Skip to main content
SpringerLink
Log in

Progress in the detection of human genome structural variations

  • Review
  • Published:
Science in China Series C: Life Sciences Aims and scope Submit manuscript

Abstract

The emerging of high-throughput and high-resolution genomic technologies led to the detection of submicroscopic variants ranging from 1 kb to 3 Mb in the human genome. These variants include copy number variations (CNVs), inversions, insertions, deletions and other complex rearrangements of DNA sequences. This paper briefly reviews the commonly used technologies to discover both genomic structural variants and their potential influences. Particularly, we highlight the array-based, PCR-based and sequencing-based assays, including array-based comparative genomic hybridization (aCGH), representational oligonucleotide microarray analysis (ROMA), multiplex amplifiable probe hybridization (MAPH), multiplex ligation-dependent probe amplification (MLPA), paired-end mapping (PEM), and next-generation DNA sequencing technologies. Furthermore, we discuss the limitations and challenges of current assays and give advices on how to make the database of genomic variations more reliable.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Pennisi E. Breakthrough of the year. Human genetic variation. Science, 2007, 318(5858): 1842–1843, 18096770, 10.1126/science.318.5858.1842, 1:CAS:528:DC%2BD2sXhsVygt7fP

    Article  CAS  Google Scholar 

  2. Feuk L, Carson A R, Scherer S W. Structural variation in the human genome. Nat Rev Genet, 2006, 7(2): 85–97, 16418744, 10.1038/nrg1767, 1:CAS:528:DC%2BD28XkvFOjuw%3D%3D

    Article  CAS  Google Scholar 

  3. Sachidanandam R, Weissman D, Schmidt S C, et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature, 2001, 409(6822): 928–933, 11237013, 10.1038/35057149, 1:CAS:528:DC%2BD3MXhsFCjtb8%3D

    Article  CAS  Google Scholar 

  4. Kruglyak L, Nickerson D A. Variation is the spice of life. Nat Genet, 2001, 27(3): 234–236, 11242096, 10.1038/85776, 1:CAS:528:DC%2BD3MXhslCrs7s%3D

    Article  CAS  Google Scholar 

  5. Frazer K A, Ballinger D G, Cox D R, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature, 2007, 449(7164): 851–861, 17943122, 10.1038/nature06258, 1:CAS:528:DC%2BD2sXhtFOjt7jL

    Article  CAS  Google Scholar 

  6. Li Y, Grupe A, Rowland C, et al. Evidence that common variation in NEDD9 is associated with susceptibility to late-onset Alzheimer’s and Parkinson’s disease. Hum Mol Genet, 2008, 17(5): 759–767, 18063669, 10.1093/hmg/ddm348, 1:CAS:528:DC%2BD1cXitVemsr0%3D

    Article  CAS  Google Scholar 

  7. Shastry B S. SNP alleles in human disease and evolution. J Hum Genet, 2002, 47(11): 561–566, 12436191, 10.1007/s100380200086, 1:CAS:528:DC%2BD38XoslOru78%3D

    Article  CAS  Google Scholar 

  8. Iafrate A J, Feuk L, Rivera M N, et al. Detection of large-scale variation in the human genome. Nat Genet, 2004, 36(9): 949–951, 15286789, 10.1038/ng1416, 1:CAS:528:DC%2BD2cXntFSku7w%3D

    Article  CAS  Google Scholar 

  9. Sebat J, Lakshmi B, Troge J, et al. Large-scale copy number polymorphism in the human genome. Science, 2004, 305(5683): 525–528, 15273396, 10.1126/science.1098918, 1:CAS:528:DC%2BD2cXlvVOkur4%3D

    Article  CAS  Google Scholar 

  10. Check E. Human genome: patchwork people. Nature, 2005, 437(7062): 1084–1086, 16237414, 10.1038/4371084a, 1:CAS:528:DC%2BD2MXhtFaht7nE

