Human Genetics

, Volume 132, Issue 9, pp 1001–1013 | Cite as

The origin and impact of embryonic aneuploidy

  • Elpida FragouliEmail author
  • Samer Alfarawati
  • Katharina Spath
  • Souraya Jaroudi
  • Jonas Sarasa
  • Maria Enciso
  • Dagan Wells
Original Investigation


Despite the clinical importance of aneuploidy, surprisingly little is known concerning its impact during the earliest stages of human development. This study aimed to shed light on the genesis, progression, and survival of different types of chromosome anomaly from the fertilized oocyte through the final stage of preimplantation development (blastocyst). 2,204 oocytes and embryos were examined using comprehensive cytogenetic methodology. A diverse array of chromosome abnormalities was detected, including many forms never recorded later in development. Advancing female age was associated with dramatic increase in aneuploidy rate and complex chromosomal abnormalities. Anaphase lag and congression failure were found to be important malsegregation causing mechanisms in oogenesis and during the first few mitotic divisions. All abnormalities appeared to be tolerated until activation of the embryonic genome, after which some forms started to decline in frequency. However, many aneuploidies continued to have little impact, with affected embryos successfully reaching the blastocyst stage. Results from the direct analyses of female meiotic divisions and early embryonic stages suggest that chromosome errors present during preimplantation development have origins that are more varied than those seen in later pregnancy, raising the intriguing possibility that the source of aneuploidy might modulate impact on embryo viability. The results of this study also narrow the window of time for selection against aneuploid embryos, indicating that most survive until the blastocyst stage and, since they are not detected in clinical pregnancies, must be lost around the time of implantation or shortly thereafter.


