gene products.

Optical mapping

A technology that uses in situ restriction digests of individual DNA molecules from genomic DNA to produce detailed optical-restriction maps of genomes.

Tiling-path array

An array that contains a set of clones that represents the sequence of a chromosome or a portion of a genome with minimum overlap.

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Feuk, L., Carson, A. & Scherer, S. Structural variation in the human genome. Nat Rev Genet 7, 85–97 (2006). https://doi.org/10.1038/nrg1767

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