Principles of Whole-Genome Amplification

  • Zbigniew Tadeusz Czyz
  • Stefan Kirsch
  • Bernhard PolzerEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1347)


Modern molecular biology relies on large amounts of high-quality genomic DNA. However, in a number of clinical or biological applications this requirement cannot be met, as starting material is either limited (e.g., preimplantation genetic diagnosis (PGD) or analysis of minimal residual cancer) or of insufficient quality (e.g., formalin-fixed paraffin-embedded tissue samples or forensics). As a consequence, in order to obtain sufficient amounts of material to analyze these demanding samples by state-of-the-art modern molecular assays, genomic DNA has to be amplified. This chapter summarizes available technologies for whole-genome amplification (WGA), bridging the last 25 years from the first developments to currently applied methods. We will especially elaborate on research application, as well as inherent advantages and limitations of various WGA technologies.

Key words

Whole-genome amplification PCR-based amplification Ligation-mediated amplification Multiple displacement amplification 


  1. 1.
    Araki T, Yamamoto A, Yamada M (1987) Accurate determination of DNA content in single cell nuclei stained with Hoechst 33258 fluorochrome at high salt concentration. Histochemistry 87(4):331–338CrossRefPubMedGoogle Scholar
  2. 2.
    Saiki RK, Scharf S, Faloona F, Mullis KB, Horn GT, Erlich HA, Arnheim N (1985) Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230(4732):1350–1354CrossRefPubMedGoogle Scholar
  3. 3.
    Nelson DL, Ledbetter SA, Corbo L, Victoria MF, Ramirez-Solis R, Webster TD, Ledbetter DH, Caskey CT (1989) Alu polymerase chain reaction: a method for rapid isolation of human-specific sequences from complex DNA sources. Proc Natl Acad Sci U S A 86(17):6686–6690PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Korenberg JR, Rykowski MC (1988) Human genome organization: Alu, lines, and the molecular structure of metaphase chromosome bands. Cell 53(3):391–400CrossRefPubMedGoogle Scholar
  5. 5.
    Wells D, Sherlock JK, Handyside AH, Delhanty JD (1999) Detailed chromosomal and molecular genetic analysis of single cells by whole genome amplification and comparative genomic hybridisation. Nucleic Acids Res 27(4):1214–1218PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Bernard LE, Brooks-Wilson AR, Wood S (1991) Isolation of DNA fragments from a human chromosomal subregion by Alu PCR differential hybridization. Genomics 9(2):241–246CrossRefPubMedGoogle Scholar
  7. 7.
    Brooks-Wilson AR, Goodfellow PN, Povey S, Nevanlinna HA, de Jong PJ, Goodfellow PJ (1990) Rapid cloning and characterization of new chromosome 10 DNA markers by Alu element-mediated PCR. Genomics 7(4):614–620CrossRefPubMedGoogle Scholar
  8. 8.
    Ledbetter SA, Nelson DL, Warren ST, Ledbetter DH (1990) Rapid isolation of DNA probes within specific chromosome regions by interspersed repetitive sequence polymerase chain reaction. Genomics 6(3):475–481CrossRefPubMedGoogle Scholar
  9. 9.
    Ludecke HJ, Senger G, Claussen U, Horsthemke B (1989) Cloning defined regions of the human genome by microdissection of banded chromosomes and enzymatic amplification. Nature 338(6213):348–350. doi: 10.1038/338348a0 CrossRefPubMedGoogle Scholar
  10. 10.
    Telenius H, Carter NP, Bebb CE, Nordenskjold M, Ponder BA, Tunnacliffe A (1992) Degenerate oligonucleotide-primed PCR: general amplification of target DNA by a single degenerate primer. Genomics 13(3):718–725CrossRefPubMedGoogle Scholar
  11. 11.
    Kittler R, Stoneking M, Kayser M (2002) A whole genome amplification method to generate long fragments from low quantities of genomic DNA. Anal Biochem 300(2):237–244. doi: 10.1006/abio.2001.5460 CrossRefPubMedGoogle Scholar
  12. 12.