    Article  CAS  Google Scholar 

  11. Freeman J L, Perry G H, Feuk L, et al. Copy number variation: new insights in genome diversity. Genome Res, 2006, 16(8): 949–961, 16809666, 10.1101/gr.3677206, 1:CAS:528:DC%2BD28Xot1Kktb8%3D

    Article  CAS  Google Scholar 

  12. Sharp A J, Cheng Z, Eichler E E. Structural variation of the human genome. Annu Rev Genomics Hum Genet, 2006, 7: 407–442, 16780417, 10.1146/annurev.genom.7.080505.115618, 1:CAS:528:DC%2BD28Xht1Wgsr3F

    Article  CAS  Google Scholar 

  13. Sebat J. Major changes in our DNA lead to major changes in our thinking. Nat Genet, 2007, 39(7 Suppl): S3–5, 17597778, 10.1038/ng2095, 1:CAS:528:DC%2BD2sXmvFKmtro%3D

    Article  CAS  Google Scholar 

  14. Redon R, Ishikawa S, Fitch K R, et al. Global variation in copy number in the human genome. Nature, 2006, 444(7118): 444–454, 17122850, 10.1038/nature05329, 1:CAS:528:DC%2BD28Xht1aku7zI

    Article  CAS  Google Scholar 

  15. Mills R E, Luttig C T, Larkins C E, et al. An initial map of insertion and deletion (INDEL) variation in the human genome. Genome Res, 2006, 16(9): 1182–1190, 16902084, 10.1101/gr.4565806, 1:CAS:528:DC%2BD28XpsFels70%3D

    Article  CAS  Google Scholar 

  16. Bauman J G, Wiegant J, Borst P, et al. A new method for fluorescence microscopical localization of specific DNA sequences by in situ hybridization of fluorochromelabelled RNA. Exp Cell Res, 1980, 128(2): 485–490, 6157553, 10.1016/0014-4827(80)90087-7, 1:CAS:528:DyaL3MXhslSi

    Article  CAS  Google Scholar 

  17. Parra I, Windle B. High resolution visual mapping of stretched DNA by fluorescent hybridization. Nat Genet, 1993, 5(1): 17–21, 8106079, 10.1038/ng0993-17, 1:CAS:528:DyaK3sXlslCqsb0%3D

    Article  CAS  Google Scholar 

  18. Speicher M R, Carter N P. The new cytogenetics: blurring the boundaries with molecular biology. Nat Rev Genet, 2005, 6(10): 782–792, 16145555, 10.1038/nrg1692, 1:CAS:528:DC%2BD2MXhtVGru77K

    Article  CAS  Google Scholar 

  19. Raap A K, Florijn R J, Blonden L A J, et al. Fiber FISH as a DNA Mapping Tool. Methods, 1996, 9(1): 67–73, 9245344, 10.1006/meth.1996.0009, 1:CAS:528:DyaK28XitVahtLY%3D

    Article  CAS  Google Scholar 

  20. de Stahl T D, Sandgren J, Piotrowski A, et al. Profiling of copy number variations (CNVs) in healthy individuals from three ethnic groups using a human genome 32 K BAC-clone-based array. Hum Mutat, 2008, 29(3): 398–408, 18058796, 10.1002/humu.20659, 1:CAS:528:DC%2BD1cXktlahsbY%3D

    Article  Google Scholar 

  21. McCarroll S A, Kuruvilla F G, Korn J M, et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet, 2008, 40(10): 1166–1174, 18776908, 10.1038/ng.238, 1:CAS:528:DC%2BD1cXhtFKht7%2FN

    Article  CAS  Google Scholar 

  22. Butler H, Ragoussis J. BeadArray-based genotyping. Methods Mol Biol, 2008, 439: 53–74, 18370095, 10.1007/978-1-59745-188-8_4, 1:CAS:528:DC%2BD1cXjsl2ktbo%3D