Meiotic Division Blastocyst Stage Cleavage Stage Preimplantation Genetic Screening Preimplantation Development 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dagan Wells is supported by the NIHR Biomedical Research Centre Oxford.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Alfarawati S, Fragouli E, Colls P, Stevens J, Gutiérrez-Mateo C, Schoolcraft WB, Katz-Jaffe MG, Wells D (2011) The relationship between blastocyst morphology, chromosomal abnormality, and embryo gender. Fertil Steril 95:520–524PubMedCrossRefGoogle Scholar
  2. Braude P, Bolton V, Moore S (1988) Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature 332:459–461PubMedCrossRefGoogle Scholar
  3. Carrell DT, Wilcox AL, Lowy L, Peterson CM, Jones KP, Erickson L, Campbell B, Branch DW, Hatasaka HH (2003) Elevated sperm chromosome aneuploidy and apoptosis in patients with unexplained recurrent pregnancy loss. Obstet Gynecol 101:1229–1235PubMedCrossRefGoogle Scholar
  4. Centers for Disease Control and Prevention (2013) 2010 Assisted Reproductive Technology National Summary ReportGoogle Scholar
  5. Christopikou D, Tsorva E, Economou K, Shelley P, Davies S, Mastrominas M, Handyside AH (2013) Polar body analysis by array comparative genomic hybridization accurately predicts aneuploidies of maternal meiotic origin in cleavage stage embryos of women of advanced maternal age. Hum Reprod. [Epub ahead of print] PMID: 23477909 [PubMed—as supplied by publisher]Google Scholar
  6. Clouston HJ, Herbert M, Fenwick J, Murdoch AP, Wolstenholme J (2002) Cytogenetic analysis of human blastocysts. Prenat Diagn 22:1143–1152PubMedCrossRefGoogle Scholar
  7. Colls P, Escudero T, Cekleniak N, Sadowy S, Cohen J, Munné S (2007) Increased efficiency of preimplantation genetic diagnosis for infertility using “no result rescue”. Fertil Steril 88:53–61PubMedCrossRefGoogle Scholar
  8. Coonen E, Derhaag JG, Dumoulin JC, van Wissen LC, Bras M, Janssen M, Evers JL, Geraedts JP (2004) Anaphase lagging mainly explains chromosomal mosaicism in human preimplantation embryos. Hum Reprod 19:316–324PubMedCrossRefGoogle Scholar
  9. Cremer T, Cremer C (2001) Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Nat Rev Genet 2:292–301PubMedCrossRefGoogle Scholar
  10. Daphnis DD, Delhanty JD, Jerkovic S, Geyer J, Craft I, Harper JC (2005) Detailed FISH analysis of day 5 human embryos reveals the mechanisms leading to mosaic aneuploidy. Hum Reprod 20:129–137PubMedCrossRefGoogle Scholar
  11. Delhanty JD, Harper JC, Ao A, Handyside AH, Winston RM (1997) Multicolour FISH detects frequent chromosomal mosaicism and chaotic division in normal preimplantation embryos from fertile patients. Hum Genet 99:755–760PubMedCrossRefGoogle Scholar
  12. Fragouli E, Katz-Jaffe M, Alfarawati S, Stevens J, Colls P, Goodall NN, Tormasi S, Gutierrez-Mateo C, Prates R, Schoolcraft WB, Munne S, Wells D (2010) Comprehensive chromosome screening of polar bodies and blastocysts from couples experiencing repeated implantation failure. Fertil Steril 94:875–887PubMedCrossRefGoogle Scholar
  13. Fragouli E, Alfarawati S, Daphnis DD, Goodall NN, Mania A, Griffiths T, Gordon A, Wells D (2011a) Cytogenetic analysis of human blastocysts with the use of FISH, CGH and aCGH: scientific data and technical evaluation. Hum Reprod 26:480–490PubMedCrossRefGoogle Scholar
  14. Fragouli E, Alfarawati S, Goodall NN, Sanchez–Garcıa JF, Colls P, Wells D (2011b) The cytogenetics of polar bodies: insights into female meiosis and the diagnosis of aneuploidy. Mol Hum Reprod 5:286–295CrossRefGoogle Scholar
  15. Fragouli E, Wells D, Iager AE, Kayisli UA, Patrizio P (2012) Alteration of gene expression in human cumulus cells as a potential indicator of oocyte aneuploidy. Hum Reprod 27:2559–2568PubMedCrossRefGoogle Scholar
  16. Gabriel AS, Thornhill AR, Ottolini CS, Gordon A, Brown AP, Taylor J, Bennett K, Handyside A, Griffin DK (2011) Array comparative genomic hybridisation on first polar bodies suggests that non-disjunction is not the predominant mechanism leading to aneuploidy in humans. J Med Genet 48:433–437PubMedCrossRefGoogle Scholar
  17. Gutierrez-Mateo C, Colls P, Sanchez-Garcıa 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 95:953–958PubMedCrossRefGoogle Scholar
  18. Handyside AH, Montag M, Magli MC, Repping S, Harper J, Schmutzler A, Vesela K, Gianaroli L, Geraedts J (2012) Multiple meiotic errors caused by predivision of chromatids in women of advanced maternal age undergoing in vitro fertilisation. Eur J Hum Genet 20:742–747PubMedCrossRefGoogle Scholar
  19. Hassold T, Hunt P (2001) To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2:280–291PubMedCrossRefGoogle Scholar
  20. Hassold T, Pettay D, Robinson A, Uchida I (1992) Molecular studies of parental origin and mosaicism in 45, X conceptuses. Hum Genet 89:647–652PubMedCrossRefGoogle Scholar
  21. Hassold T, Hall H, Hunt P (2007) The origin of human aneuploidy: where we have been, where we are going. Hum Mol Genet 16:R203–R208PubMedCrossRefGoogle Scholar
  22. Kuliev A, Cieslak J, Ilkevitch Y, Verlinsky Y (2003) Chromosomal abnormalities in a series of 6,733 human oocytes in preimplantation diagnosis for age-related aneuploidies. RBM Online 6:54–59PubMedGoogle Scholar
  23. Lebedev I (2011) Mosaic aneuploidy in early fetal losses. Cytogenet Genome Res 133:169–183PubMedCrossRefGoogle Scholar
  24. Lestou VS, Kalousek DK (1998) Confined placental mosaicism and intrauterine fetal growth. Arch Dis Child Fetal Neonatal Ed 79:223–226CrossRefGoogle Scholar
