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Chromosome instability is common in human cleavage-stage embryos

Abstract

Chromosome instability is a hallmark of tumorigenesis. This study establishes that chromosome instability is also common during early human embryogenesis. A new array-based method allowed screening of genome-wide copy number and loss of heterozygosity in single cells. This revealed not only mosaicism for whole-chromosome aneuploidies and uniparental disomies in most cleavage-stage embryos but also frequent segmental deletions, duplications and amplifications that were reciprocal in sister blastomeres, implying the occurrence of breakage-fusion-bridge cycles. This explains the low human fecundity and identifies post-zygotic chromosome instability as a leading cause of constitutional chromosomal disorders.

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Figure 1: Genome-wide CNV and LOH detection in single cells.
Figure 2: Compilation of CNV and LOH data of single blastomeres per embryo.
Figure 3: Genesis of simple and complex terminal imbalances.

References

  1. Geigl, J.B., Obenauf, A.C., Schwarzbraun, T. & Speicher, M.R. Defining 'chromosomal instability'. Trends Genet. 24, 64–69 (2008).

    Article  CAS  Google Scholar 

  2. Lengauer, C., Kinzler, K.W. & Vogelstein, B. Genetic instability in colorectal cancers. Nature 386, 623–627 (1997).

    Article  CAS  Google Scholar 

  3. Gao, C. et al. Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations. Proc. Natl. Acad. Sci. USA 104, 8995–9000 (2007).

    Article  CAS  Google Scholar 

  4. Rajagopalan, H. & Lengauer, C. Aneuploidy and cancer. Nature 432, 338–341 (2004).

    Article  CAS  Google Scholar 

  5. Delhanty, J.D. Mechanisms of aneuploidy induction in human oogenesis and early embryogenesis. Cytogenet. Genome Res. 111, 237–244 (2005).

    Article  CAS  Google Scholar 

  6. Voullaire, L., Slater, H., Williamson, R. & Wilton, L. Chromosome analysis of blastomeres from human embryos by using comparative genomic hybridization. Hum. Genet. 106, 210–217 (2000).

    Article  CAS  Google Scholar 

  7. Wells, D. & Delhanty, J.D. Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization. Mol. Hum. Reprod. 6, 1055–1062 (2000).

    Article  CAS  Google Scholar 

  8. Daphnis, D.D. et al. Analysis of the evolution of chromosome abnormalities in human embryos from Day 3 to 5 using CGH and FISH. Mol. Hum. Reprod. 14, 117–125 (2008).

    Article  CAS  Google Scholar 

  9. Harper, J. et al. What next for preimplantation genetic screening? Hum. Reprod. 23, 478–480 (2008).

    Article  Google Scholar 

  10. Le Caignec, C. et al. Single-cell chromosomal imbalances detection by array CGH. Nucleic Acids Res. 34, e68 (2006).

    Article  Google Scholar 

  11. Fiegler, H. et al. High resolution array–CGH analysis of single cells. Nucleic Acids Res. 35, e15 (2007).

    Article  Google Scholar 

  12. Iwamoto, K. et al. Detection of chromosomal structural alterations in single cells by SNP arrays: a systematic survey of amplification bias and optimized workflow. PLoS One 2, e1306 (2007).

    Article  Google Scholar 

  13. Ballif, B.C., Yu, W., Shaw, C.A., Kashork, C.D. & Shaffer, L.G. Monosomy 1p36 breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cycles are involved in generating terminal deletions. Hum. Mol. Genet. 12, 2153–2165 (2003).

    Article  CAS  Google Scholar 

  14. Rossi, E. et al. Duplications in addition to terminal deletions are present in a proportion of ring chromosomes. Clues to the mechanisms of formation. J. Med. Genet. 45, 147–154 (2008).

    Article  CAS  Google Scholar 

  15. Marshall, O.J., Chueh, A.C., Wong, L.H. & Choo, K.H. Neocentromeres: new insights into centromere structure, disease development, and karyotype evolution. Am. J. Hum. Genet. 82, 261–282 (2008).

    Article  CAS  Google Scholar 

  16. Ballif, B.C. et al. Detecting sex chromosome anomalies and common triploidies in products of conception by array-based comparative genomic hybridization. Prenat. Diagn. 26, 333–339 (2006).

    Article  CAS  Google Scholar 

  17. Kotzot, D. Abnormal phenotypes in uniparental disomy (UPD): fundamental aspects and a critical review with bibliography of UPD other than 15. Am. J. Med. Genet. 82, 265–274 (1999).

    Article  CAS  Google Scholar 

  18. Kotzot, D. Complex and segmental uniparental disomy (UPD): review and lessons from rare chromosomal complements. J. Med. Genet. 38, 497–507 (2001).

    Article  CAS  Google Scholar 

  19. Perry, J., Slater, H.R. & Choo, K.H. Centric fission—simple and complex mechanisms. Chromosome Res. 12, 627–640 (2004).

    Article  CAS  Google Scholar 

  20. Pipiras, E., Coquelle, A., Bieth, A. & Debatisse, M. Interstitial deletions and intrachromosomal amplification initiated from a double-strand break targeted to a mammalian chromosome. EMBO J. 17, 325–333 (1998).