    Dean FB, Hosono S, Fang L, Wu X, Faruqi AF, Bray-Ward P, Sun Z, Zong Q, Du Y, Du J, Driscoll M, Song W, Kingsmore SF, Egholm M, Lasken RS (2002) Comprehensive human genome amplification using multiple displacement amplification. Proc Natl Acad Sci U S A 99(8):5261–5266. doi: 10.1073/pnas.082089499 PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Aubele M, Mattis A, Zitzelsberger H, Walch A, Kremer M, Hutzler P, Hofler H, Werner M (1999) Intratumoral heterogeneity in breast carcinoma revealed by laser-microdissection and comparative genomic hybridization. Cancer Genet Cytogenet 110(2):94–102CrossRefPubMedGoogle Scholar
  14. 14.
    Harada T, Okita K, Shiraishi K, Kusano N, Kondoh S, Sasaki K (2002) Interglandular cytogenetic heterogeneity detected by comparative genomic hybridization in pancreatic cancer. Cancer Res 62(3):835–839PubMedGoogle Scholar
  15. 15.
    Marchio A, Terris B, Meddeb M, Pineau P, Duverger A, Tiollais P, Bernheim A, Dejean A (2001) Chromosomal abnormalities in liver cell dysplasia detected by comparative genomic hybridisation. Mol Pathol 54(4):270–274PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Zitzelsberger H, Kulka U, Lehmann L, Walch A, Smida J, Aubele M, Lorch T, Hofler H, Bauchinger M, Werner M (1998) Genetic heterogeneity in a prostatic carcinoma and associated prostatic intraepithelial neoplasia as demonstrated by combined use of laser-microdissection, degenerate oligonucleotide primed PCR and comparative genomic hybridization. Virchows Arch 433(4):297–304CrossRefPubMedGoogle Scholar
  17. 17.
    Daigo Y, Chin SF, Gorringe KL, Bobrow LG, Ponder BA, Pharoah PD, Caldas C (2001) Degenerate oligonucleotide primed-polymerase chain reaction-based array comparative genomic hybridization for extensive amplicon profiling of breast cancers : a new approach for the molecular analysis of paraffin-embedded cancer tissue. Am J Pathol 158(5):1623–1631. doi: 10.1016/S0002-9440(10)64118-1 PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Voullaire L, Wilton L, Slater H, Williamson R (1999) Detection of aneuploidy in single cells using comparative genomic hybridization. Prenat Diagn 19(9):846–851CrossRefPubMedGoogle Scholar
  19. 19.
    Wells D, Delhanty JD (2000) Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization. Mol Hum Reprod 6(11):1055–1062CrossRefPubMedGoogle Scholar
  20. 20.
    Wilton L, Williamson R, McBain J, Edgar D, Voullaire L (2001) Birth of a healthy infant after preimplantation confirmation of euploidy by comparative genomic hybridization. N Engl J Med 345(21):1537–1541. doi: 10.1056/NEJMoa011052 CrossRefPubMedGoogle Scholar
  21. 21.
    Wells D, Escudero T, Levy B, Hirschhorn K, Delhanty JD, Munne S (2002) First clinical application of comparative genomic hybridization and polar body testing for preimplantation genetic diagnosis of aneuploidy. Fertil Steril 78(3):543–549CrossRefPubMedGoogle Scholar
  22. 22.
    Gutierrez-Mateo C, Wells D, Benet J, Sanchez-Garcia JF, Bermudez MG, Belil I, Egozcue J, Munne S, Navarro J (2004) Reliability of comparative genomic hybridization to detect chromosome abnormalities in first polar bodies and metaphase II oocytes. Hum Reprod 19(9):2118–2125. doi: 10.1093/humrep/deh367 CrossRefPubMedGoogle Scholar
  23. 23.
    Voullaire L, Slater H, Williamson R, Wilton L (2000) Chromosome analysis of blastomeres from human embryos by using comparative genomic hybridization. Hum Genet 106(2):210–217CrossRefPubMedGoogle Scholar
  24. 24.