    Article  CAS  Google Scholar 

  23. Dhami P, Coffey A J, Abbs S, et al. Exon array CGH: detection of copy-number changes at the resolution of individual exons in the human genome. Am J Hum Genet, 2005, 76(5): 750–762, 15756638, 10.1086/429588, 1:CAS:528:DC%2BD2MXjs12rt7s%3D

    Article  CAS  Google Scholar 

  24. Ijssel P, Ylstra B. Oligonucleotide array comparative genomic hybridization. Methods Mol Biol, 2007, 396: 207–221, 18025695, 10.1007/978-1-59745-515-2_14

    Article  Google Scholar 

  25. Lucito R, Healy J, Alexander J, et al. Representational oligonucleotide microarray analysis: a high-resolution method to detect genome copy number variation. Genome Res, 2003, 13(10): 2291–2305, 12975311, 10.1101/gr.1349003, 1:CAS:528:DC%2BD3sXotF2hsb8%3D

    Article  CAS  Google Scholar 

  26. Jobanputra V, Sebat J, Troge J, et al. Application of ROMA (representational oligonucleotide microarray analysis) to patients with cytogenetic rearrangements. Genet Med, 2005, 7(2): 111–118, 15714078, 1:CAS:528:DC%2BD2MXhtl2mtLw%3D

    Article  CAS  Google Scholar 

  27. Backx L, Van Esch H, Melotte C, et al. Array painting using microdissected chromosomes to map chromosomal breakpoints. Cytogenet Genome Res, 2007, 116(3): 158–166, 17317954, 10.1159/000098181, 1:CAS:528:DC%2BD2sXitVCjt7s%3D

    Article  CAS  Google Scholar 

  28. Feuk L, Marshall C R, Wintle R F, et al. Structural variants: changing the landscape of chromosomes and design of disease studies. Hum Mol Genet, 2006, 15(1): R57–66, 16651370, 10.1093/hmg/ddl057, 1:CAS:528:DC%2BD28XktlSisro%3D

    Article  CAS  Google Scholar 

  29. Hollox E J, Atia T, Cross G, et al. High throughput screening of human subtelomeric DNA for copy number changes using multiplex amplifiable probe hybridisation (MAPH). J Med Genet, 2002, 39(11): 790–795, 12414816, 10.1136/jmg.39.11.790, 1:CAS:528:DC%2BD38XpsVWjtr4%3D

    Article  CAS  Google Scholar 

  30. Sellner L N, Taylor G R. MLPA and MAPH: new techniques for detection of gene deletions. Hum Mutat, 2004, 23(5): 413–419, 15108271, 10.1002/humu.20035, 1:CAS:528:DC%2BD2cXkslyhsbw%3D

    Article  CAS  Google Scholar 

  31. Gibbons B, Datta P, Wu Y, et al. Microarray MAPH: accurate array-based detection of relative copy number in genomic DNA. BMC Genomics, 2006, 7: 163, 16813644, 10.1186/1471-2164-7-163, 1:CAS:528:DC%2BD28XnvFahu7s%3D

    Article  Google Scholar 

  32. Patsalis P C, Kousoulidou L, Mannik K, et al. Detection of small genomic imbalances using microarray-based multiplex amplifiable probe hybridization. Eur J Hum Genet, 2007, 15(2): 162–172, 17119536, 10.1038/sj.ejhg.5201738, 1:CAS:528:DC%2BD2sXmt1Okug%3D%3D

    Article  CAS  Google Scholar 

  33. Schouten J P, McElgunn C J, Waaijer R, et al. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res, 2002, 30(12): e57, 12060695, 10.1093/nar/gnf056

    Article  Google Scholar 

  34. Gatta V, Antonucci I, Morizio E, et al. Identification and characterization of different SHOX gene deletions in patients with Leri-Weill dyschondrosteosys by MLPA assay. J Hum Genet, 2007, 52(1): 21–27, 17091221, 10.1007/s10038-006-0074-5, 1:CAS:528:DC%2BD28XhtlWntbjF

