Although chromosomal instability (CIN) is a common phenomenon in cleavage-stage embryogenesis following in vitro fertilization (IVF)1,2,3, its rate in naturally conceived human embryos is unknown. CIN leads to mosaic embryos that contain a combination of genetically normal and abnormal cells, and is significantly higher in in vitro-produced preimplantation embryos as compared to in vivo-conceived preimplantation embryos4. Even though embryos with CIN-derived complex aneuploidies may arrest between the cleavage and blastocyst stages of embryogenesis5,6, a high number of embryos containing abnormal cells can pass this strong selection barrier7,8. However, neither the prevalence nor extent of CIN during prenatal development and at birth, following IVF treatment, is well understood. Here we profiled the genomic landscape of fetal and placental tissues postpartum from both IVF and naturally conceived children, to investigate the prevalence and persistence of large genetic aberrations that probably arose from IVF-related CIN. We demonstrate that CIN is not preserved at later stages of prenatal development, and that de novo numerical aberrations or large structural DNA imbalances occur at similar rates in IVF and naturally conceived live-born neonates. Our findings affirm that human IVF treatment has no detrimental effect on the chromosomal constitution of fetal and placental lineages.
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All SNP array data generated in this study were deposited in the NCBI Gene Expression Omnibus under accession no. GSE93353.
Custom code is available from the author upon reasonable request.
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We gratefully thank all families that participated in this study in Estonia and Finland. This research was funded by an institutional research grant from the Estonian Ministry of Education and Research (no. IUT34-16 to A.S.); Enterprise Estonia (grant no. EU48695 to A.S.); the Horizon 2020 innovation (WIDENLIFE) (grant no. EU692065 to A.K.); the European Union’s FP7 Marie Curie Industry-Academia Partnerships and Pathways (grant no. EU324509 to A.S.); the Helsinki University Hospital fund (to A.Tiitinen); the Faculty of Medicine, University of Helsinki fund (to N.K.-A.); the EVA (Erfelijkheid Voortplanting & Aanleg) specialty program fund of Maastricht University Medical Centre (MUMC+) (to M.Z.E.); the Estonian Research Council (grant nos. IUT20-60 and IUT24-6); the European Union through the European Regional Development Fund Project (nos. 2014-2020.4.01.15-0012 GENTRANSMED and 2014-2020.4.01.16-0125 to R.M.); and KU Leuven funding (no. C1/018) and FWO grant (no. G.0392.14N to J.R.V. and T.Voet). We thank B. de Greef, A. van Montfoort and N. Davarzani for statistical consultations.
M.Z.E., J.R.V. and T.Voet are co-inventors on patent application ZL913096-PCT/EP2014/068315-WO/2015/028576, ‘Haplotyping and copy-number typing using polymorphic variant allelic frequencies’.
Peer review information Brett Benedetti was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The mosaic partial trisomies (purple arrows) on Chr6, Chr9 and Chr21 are only present in one biopsy (Biopsy I) out of all the spatially different biopsies of P172 placenta.
Extended Data Fig. 3 The full Chr 2 mosaic trisomy is persistently present across the P106 placenta.
The full Chr 2 mosaic trisomy (purple arrows) is persistently present in all the spatially different biopsies of P106 placenta.
Extended Data Fig. 5 Determining fetal and maternal compartments in placenta DNA-samples using haplarithmisis.
We performed an in silico simulation by combining genotypes of the child and the mother with different proportions (from 1%Mother : 99%Child to 99%Mother : 1%Child) and deduced haplarithm profiles for each of these combinations, representing fetal and maternal compartments in placenta DNA samples (see also Source Data).
Extended Data Fig. 6 Proof-of-concept assay for the detection of mosaic aberrations using droplet digital PCR.
We mixed up a DNA sample from a trisomy 21 (copy number, CN=3) cell line with a DNA sample derived from a normal diploid cell line (CN=2) at different ratios, creating admixture series of DNA samples with 100%, 75%, 50%, 25%, 10–15% and 0% of abnormal alleles. Mosaic DNA samples were normalized to the number of fully diploid control (i.e. 0% abnormal). Each circle and error bar indicate mean and standard deviation, respectively, of four independent measurements.
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Zamani Esteki, M., Viltrop, T., Tšuiko, O. et al. In vitro fertilization does not increase the incidence of de novo copy number alterations in fetal and placental lineages. Nat Med 25, 1699–1705 (2019). https://doi.org/10.1038/s41591-019-0620-2
Confined placental mosaicism involving multiple de novo copy number variants associated with fetal growth restriction: A case report
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