    Hu DG, Webb G, Hussey N (2004) Aneuploidy detection in single cells using DNA array-based comparative genomic hybridization. Mol Hum Reprod 10(4):283–289. doi: 10.1093/humrep/gah038 CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang L, Cui X, Schmitt K, Hubert R, Navidi W, Arnheim N (1992) Whole genome amplification from a single cell: implications for genetic analysis. Proc Natl Acad Sci U S A 89(13):5847–5851PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Snabes MC, Chong SS, Subramanian SB, Kristjansson K, DiSepio D, Hughes MR (1994) Preimplantation single-cell analysis of multiple genetic loci by whole-genome amplification. Proc Natl Acad Sci U S A 91(13):6181–6185PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Kristjansson K, Chong SS, Van den Veyver IB, Subramanian S, Snabes MC, Hughes MR (1994) Preimplantation single cell analyses of dystrophin gene deletions using whole genome amplification. Nat Genet 6(1):19–23. doi: 10.1038/ng0194-19 CrossRefPubMedGoogle Scholar
  28. 28.
    Dietmaier W, Hartmann A, Wallinger S, Heinmoller E, Kerner T, Endl E, Jauch KW, Hofstadter F, Ruschoff J (1999) Multiple mutation analyses in single tumor cells with improved whole genome amplification. Am J Pathol 154(1):83–95. doi: 10.1016/S0002-9440(10)65254-6 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Heinmoller E, Schlake G, Renke B, Liu Q, Hill KA, Sommer SS, Ruschoff J (2002) Microdissection and molecular analysis of single cells or small cell clusters in pathology and diagnosis–significance and challenges. Anal Cell Pathol 24(4-5):125–134CrossRefPubMedGoogle Scholar
  30. 30.
    Grothues D, Cantor CR, Smith CL (1993) PCR amplification of megabase DNA with tagged random primers (T-PCR). Nucleic Acids Res 21(5):1321–1322PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Lucito R, Nakimura M, West JA, Han Y, Chin K, Jensen K, McCombie R, Gray JW, Wigler M (1998) Genetic analysis using genomic representations. Proc Natl Acad Sci U S A 95(8):4487–4492PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Kinzler KW, Vogelstein B (1989) Whole genome PCR: application to the identification of sequences bound by gene regulatory proteins. Nucleic Acids Res 17(10):3645–3653PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Saunders RD, Glover DM, Ashburner M, Siden-Kiamos I, Louis C, Monastirioti M, Savakis C, Kafatos F (1989) PCR amplification of DNA microdissected from a single polytene chromosome band: a comparison with conventional microcloning. Nucleic Acids Res 17(22):9027–9037PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    VanDevanter DR, Choongkittaworn NM, Dyer KA, Aten J, Otto P, Behler C, Bryant EM, Rabinovitch PS (1994) Pure chromosome-specific PCR libraries from single sorted chromosomes. Proc Natl Acad Sci U S A 91(13):5858–5862PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Thorstenson YR, Hunicke-Smith SP, Oefner PJ, Davis RW (1998) An automated hydrodynamic process for controlled, unbiased DNA shearing. Genome Res 8(8):848–855PubMedCentralPubMedGoogle Scholar
  36. 36.
    Gribble S, Ng BL, Prigmore E, Burford DC, Carter NP (2004) Chromosome paints from single copies of chromosomes. Chromosome Res 12(2):143–151CrossRefPubMedGoogle Scholar
  37. 37.
    Langmore JP (2002) Rubicon Genomics, Inc. Pharmacogenomics 3(4):557–560. doi: 10.1517/14622416.3.4.557 CrossRefPubMedGoogle Scholar
  38. 38.
    Little SE, Vuononvirta R, Reis-Filho JS, Natrajan R, Iravani M, Fenwick K, Mackay A, Ashworth A, Pritchard-Jones K, Jones C (2006) Array CGH using whole genome amplification of fresh-frozen and formalin-fixed, paraffin-embedded tumor DNA. Genomics 87(2):298–306. doi: 10.1016/j.ygeno.2005.09.019 CrossRefPubMedGoogle Scholar
  39. 39.