    Article  CAS  Google Scholar 

  35. Isaksson M, Stenberg J, Dahl F, et al. MLGA—a rapid and cost-efficient assay for gene copy-number analysis. Nucleic Acids Res, 2007, 35(17): e115, 17823203, 10.1093/nar/gkm651, 1:CAS:528:DC%2BD2sXhtFWiu7nF

    Article  Google Scholar 

  36. Abdellah Z, Ahmadi A, Ahmed S, et al. Finishing the euchromatic sequence of the human genome. Nature, 2004, 431(7011): 931–945, 10.1038/nature03001, 1:CAS:528:DC%2BD2cXoslSlt7o%3D

    Article  Google Scholar 

  37. Tuzun E, Sharp A J, Bailey J A, et al. Fine-scale structural variation of the human genome. Nat Genet, 2005, 37(7): 727–732, 15895083, 10.1038/ng1562, 1:CAS:528:DC%2BD2MXlslWhsrk%3D

    Article  CAS  Google Scholar 

  38. Korbel J O, Urban A E, Affourtit J P, et al. Paired-end mapping reveals extensive structural variation in the human genome. Science, 2007, 318(5849): 420–426, 17901297, 10.1126/science.1149504, 1:CAS:528:DC%2BD2sXhtFOjtbzL

    Article  CAS  Google Scholar 

  39. Jarvie T, Harkins T. De novo assembly and genomic structural variation analysis with genome sequencer FLX 3K long-tag paired end reads. Biotechniques, 2008, 44(6): 829–831, 18476839, 10.2144/000112894, 1:CAS:528:DC%2BD1cXmtFamu78%3D

    Article  CAS  Google Scholar 

  40. Khaja R, Zhang J, MacDonald J R, et al. Genome assembly comparison identifies structural variants in the human genome. Nat Genet, 2006, 38(12): 1413–1418, 17115057, 10.1038/ng1921, 1:CAS:528:DC%2BD28Xht1CntrfJ

    Article  CAS  Google Scholar 

  41. Feuk L, MacDonald J R, Tang T, et al. Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies. PLoS Genet, 2005, 1(4): e56, 16254605, 10.1371/journal.pgen.0010056, 1:CAS:528:DC%2BD2MXhtFOnsL3F

    Article  Google Scholar 

  42. Krzywinski M, Bosdet I, Mathewson C, et al. A BAC clone fingerprinting approach to the detection of human genome rearrangements. Genome Biol, 2007, 8(10): R224, 17953769, 10.1186/gb-2007-8-10-r224, 1:CAS:528:DC%2BD1cXhs1Cnur8%3D

    Article  Google Scholar 

  43. Holt K E, Parkhill J, Mazzoni C J, et al. High-throughput sequencing provides insights into genome variation and evolution in Salmonella Typhi. Nat Genet, 2008, 40(8): 987–993, 18660809, 10.1038/ng.195, 1:CAS:528:DC%2BD1cXptVKkurk%3D

    Article  CAS  Google Scholar 

  44. Conrad D F, Hurles M E. The population genetics of structural variation. Nat Genet, 2007, 39(7 Suppl): S30–36, 17597779, 10.1038/ng2042, 1:CAS:528:DC%2BD2sXmvFKmsbY%3D

    Article  CAS  Google Scholar 

  45. Rodriguez-Revenga L, Mila M, Rosenberg C, et al. Structural variation in the human genome: the impact of copy number variants on clinical diagnosis. Genet Med, 2007, 9(9): 600–606, 17873648, 1:CAS:528:DC%2BD2sXhtVCru7%2FI, 10.1097/GIM.0b013e318149e1e3

    Article  CAS  Google Scholar 

  46. Barbour V M, Tufarelli C, Sharpe J A, et al. alpha-thalassemia resulting from a negative chromosomal position effect. Blood, 2000, 96(3): 800–807, 10910890, 1:CAS:528:DC%2BD3cXltlKitro%3D

