In vitro fertilization does not increase the incidence of de novo copy number alterations in fetal and placental lineages

Esteki, Masoud Zamani; Viltrop, Triin; Tšuiko, Olga; Tiirats, Airi; Koel, Mariann; Nõukas, Margit; Žilina, Olga; Teearu, Katre; Marjonen, Heidi; Kahila, Hanna; Meekels, Jeroen; Söderström‐Anttila, Viveca; Suikkari, Anne‐Maria; Tiitinen, Aila; Mägi, Reedik; Kõks, Sulev; Kaminen‐Ahola, Nina; Kurg, Ants; Voet, Thierry; Vermeesch, Joris Robert; Salumets, Andres

doi:10.1038/s41591-019-0620-2

Cited by 42 publications

(29 citation statements)

References 49 publications

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“…One persistent concern with all studies of preimplantation embryos is the possibility that IVF culture conditions impact chromosome stability. Indeed, such impacts have been documented by comparing in vitro versus in vivo matured bovine embryos (Tšuiko et al 2017), although no such differences have been detected in humans during preimplantation development (Munné et al 2020) or at live birth (Zamani Esteki et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

2020

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Less than half of human zygotes survive to birth, primarily due to aneuploidies of meiotic or mitotic origin. Mitotic errors generate chromosomal mosaicism, defined by multiple cell lineages with distinct chromosome complements. The incidence and impacts of mosaicism in human embryos remain controversial, with most previous studies based on bulk DNA assays or comparisons of multiple biopsies of few embryonic cells. Single-cell genomic data provide an opportunity to quantify mosaicism on an embryo-wide scale. To this end, we extended an approach to infer aneuploidies based on dosage-associated changes in gene expression by integrating signatures of allelic imbalance. We applied this method to published single-cell RNA sequencing data from 74 human embryos, spanning the morula to blastocyst stages. Our analysis revealed widespread mosaic aneuploidies, with 59 of 74 (80%) embryos harboring at least one putative aneuploid cell (1% FDR). By clustering copy number calls, we reconstructed histories of chromosome segregation, inferring that 55 (74%) embryos possessed mitotic aneuploidies and 23 (31%) embryos possessed meiotic aneuploidies. We found no significant enrichment of aneuploid cells in the trophectoderm compared to the inner cell mass, although we do detect such enrichment in data from later postimplantation stages. Finally, we observed that aneuploid cells up-regulate immune response genes and down-regulate genes involved in proliferation, metabolism, and protein processing, consistent with stress responses documented in other stages and systems. Together, our work provides a high-resolution view of aneuploidy in preimplantation embryos, and supports the conclusion that low-level mosaicism is a common feature of early human development.

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Section: Discussionmentioning

confidence: 99%

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

2020

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“…These multiple de novo CNVs were associated with replication‐based mechanisms, evidenced by short microhomologies and microhomeologies near breakpoints, and mosaicism was not observed (Liu et al, 2017). Another case of an SGA infant was reported with a placenta carrying 3 “partial trisomies”: a 22 Mb dup(6)(p22.3pter), a 5.8 Mb dup(9)(q34.13), and a 22 Mb dup(21)(q21.2qter), present in only one of five placenta biopsies (Zamani Esteki et al, 2019). The alterations were all terminal, in contrast to the smaller interstitial duplications we identified.…”

Section: Discussionmentioning

confidence: 99%

Confined placental mosaicism involving multiple de novo copy number variants associated with fetal growth restriction: A case report

Gobbo

Yuan

Robinson

2021

American J of Med Genetics Pt A

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The presence of multiple large (>1 Mb) copy number variants (CNVs) in non‐malignant tissue is rare in human genetics. We present a liveborn male with a birth weight below the first percentile associated with placental mosaicism involving eight 2.4–3.9 Mb de novo duplications. We found that the duplications likely co‐localized to the same cells, were mosaic in the placenta, and impacted maternal and paternal chromosomes. In addition, 27.4 Mb and 240 genes were duplicated in affected cells, including candidate placental genes KISS1 and REN. We ruled out involvement of homologous recombination‐based mechanisms or an altered epigenome in generating the CNVs. This case highlights the diversity of genetic abnormalities in the human placenta and the gaps in our knowledge of how such errors arise.

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“…However, there was no difference in aneuploidy levels between human IVF embryos and in vivo-derived embryos, obtained via uterine lavage (Munné et al 2019). Similarly, no significant difference between IVF and natural conception was observed at live birth (Zamani Esteki et al 2019b). Although the latter study identified sporadic de novo genomic aberrations in 10% of pregnancies, they were scattered across the genome, representing random events of postzygotic aneuploidy that had no functional consequences on placental biology or fetal health.…”

Section: Consequence Of Chromosomal Mosaicism On Embryo Developmentmentioning

confidence: 77%

PREIMPLANTATION GENETIC TESTING: Single-cell technologies at the forefront of PGT and embryo research

et al. 2020

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While chromosomal mosaicism in the embryo was observed already in the ‘90s using both karyotyping and FISH technologies, the full extent of this phenomenon and the overall awareness of the consequences of chromosomal instability on embryo development has only come with the advent of sophisticated single-cell technologies. High-throughput techniques, such as DNA microarrays and massive parallel sequencing, have shifted single-cell genome research from evaluating a few loci at a time to the ability to perform comprehensive screening of all 24 chromosomes. The development of genome-wide single-cell haplotyping methods have also enabled for simultaneous detection of single-gene disorders and aneuploidy using a single universal protocol. Today, three decades later haplotyping-based embryo testing is performed worldwide to reliably detect virtually any Mendelian hereditary disease with a known cause, including autosomal-recessive, autosomal-dominant and X-linked disorders. At the same time, these single-cell assays have also provided unique insight into the complexity of embryo genome dynamics, by elucidating mechanistic origin, nature and developmental fate of embryonic aneuploidy. Understanding the impact of post-zygotically acquired genomic aberrations on embryo development is essential to determine the still controversial diagnostic value of aneuploidy screening. For that reason, considerable efforts have been put into linking the genetic constitution of the embryo not only to its morphology and implantation potential, but more importantly to its transcriptome using single-cell RNA sequencing. Collectively, these breakthrough technologies have revolutionized single-cell research and clinical practice in assisted reproduction and led to unique discoveries in early embryogenesis.

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In vitro fertilization does not increase the incidence of de novo copy number alterations in fetal and placental lineages

Cited by 42 publications

References 49 publications

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

Confined placental mosaicism involving multiple de novo copy number variants associated with fetal growth restriction: A case report

PREIMPLANTATION GENETIC TESTING: Single-cell technologies at the forefront of PGT and embryo research

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