    Johnson NA, Hamoudi RA, Ichimura K, Liu L, Pearson DM, Collins VP, Du MQ (2006) Application of array CGH on archival formalin-fixed paraffin-embedded tissues including small numbers of microdissected cells. Lab Invest 86(9):968–978. doi: 10.1038/labinvest.3700441 PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Fiegler H, Geigl JB, Langer S, Rigler D, Porter K, Unger K, Carter NP, Speicher MR (2007) High resolution array-CGH analysis of single cells. Nucleic Acids Res 35(3):e15. doi: 10.1093/nar/gkl1030 PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Geigl JB, Obenauf AC, Waldispuehl-Geigl J, Hoffmann EM, Auer M, Hormann M, Fischer M, Trajanoski Z, Schenk MA, Baumbusch LO, Speicher MR (2009) Identification of small gains and losses in single cells after whole genome amplification on tiling oligo arrays. Nucleic Acids Res 37(15):e105. doi: 10.1093/nar/gkp526 PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Mathiesen RR, Fjelldal R, Liestol K, Due EU, Geigl JB, Riethdorf S, Borgen E, Rye IH, Schneider IJ, Obenauf AC, Mauermann O, Nilsen G, Christian Lingjaerde O, Borresen-Dale AL, Pantel K, Speicher MR, Naume B, Baumbusch LO (2012) High-resolution analyses of copy number changes in disseminated tumor cells of patients with breast cancer. Int J Cancer 131(4):E405–E415. doi: 10.1002/ijc.26444 CrossRefPubMedGoogle Scholar
  43. 43.
    Magbanua MJ, Sosa EV, Roy R, Eisenbud LE, Scott JH, Olshen A, Pinkel D, Rugo HS, Park JW (2013) Genomic profiling of isolated circulating tumor cells from metastatic breast cancer patients. Cancer Res 73(1):30–40. doi: 10.1158/0008-5472.CAN-11-3017 PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Magbanua MJ, Sosa EV, Scott JH, Simko J, Collins C, Pinkel D, Ryan CJ, Park JW (2012) Isolation and genomic analysis of circulating tumor cells from castration resistant metastatic prostate cancer. BMC Cancer 12:78. doi: 10.1186/1471-2407-12-78 PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Gutierrez-Mateo C, Colls P, Sanchez-Garcia J, Escudero T, Prates R, Ketterson K, Wells D, Munne S (2011) Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril 95(3):953–958. doi: 10.1016/j.fertnstert.2010.09.010 CrossRefPubMedGoogle Scholar
  46. 46.
    Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie WR, Hicks J, Wigler M (2011) Tumour evolution inferred by single-cell sequencing. Nature 472(7341):90–94. doi: 10.1038/nature09807 PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Heitzer E, Auer M, Gasch C, Pichler M, Ulz P, Hoffmann EM, Lax S, Waldispuehl-Geigl J, Mauermann O, Lackner C, Hofler G, Eisner F, Sill H, Samonigg H, Pantel K, Riethdorf S, Bauernhofer T, Geigl JB, Speicher MR (2013) Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing. Cancer Res 73(10):2965–2975. doi: 10.1158/0008-5472.CAN-12-4140 CrossRefPubMedGoogle Scholar
  48. 48.
    Klein CA, Schmidt-Kittler O, Schardt JA, Pantel K, Speicher MR, Riethmuller G (1999) Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells. Proc Natl Acad Sci U S A 96(8):4494–4499PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Klein CA, Blankenstein TJ, Schmidt-Kittler O, Petronio M, Polzer B, Stoecklein NH, Riethmuller G (2002) Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 360(9334):683–689. doi: 10.1016/S0140-6736(02)09838-0 CrossRefPubMedGoogle Scholar
  50. 50.
    Schardt JA, Meyer M, Hartmann CH, Schubert F, Schmidt-Kittler O, Fuhrmann C, Polzer B, Petronio M, Eils R, Klein CA (2005) Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell 8(3):227–239. doi: 10.1016/j.ccr.2005.08.003 CrossRefPubMedGoogle Scholar
  51. 51.
    Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmuller G, Klein CA (2008) Systemic spread is an early step in breast cancer. Cancer Cell 13(1):58–68CrossRefPubMedGoogle Scholar
  52. 52.
    Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJ, Kaufmann M, Diebold J, Arnholdt H, Muller P, Bischoff J, Harich D, Schlimok G, Riethmuller G, Eils R, Klein CA (2003) From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci U S A 100(13):7737–7742. doi: 10.1073/pnas.1331931100 PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Stoecklein NH, Hosch SB, Bezler M, Stern F, Hartmann CH, Vay C, Siegmund A, Scheunemann P, Schurr P, Knoefel WT, Verde PE, Reichelt U, Erbersdobler A, Grau R, Ullrich A, Izbicki JR, Klein CA (2008) Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell 13(5):441–453. doi: 10.1016/j.ccr.2008.04.005 CrossRefPubMedGoogle Scholar
  54. 54.