    CAS  Google Scholar 

  47. Kleinjan D J, van Heyningen V. Position effect in human genetic disease. Hum Mol Genet, 1998, 7(10): 1611–1618, 9735382, 10.1093/hmg/7.10.1611, 1:CAS:528:DyaK1cXmsFWqurw%3D

    Article  CAS  Google Scholar 

  48. Lupski J R. Structural variation in the human genome. N Engl J Med, 2007, 356(11): 1169–1171, 17360997, 10.1056/NEJMcibr067658, 1:CAS:528:DC%2BD2sXivVKnsL0%3D

    Article  CAS  Google Scholar 

  49. Sharp A J. Emerging themes and new challenges in defining the role of structural variation in human disease. Hum Mutat, 2009,30(2): 135–144, 18837009, 10.1002/humu.20843, 1:CAS:528:DC%2BD1MXjtFKms7s%3D

    Article  CAS  Google Scholar 

  50. Bridges C B. The Bar “Gene” a Duplication. Science, 1936, 83(2148): 210–211, 17796454, 10.1126/science.83.2148.210

    Article  CAS  Google Scholar 

  51. Hurles M E, Dermitzakis E T, Tyler-Smith C. The functional impact of structural variation in humans. Trends Genet, 2008, 24(5): 238–245, 18378036, 10.1016/j.tig.2008.03.001, 1:CAS:528:DC%2BD1cXlslWisbg%3D

    Article  CAS  Google Scholar 

  52. McCarroll S A, Altshuler D M. Copy-number variation and association studies of human disease. Nat Genet, 2007, 39(7 Suppl): S37–42, 17597780, 10.1038/ng2080, 1:CAS:528:DC%2BD2sXmvFKmtr4%3D

    Article  CAS  Google Scholar 

  53. Nathans J, Piantanida T P, Eddy R L, et al. Molecular genetics of inherited variation in human color vision. Science, 1986, 232(4747): 203–210, 3485310, 10.1126/science.3485310, 1:CAS:528:DyaL28XitVWntLw%3D

    Article  CAS  Google Scholar 

  54. Blunt T, Steers F, Daniels G, et al. Lack of RH C/E expression in the Rhesus D—phenotype is the result of a gene deletion. Ann Hum Genet, 1994, 58(Pt 1): 19–24, 7913307, 10.1111/j.1469-1809.1994.tb00722.x, 1:STN:280:DyaK2czgsVSruw%3D%3D

    Article  CAS  Google Scholar 

  55. Jamain S, Quach H, Betancur C, et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet, 2003, 34(1): 27–29, 12669065, 10.1038/ng1136, 1:CAS:528:DC%2BD3sXjt1Ontrg%3D

    Article  CAS  Google Scholar 

  56. Butler M G, Fischer W, Kibiryeva N, et al. Array comparative genomic hybridization (aCGH) analysis in Prader-Willi syndrome. Am J Med Genet A, 2008, 146(7): 854–860, 18266248

    Article  Google Scholar 

  57. Armour J A, Barton D E, Cockburn D J, et al. The detection of large deletions or duplications in genomic DNA. Hum Mutat, 2002, 20(5): 325–337, 12402329, 10.1002/humu.10133, 1:CAS:528:DC%2BD38XptV2nurY%3D

    Article  CAS  Google Scholar 

  58. Scherer S W, Lee C, Birney E, et al. Challenges and standards in integrating surveys of structural variation. Nat Genet, 2007, 39(7 Suppl): S7–15, 17597783, 10.1038/ng2093, 1:CAS:528:DC%2BD2sXmvFKmtr0%3D

    Article  CAS  Google Scholar 

  59. Lakich D, Kazazian H H, Antonarakis S E, et al. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet, 1993, 5(3): 236–241, 8275087, 10.1038/ng1193-236, 1:CAS:528:DyaK2cXivVGlsw%3D%3D