  25. Li M, DeUgarte CM, Surrey M, Danzer H, DeCherney A, Hill DL (2005) Fluorescence in situ hybridization reanalysis of day–6 human blastocysts diagnosed with aneuploidy on day 3. Fertil Steril 84:1395–1400PubMedCrossRefGoogle Scholar
  26. Liu P, Erez A, Nagamani SCS, Dhar SU, Kołodziejska KE, Dharmadhikari AV, Cooper ML, Wiszniewska J, Zhang F, Withers MA, Bacino CA, Campos-Acevedo LD, Delgado MR, Freedenberg D, Garnica A, Grebe TA, Hernandez-Almaguer D, Immken LD, Lalani SR, McLean SD, Northrup H, Scaglia F, Strathearn L, Trapane P, Kang SHL, Patel A, Cheung SW, Hastings PJ, Stankiewicz P, Lupski JR, Bi W (2011) Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146:889–903PubMedCrossRefGoogle Scholar
  27. Magli MC, Montag M, Köster M, Muzi L, Geraedts J, Collins J, Goossens V, Handyside AH, Harper J, Repping S, Schmutzler A, Vesela K, Gianaroli L (2011) Polar body array CGH for prediction of the status of the corresponding oocyte. Part II: technical aspects. Hum Reprod 26:3181–3185PubMedCrossRefGoogle Scholar
  28. Mantzouratou A, Mania A, Fragouli E, Xanthopoulou L, Tashkandi S, Fordham K, Ranieri DM, Doshi A, Nuttall S, Harper JC, Serhal P, Delhanty JD (2007) Variable aneuploidy mechanisms in embryos from couples with poor reproductive histories undergoing preimplantation genetic screening. Hum Reprod 22:1844–1853PubMedCrossRefGoogle Scholar
  29. Menasha J, Levy B, Hirschhorn K, Kardon NB (2005) Incidence and spectrum of chromosome abnormalities in spontaneous abortions: new insights from a 12-year study. Genet Med 7:251–263PubMedCrossRefGoogle Scholar
  30. Mertzanidou A, Spits C, Nguyen HT, Van de Velde H, Sermon K (2013) Evolution of aneuploidy up to Day 4 of human preimplantation development. Hum Reprod. [Epub ahead of print] PMID: 23526301 [PubMed—as supplied by publisher]Google Scholar
  31. Munne S, Marquez C, Magli C, Morton P, Morrison L (1998) Scoring criteria for preimplantation genetic diagnosis of numerical abnormalities for chromosomes X, Y, 13, 16, 18 and 21. Mol Hum Reprod 4:863–870PubMedCrossRefGoogle Scholar
  32. Munné S, Sandalinas M, Escudero T, Márquez C, Cohen J (2002) Chromosome mosaicism in cleavage-stage human embryos: evidence of a maternal age effect. RBM Online 4:223–232PubMedGoogle Scholar
  33. Northrop LE, Treff NR, Levy B, Scott RT (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 16:590–600PubMedCrossRefGoogle Scholar
  34. Pellestor F, Andreo B, Arnal F, Humaeu C, Demaille J (2003) Maternal ageing and chromosomal abnormalities: new data drawn from in vitro unfertilized human oocytes. Hum Genet 112:195–203PubMedGoogle Scholar
  35. Petit FM, Frydman N, Benkhalifa M, Le Du A, Aboura A, Fanchin R, Frydman R, Tachdjian G (2005) Could sperm aneuploidy rate determination be used as a predictive test before intracytoplasmic sperm injection? J Androl 26:235–241PubMedGoogle Scholar
  36. Platteau P, Staessen C, Michiels A, Van Steirteghem A, Liebaers I, Devroey P (2005) Preimplantation genetic diagnosis for aneuploidy screening in women older than 37 years. Fertil Steril 84:319–324PubMedCrossRefGoogle Scholar
  37. Rubio C, Rodrigo L, Mercader A, Mateu E, Buendía P, Pehlivan T, Viloria T, De los Santos MJ, Simón C, Remohí J, Pellicer A (2007) Impact of chromosomal abnormalities on preimplantation embryo development. Prenat Diagn 27:748–756PubMedCrossRefGoogle Scholar
  38. Sandalinas M, Sadowy S, Alikani M, Calderon G, Cohen J, Munne S (2001) Developmental ability of chromosomally abnormal human embryos to develop to the blastocyst stage. Hum Reprod 16:1954–1958PubMedCrossRefGoogle Scholar
  39. Santos MA, Teklenburg G, Macklon NS, Van Opstal D, Schuring-Blom GH, Krijtenburg PJ, de Vreeden-Elbertse J, Fauser BC, Baart EB (2010) The fate of the mosaic embryo: chromosomal constitution and development of Day 4, 5 and 8 human embryos. Hum Reprod 25:1916–1926PubMedCrossRefGoogle Scholar
  40. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Quail MA, Burton J, Swerdlow H, Carter NP, Morsberger LA, Iacobuzio-Donahue C, Follows GA, Green AR, Flanagan AM, Stratton MR, Futreal PA, Campbell PJ (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:27–40PubMedCrossRefGoogle Scholar
  41. Vanneste E, Voet T, Le Caignec C, Ampe M, Konings P, Melotte C, Debrock S, Amyere M, Vikkula M, Schuit F, Fryns JP, Verbeke G, D’Hooghe T, Moreau Y, Vermeesch JR (2009) Chromosome instability is common in human cleavage-stage embryos. Nat Med 15:577–583PubMedCrossRefGoogle Scholar
  42. Verpoest W, Fauser BC, Papanikolaou E, Staessen C, Van Landuyt L, Donoso P, Tournaye H, Liebaers I, Devroey P (2008) Chromosomal aneuploidy in embryos conceived with unstimulated cycle IVF. Hum Reprod 10:2369–2371CrossRefGoogle Scholar
  43. Voullaire L, Slater H, Williamson R, Wilton L (2000) Chromosome analysis of blastomeres from human embryos by using comparative genomic hybridization. Hum Genet 106:210–217PubMedCrossRefGoogle Scholar
  44. 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 6:1055–1062PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Elpida Fragouli
    • 1
    • 2
    Email author
  • Samer Alfarawati
    • 2
  • Katharina Spath
    • 1
  • Souraya Jaroudi
    • 2
  • Jonas Sarasa
    • 2
  • Maria Enciso
    • 1
  • Dagan Wells
    • 1
    • 2
  1. 1.Nuffield Department of Obstetrics and GynaecologyUniversity of OxfordOxfordUK
  2. 2.Reprogenetics UKOxfordUK

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