    Weckermann D, Polzer B, Ragg T, Blana A, Schlimok G, Arnholdt H, Bertz S, Harzmann R, Klein CA (2009) Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. J Clin Oncol 27(10):1549–1556. doi: 10.1200/JCO.2008.17.0563 CrossRefPubMedGoogle Scholar
  55. 55.
    Malmgren H, Sahlen S, Inzunza J, Aho M, Rosenlund B, Fridstrom M, Hovatta O, Ahrlund-Richter L, Nordenskjold M, Blennow E (2002) Single cell CGH analysis reveals a high degree of mosaicism in human embryos from patients with balanced structural chromosome aberrations. Mol Hum Reprod 8(5):502–510CrossRefPubMedGoogle Scholar
  56. 56.
    Fuhrmann C, Schmidt-Kittler O, Stoecklein NH, Petat-Dutter K, Vay C, Bockler K, Reinhardt R, Ragg T, Klein CA (2008) High-resolution array comparative genomic hybridization of single micrometastatic tumor cells. Nucleic Acids Res 36(7):e39. doi: 10.1093/nar/gkn101 PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Czyz ZT, Hoffmann M, Schlimok G, Polzer B, Klein CA (2014) Reliable single cell array CGH for clinical samples. PLoS One 9(1):e85907. doi: 10.1371/journal.pone.0085907 PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Mohlendick B, Bartenhagen C, Behrens B, Honisch E, Raba K, Knoefel WT, Stoecklein NH (2013) A robust method to analyze copy number alterations of less than 100 kb in single cells using oligonucleotide array CGH. PLoS One 8(6):e67031. doi: 10.1371/journal.pone.0067031 PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Arneson N, Moreno J, Iakovlev V, Ghazani A, Warren K, McCready D, Jurisica I, Done SJ (2012) Comparison of whole genome amplification methods for analysis of DNA extracted from microdissected early breast lesions in formalin-fixed paraffin-embedded tissue. ISRN Oncol 2012:710692. doi: 10.5402/2012/710692 PubMedCentralPubMedGoogle Scholar
  60. 60.
    Stoecklein NH, Erbersdobler A, Schmidt-Kittler O, Diebold J, Schardt JA, Izbicki JR, Klein CA (2002) SCOMP is superior to degenerated oligonucleotide primed-polymerase chain reaction for global amplification of minute amounts of DNA from microdissected archival tissue samples. Am J Pathol 161(1):43–51PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Lizardi PM (2000) Multiple displacement amplification. US Patent No. 6,124,120Google Scholar
  62. 62.
    Brown TA (2002) Genomes, 2nd edn. Wiley-Liss, Oxford, UKGoogle Scholar
  63. 63.
    Dean FB, Nelson JR, Giesler TL, Lasken RS (2001) Rapid amplification of plasmid and phage DNA using Phi 29 DNA polymerase and multiply-primed rolling circle amplification. Genome Res 11(6):1095–1099. doi: 10.1101/gr.180501 PubMedCentralCrossRefPubMedGoogle Scholar
  64. 64.
    Lage JM, Leamon JH, Pejovic T, Hamann S, Lacey M, Dillon D, Segraves R, Vossbrinck B, Gonzalez A, Pinkel D, Albertson DG, Costa J, Lizardi PM (2003) Whole genome analysis of genetic alterations in small DNA samples using hyperbranched strand displacement amplification and array-CGH. Genome Res 13(2):294–307. doi: 10.1101/gr.377203 PubMedCentralCrossRefPubMedGoogle Scholar
  65. 65.
    Esteban JA, Salas M, Blanco L (1993) Fidelity of phi 29 DNA polymerase. Comparison between protein-primed initiation and DNA polymerization. J Biol Chem 268(4):2719–2726PubMedGoogle Scholar
  66. 66.
    Blanco L, Bernad A, Lazaro JM, Martin G, Garmendia C, Salas M (1989) Highly efficient DNA synthesis by the phage phi 29 DNA polymerase. Symmetrical mode of DNA replication. J Biol Chem 264(15):8935–8940PubMedGoogle Scholar
  67. 67.