    Article  CAS  Google Scholar 

  60. Castermans D, Vermeesch J R, Fryns J P, et al. Identification and characterization of the TRIP8 and REEP3 genes on chromosome 10q21.3 as novel candidate genes for autism. Eur J Hum Genet, 2007, 15(4): 422–431, 17290275, 10.1038/sj.ejhg.5201785, 1:CAS:528:DC%2BD2sXjtlWns7o%3D

    Article  CAS  Google Scholar 

  61. Jakobsson J, Ekstrom L, Inotsume N, et al. Large differences in testosterone excretion in Korean and Swedish men are strongly associated with a UDP-glucuronosyl transferase 2B17 polymorphism. J Clin Endocrinol Metab, 2006, 91(2): 687–693, 16332934, 10.1210/jc.2005-1643, 1:CAS:528:DC%2BD28XhsFKmsrw%3D

    Article  CAS  Google Scholar 

  62. Gonzalez E, Kulkarni H, Bolivar H, et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science, 2005, 307(5714): 1434–1440, 15637236, 10.1126/science.1101160, 1:CAS:528:DC%2BD2MXhslKrtLs%3D

    Article  CAS  Google Scholar 

  63. Buckland P R. Polymorphically duplicated genes: their relevance to phenotypic variation in humans. Ann Med, 2003, 35(5): 308–315, 12952017, 10.1080/07853890310001276, 1:CAS:528:DC%2BD3sXmtVeltrc%3D

    Article  CAS  Google Scholar 

  64. Agundez J A, Gallardo L, Ledesma M C, et al. Functionally active duplications of the CYP2D6 gene are more prevalent among larynx and lung cancer patients. Oncology, 2001, 61(1): 59–63, 11474250, 10.1159/000055354, 1:CAS:528:DC%2BD3MXmtF2qsrs%3D

    Article  CAS  Google Scholar 

  65. Garcia-Closas M, Malats N, Silverman D, et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet, 2005, 366(9486): 649–659, 16112301, 10.1016/S0140-6736(05)67137-1, 1:CAS:528:DC%2BD2MXosVajsb0%3D

    Article  CAS  Google Scholar 

  66. Conrad D F, Andrews T D, Carter N P, et al. A high-resolution survey of deletion polymorphism in the human genome. Nat Genet, 2006, 38(1): 75–81, 16327808, 10.1038/ng1697, 1:CAS:528:DC%2BD2MXhtlCmtr%2FP

    Article  CAS  Google Scholar 

  67. Jakobsson M, Scholz S W, Scheet P, et al. Genotype, haplotype and copy-number variation in worldwide human populations. Nature, 2008, 451(7181): 998–1003, 18288195, 10.1038/nature06742, 1:CAS:528:DC%2BD1cXit1ynsLw%3D

    Article  CAS  Google Scholar 

  68. Eichler E E. Widening the spectrum of human genetic variation. Nat Genet, 2006, 38(1): 9–11, 16380720, 10.1038/ng0106-9, 1:CAS:528:DC%2BD2MXhtlCmtr7J

    Article  CAS  Google Scholar 

  69. Eichler E E, Nickerson D A, Altshuler D, et al. Completing the map of human genetic variation. Nature, 2007, 447(7141): 161–165, 17495918, 10.1038/447161a, 1:CAS:528:DC%2BD2sXltVGku70%3D

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center of Functional Genomics, Key Laboratory of System Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    XueMei Wu & HuaSheng Xiao

  2. National Engineering Center for Biochip at Shanghai, Shanghai, 201203, China

    HuaSheng Xiao

  3. Graduate School of the Chinese Academy of Sciences, Shanghai, 200031, China

    XueMei Wu

Authors
  1. XueMei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. HuaSheng Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to HuaSheng Xiao.

Additional information

Supported by the National High Technology Research and Development Program of China (Grant No. 2006AA020704).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, X., Xiao, H. Progress in the detection of human genome structural variations. SCI CHINA SER C 52, 560–567 (2009). https://doi.org/10.1007/s11427-009-0078-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-009-0078-4

Keywords

Search

Navigation