    Article  CAS  Google Scholar 

  21. Artandi, S.E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000).

    Article  CAS  Google Scholar 

  22. Bignell, G.R. et al. Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution. Genome Res. 17, 1296–1303 (2007).

    Article  CAS  Google Scholar 

  23. Munné, S. et al. Treatment-related chromosome abnormalities in human embryos. Hum. Reprod. 12, 780–784 (1997).

    Article  Google Scholar 

  24. Weghofer, A. et al. The impact of LH-containing gonadotropins on diploidy rates in preimplantation embryos: long protocol stimulation. Hum. Reprod. 23, 499–503 (2008).

    Article  CAS  Google Scholar 

  25. Harper, J.C. et al. ESHRE PGD consortium data collection VII: cycles from January to December 2004 with pregnancy follow-up to October 2005. Hum. Reprod. 23, 741–755 (2008).

    Article  CAS  Google Scholar 

  26. Rubio, C. et al. Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum. Reprod. 18, 182–188 (2003).

    Article  CAS  Google Scholar 

  27. Munné, S. et al. Increased rate of aneuploid embryos in young women with previous aneuploid conceptions. Prenat. Diagn. 24, 638–643 (2004).

    Article  Google Scholar 

  28. Baart, E.B. et al. Preimplantation genetic screening reveals a high incidence of aneuploidy and mosaicism in embryos from young women undergoing IVF. Hum. Reprod. 21, 223–233 (2006).

    Article  CAS  Google Scholar 

  29. Braude, P., Bolton, V. & Moore, S. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature 332, 459–461 (1988).

    Article  CAS  Google Scholar 

  30. Macklon, N.S., Geraedts, J.P. & Fauser, B.C. Conception to ongoing pregnancy: the 'black box' of early pregnancy loss. Hum. Reprod. Update 8, 333–343 (2002).

    Article  CAS  Google Scholar 

  31. Pflueger, S. Cytogenetics of spontaneous abortion. in The Principles of Clinical Cytogenetics (eds. Gersen, S. & Keagle, M.) 317–343 (Humana Press, New Jersey, 1999).

    Chapter  Google Scholar 

  32. Fritz, B. et al. Cytogenetic analyses of culture failures by comparative genomic hybridisation (CGH)—re-evaluation of chromosome aberration rates in early spontaneous abortions. Eur. J. Hum. Genet. 9, 539–547 (2001).

    Article  CAS  Google Scholar 

  33. Benkhalifa, M. et al. Array comparative genomic hybridization profiling of first-trimester spontaneous abortions that fail to grow in vitro. Prenat. Diagn. 25, 894–900 (2005).

    Article  CAS  Google Scholar 

  34. Schinzel, A. Catalogue of Unbalanced Chromosome Aberrations in Man (Walter de Gruyter, New York, 2001).

    Google Scholar 

  35. Staessen, C. et al. Comparison of blastocyst transfer with or without preimplantation genetic diagnosis for aneuploidy screening in couples with advanced maternal age: a prospective randomized controlled trial. Hum. Reprod. 19, 2849–2858 (2004).

    Article  Google Scholar 

  36. Li, M. et al. Fluorescence in situ hybridization reanalysis of day-6 human blastocysts diagnosed with aneuploidy on day 3. Fertil. Steril. 84, 1395–1400 (2005).

    Article  Google Scholar 

  37. Munné, S. et al. Self-correction of chromosomally abnormal embryos in culture and implications for stem cell production. Fertil. Steril. 84, 1328–1334 (2005).

    Article  Google Scholar 

  38. Yurov, Y.B. et al. Aneuploidy and confined chromosomal mosaicism in the developing human brain. PLoS One 2, e558 (2007).

    Article  Google Scholar 

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Acknowledgements

We thank all families who participated in the study, the Leuven University Fertility Center for technical assistance and S. Jackmaert for her help with the SNP arrays. We are also grateful to the Mapping Core and Map finishing groups of the Wellcome Trust Sanger Institute for initial BAC clone supply and verification and to the microarray facility of the Flanders Interuniversity Institute for Biotechnology for their help in spotting the arrays. We would like to thank C. Spiessens, E. Legius, T. de Ravel de l'Argentière, H. van Esch and K. Devriendt for the critical reading of the manuscript. This work was made possible by grants from the Institute for the Promotion of Innovation through Science and Technology (IWT-Flanders) (SBO-60848) and GOA/2006/12 and Center of Excellence SymBioSys (Research Council K.U.Leuven EF/05/007) to J.R.V. and Fonds de la Recherche Scientifique to M.V. E.V. was supported by the Institute for the Promotion of Innovation through Science and Technology in Flanders.

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Authors and Affiliations

Authors

Contributions

E.V., T.V. and J.R.V. designed the experiments and wrote the manuscript. E.V., T.V., C.L.C. and C.M. conducted the experiments. M. Ampe, G.V., P.K. and Y.M. developed the statistical algorithms and software for data analysis. M. Amyere, M.V. and F.S. provided expertise on SNP typing. J.-P.F. performed the genetic counseling of the couples opting for PGD. T.D. and S.D. performed IVF and provided the embryos. J.R.V. supervised.

Corresponding author

Correspondence to Joris R Vermeesch.

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Supplementary Text and Figures

Supplementary Figs. 1–3, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 12875 kb)

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Vanneste, E., Voet, T., Le Caignec, C. et al. Chromosome instability is common in human cleavage-stage embryos. Nat Med 15, 577–583 (2009). https://doi.org/10.1038/nm.1924

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