    Voet T, Kumar P, Van Loo P, Cooke SL, Marshall J, Lin ML, Zamani Esteki M, Van der Aa N, Mateiu L, McBride DJ, Bignell GR, McLaren S, Teague J, Butler A, Raine K, Stebbings LA, Quail MA, D‘Hooghe T, Moreau Y, Futreal PA, Stratton MR, Vermeesch JR, Campbell PJ (2013) Single-cell paired-end genome sequencing reveals structural variation per cell cycle. Nucleic Acids Res 41(12):6119–6138. doi: 10.1093/nar/gkt345 PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    Spits C, Le Caignec C, De Rycke M, Van Haute L, Van Steirteghem A, Liebaers I, Sermon K (2006) Optimization and evaluation of single-cell whole-genome multiple displacement amplification. Hum Mutat 27(5):496–503CrossRefPubMedGoogle Scholar
  69. 69.
    Lasken RS, Stockwell TB (2007) Mechanism of chimera formation during the multiple displacement amplification reaction. BMC Biotechnol 7:19. doi: 10.1186/1472-6750-7-19 PubMedCentralCrossRefPubMedGoogle Scholar
  70. 70.
    Iwamoto K, Bundo M, Ueda J, Nakano Y, Ukai W, Hashimoto E, Saito T, Kato T (2007) Detection of chromosomal structural alterations in single cells by SNP arrays: a systematic survey of amplification bias and optimized workflow. PLoS One 2(12), e1306PubMedCentralCrossRefPubMedGoogle Scholar
  71. 71.
    Murthy KK, Mahboubi VS, Santiago A, Barragan MT, Knoll R, Schultheiss HP, O‘Connor DT, Schork NJ, Rana BK (2005) Assessment of multiple displacement amplification for polymorphism discovery and haplotype determination at a highly polymorphic locus, MC1R. Hum Mutat 26(2):145–152. doi: 10.1002/humu.20199 CrossRefPubMedGoogle Scholar
  72. 72.
    Bergen AW, Haque KA, Qi Y, Beerman MB, Garcia-Closas M, Rothman N, Chanock SJ (2005) Comparison of yield and genotyping performance of multiple displacement amplification and OmniPlex whole genome amplified DNA generated from multiple DNA sources. Hum Mutat 26(3):262–270. doi: 10.1002/humu.20213 CrossRefPubMedGoogle Scholar
  73. 73.
    Rook MS, Delach SM, Deyneko G, Worlock A, Wolfe JL (2004) Whole genome amplification of DNA from laser capture-microdissected tissue for high-throughput single nucleotide polymorphism and short tandem repeat genotyping. Am J Pathol 164(1):23–33PubMedCentralCrossRefPubMedGoogle Scholar
  74. 74.
    Maciejewska A, Jakubowska J, Pawlowski R (2013) Whole genome amplification of degraded and nondegraded DNA for forensic purposes. Int J Legal Med 127(2):309–319. doi: 10.1007/s00414-012-0764-9 PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    Lovmar L, Syvanen AC (2006) Multiple displacement amplification to create a long-lasting source of DNA for genetic studies. Hum Mutat 27(7):603–614. doi: 10.1002/humu.20341 CrossRefPubMedGoogle Scholar
  76. 76.
    Ren Z, Zhou C, Xu Y, Deng J, Zeng H, Zeng Y (2007) Mutation and haplotype analysis for Duchenne muscular dystrophy by single cell multiple displacement amplification. Mol Hum Reprod 13(6):431–436. doi: 10.1093/molehr/gam020 CrossRefPubMedGoogle Scholar
  77. 77.
    Renwick PJ, Lewis CM, Abbs S, Ogilvie CM (2007) Determination of the genetic status of cleavage-stage human embryos by microsatellite marker analysis following multiple displacement amplification. Prenat Diagn 27(3):206–215. doi: 10.1002/pd.1638 CrossRefPubMedGoogle Scholar
  78. 78.
    Hellani A, Abu-Amero K, Azouri J, El-Akoum S (2008) Successful pregnancies after application of array-comparative genomic hybridization in PGS-aneuploidy screening. Reprod Biomed Online 17(6):841–847CrossRefPubMedGoogle Scholar
  79. 79.
    Le Caignec C, Spits C, Sermon K, De Rycke M, Thienpont B, Debrock S, Staessen C, Moreau Y, Fryns JP, Van Steirteghem A, Liebaers I, Vermeesch JR (2006) Single-cell chromosomal imbalances detection by array CGH. Nucleic Acids Res 34(9):e68. doi: 10.1093/nar/gkl336 PubMedCentralCrossRefPubMedGoogle Scholar
  80. 80.
    Evrony GD, Cai X, Lee E, Hills LB, Elhosary PC, Lehmann HS, Parker JJ, Atabay KD, Gilmore EC, Poduri A, Park PJ, Walsh CA (2012) Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151(3):483–496. doi: 10.1016/j.cell.2012.09.035 PubMedCentralCrossRefPubMedGoogle Scholar
  81. 81.
    Hou Y, Song L, Zhu P, Zhang B, Tao Y, Xu X, Li F, Wu K, Liang J, Shao D, Wu H, Ye X, Ye C, Wu R, Jian M, Chen Y, Xie W, Zhang R, Chen L, Liu X, Yao X, Zheng H, Yu C, Li Q, Gong Z, Mao M, Yang X, Yang L, Li J, Wang W, Lu Z, Gu N, Laurie G, Bolund L, Kristiansen K, Wang J, Yang H, Li Y, Zhang X, Wang J (2012) Single-cell exome sequencing and monoclonal evolution of a JAK2-negative myeloproliferative neoplasm. Cell 148(5):873–885. doi: 10.1016/j.cell.2012.02.028 CrossRefPubMedGoogle Scholar
  82. 82.
    Wang J, Fan HC, Behr B, Quake SR (2012) Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm. Cell 150(2):402–412. doi: 10.1016/j.cell.2012.06.030 PubMedCentralCrossRefPubMedGoogle Scholar
  83. 83.
    Xu X, Hou Y, Yin X, Bao L, Tang A, Song L, Li F, Tsang S, Wu K, Wu H, He W, Zeng L, Xing M, Wu R, Jiang H, Liu X, Cao D, Guo G, Hu X, Gui Y, Li Z, Xie W, Sun X, Shi M, Cai Z, Wang B, Zhong M, Li J, Lu Z, Gu N, Zhang X, Goodman L, Bolund L, Wang J, Yang H, Kristiansen K, Dean M, Li Y, Wang J (2012) Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell 148(5):886–895. doi: 10.1016/j.cell.2012.02.025 CrossRefPubMedGoogle Scholar
  84. 84.
    Kroneis T, Geigl JB, El-Heliebi A, Auer M, Ulz P, Schwarzbraun T, Dohr G, Sedlmayr P (2011) Combined molecular genetic and cytogenetic analysis from single cells after isothermal whole-genome amplification. Clin Chem 57(7):1032–1041PubMedCentralCrossRefPubMedGoogle Scholar
  85. 85.
    Kamberov E, Sun T, Bruening E, Pinter J, Sleptsova I, Kurihara T, Makarov V (2004) Amplification and analysis of whole genome and whole transcriptome libraries generated by a DNA polymerization process. US Patent No. US 2004/0209298 A1Google Scholar
  86. 86.
    Fragouli E, Alfarawati S, Spath K, Jaroudi S, Sarasa J, Enciso M, Wells D (2013) The origin and impact of embryonic aneuploidy. Hum Genet 132(9):1001–1013. doi: 10.1007/s00439-013-1309-0 CrossRefPubMedGoogle Scholar
  87. 87.
    Yang Z, Liu J, Collins GS, Salem SA, Liu X, Lyle SS, Peck AC, Sills ES, Salem RD (2012) Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet 5(1):24. doi: 10.1186/1755-8166-5-24 PubMedCentralCrossRefPubMedGoogle Scholar
  88. 88.
    Harton GL, Munne S, Surrey M, Grifo J, Kaplan B, McCulloh DH, Griffin DK, Wells D, Group PGDP (2013) Diminished effect of maternal age on implantation after preimplantation genetic diagnosis with array comparative genomic hybridization. Fertil Steril 100(6):1695–1703. doi: 10.1016/j.fertnstert.2013.07.2002 CrossRefPubMedGoogle Scholar
  89. 89.
    Northrop LE, Treff NR, Levy B, Scott RT Jr (2010) SNP microarray-based 24 chromosome aneuploidy screening demonstrates that cleavage-stage FISH poorly predicts aneuploidy in embryos that develop to morphologically normal blastocysts. Mol Hum Reprod 16(8):590–600. doi: 10.1093/molehr/gaq037 PubMedCentralCrossRefPubMedGoogle Scholar
  90. 90.
    Treff NR, Levy B, Su J, Northrop LE, Tao X, Scott RT Jr (2010) SNP microarray-based 24 chromosome aneuploidy screening is significantly more consistent than FISH. Mol Hum Reprod 16(8):583–589. doi: 10.1093/molehr/gaq039 PubMedCentralCrossRefPubMedGoogle Scholar
  91. 91.
    Fiorentino F, Spizzichino L, Bono S, Biricik A, Kokkali G, Rienzi L, Ubaldi FM, Iammarrone E, Gordon A, Pantos K (2011) PGD for reciprocal and Robertsonian translocations using array comparative genomic hybridization. Hum Reprod 26(7):1925–1935. doi: 10.1093/humrep/der082 CrossRefPubMedGoogle Scholar
  92. 92.
    Alfarawati S, Fragouli E, Colls P, Wells D (2011) First births after preimplantation genetic diagnosis of structural chromosome abnormalities using comparative genomic hybridization and microarray analysis. Hum Reprod 26(6):1560–1574. doi: 10.1093/humrep/der068 CrossRefPubMedGoogle Scholar
  93. 93.
    Bi W, Breman A, Shaw CA, Stankiewicz P, Gambin T, Lu X, Cheung SW, Jackson LG, Lupski JR, Van den Veyver IB, Beaudet AL (2012) Detection of >/=1Mb microdeletions and microduplications in a single cell using custom oligonucleotide arrays. Prenat Diagn 32(1):10–20CrossRefPubMedGoogle Scholar
  94. 94.
    Yang H, Chen X, Wong WH (2011) Completely phased genome sequencing through chromosome sorting. Proc Natl Acad Sci U S A 108(1):12–17. doi: 10.1073/pnas.1016725108 PubMedCentralCrossRefPubMedGoogle Scholar
  95. 95.
    Zong C, Lu S, Chapman AR, Xie XS (2012) Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science 338(6114):1622–1626. doi: 10.1126/science.1229164 PubMedCentralCrossRefPubMedGoogle Scholar
  96. 96.
    Lu S, Zong C, Fan W, Yang M, Li J, Chapman AR, Zhu P, Hu X, Xu L, Yan L, Bai F, Qiao J, Tang F, Li R, Xie XS (2012) Probing meiotic recombination and aneuploidy of single sperm cells by whole-genome sequencing. Science 338(6114):1627–1630. doi: 10.1126/science.1229112 PubMedCentralCrossRefPubMedGoogle Scholar
  97. 97.
    Hou Y, Fan W, Yan L, Li R, Lian Y, Huang J, Li J, Xu L, Tang F, Xie XS, Qiao J (2013) Genome analyses of single human oocytes. Cell 155(7):1492–1506. doi: 10.1016/j.cell.2013.11.040 CrossRefPubMedGoogle Scholar
  98. 98.
    Ni X, Zhuo M, Su Z, Duan J, Gao Y, Wang Z, Zong C, Bai H, Chapman AR, Zhao J, Xu L, An T, Ma Q, Wang Y, Wu M, Sun Y, Wang S, Li Z, Yang X, Yong J, Su XD, Lu Y, Bai F, Xie XS, Wang J (2013) Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients. Proc Natl Acad Sci U S A 110(52):21083–21088. doi: 10.1073/pnas.1320659110 PubMedCentralCrossRefPubMedGoogle Scholar
  99. 99.
    Klein CA, Seidl S, Petat-Dutter K, Offner S, Geigl JB, Schmidt-Kittler O, Wendler N, Passlick B, Huber RM, Schlimok G, Baeuerle PA, Riethmuller G (2002) Combined transcriptome and genome analysis of single micrometastatic cells. Nat Biotechnol 20(4):387–392. doi: 10.1038/nbt0402-387 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Zbigniew Tadeusz Czyz
    • 1
  • Stefan Kirsch
    • 1
  • Bernhard Polzer
    • 1
    Email author
  1. 1.Project Group, Personalized Tumor TherapyFraunhofer Institute for Toxicology and Experimental Medicine (ITEM)RegensburgGermany

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