Origins and mechanisms leading to aneuploidy in human eggs

Wartosch, Lena; Schindler, Karen; Schuh, Melina; Gruhn, Jennifer R.; Hoffmann, Eva R.; McCoy, Rajiv C.; Xing, Jinchuan

doi:10.1002/pd.5927

Cited by 45 publications

(34 citation statements)

References 107 publications

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“…Oocyte-stored SMC3 is required to support the integrity of the zygotic genome during the very first round of DNA replication and sister chromatid segregation to pass successfully through the first and second mitotic divisions in the embryo. Our findings are broadly consistent with the recent proposal that meiosis-derived aneuploidy persists into embryogenesis, but that mitosis-derived aneuploidy triggers arrest ( Wartosch et al, 2021 ). Furthermore, our results suggest that elongated spindles in zygotes and micronuclei in the two-cell embryo are visual markers of poor developmental outcomes, which could be useful for in vitro fertilization.…”

Section: Discussionsupporting

confidence: 92%

Maternal Smc3 protects the integrity of the zygotic genome through DNA replication and mitosis

2021

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Aneuploidy is frequently observed in oocytes and early embryos, begging the question of how genome integrity is monitored and preserved during this critical period. SMC3 is a subunit of the cohesin complex that supports genome integrity, but its role in maintaining the genome in this window of mammalian development is unknown. We discovered that although depletion of Smc3 following meiotic S phase in mouse oocytes allowed accurate meiotic chromosome segregation, adult females were infertile. We provide evidence that DNA lesions accumulated following S phase in SMC3-deficient zygotes, followed by mitosis with lagging chromosomes, elongated spindles, micronuclei, and arrest at the 2-cell stage. Remarkably, although centromeric cohesion was defective, the dosage of SMC3 was sufficient to enable embryogenesis in juvenile mutant females. Our findings suggest that despite previous reports of aneuploidy in early embryos, chromosome missegregation in zygotes halts embryogenesis at the 2-cell stage. Smc3 is a maternal gene with essential functions in repair of spontaneous damage associated with DNA replication and subsequent chromosome segregation in zygotes, making cohesin a key protector of the zygotic genome.

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Section: Discussionsupporting

confidence: 92%

Maternal Smc3 protects the integrity of the zygotic genome through DNA replication and mitosis

2021

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“…A number of studies have been published describing the origins and mechanisms leading to aneuploidy in ageing human oocytes, arising due to chromosome segregation errors during meiosis I and II, mainly during the two consecutive cell divisions and during the two cell cycle arrests [ 4 , 20 ]. Current views based on recent oocyte studies suggest that less stringent spindle assembly checkpoint (SAC), spindle instability, multipolarity and merotelic attachments during meiosis I contribute to high aneuploidy in both younger and older women [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…In humans, reproduction is regarded as a highly inefficient process. A major factor lies with the uniquely high frequency of aneuploidy in human gametes and embryos [ 1 , 2 , 3 , 4 ]. Autosomal aneuploidy in human gametes arises mostly from errors in meiosis I or II of oogenesis, but mosaicism from errors in early embryogenesis is also a major cause of embryonic death [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Next Generation Sequencing Detects Premeiotic Errors in Human Oocytes

Ghevaria

SenGupta

Naja

et al. 2022

IJMS

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Autosomal aneuploidy is the leading cause of embryonic and foetal death in humans. This arises mainly from errors in meiosis I or II of oogenesis. A largely ignored source of error stems from germinal mosaicism, which leads to premeiotic aneuploidy. Molecular cytogenetic studies employing metaphase fluorescence in situ hybridization and comparative genomic hybridisation suggest that premeiotic aneuploidy may affect 10–20% of oocytes overall. Such studies have been criticised on technical grounds. We report here an independent study carried out on unmanipulated oocytes that have been analysed using next generation sequencing (NGS). This study confirms that the incidence of premeiotic aneuploidy in an unselected series of oocytes exceeds 10%. A total of 140 oocytes donated by 42 women gave conclusive results; of these, 124 (88.5%) were euploid. Sixteen out of 140 (11.4%) provided evidence of premeiotic aneuploidy. Of the 140, 112 oocytes were immature (germinal vesicle or metaphase I), of which 10 were aneuploid (8.93%); the remaining 28 were intact metaphase II - first polar body complexes, and six of these were aneuploid (21.4%). Of the 16 aneuploid cells, half contained simple errors (one or two abnormal chromosomes) and half contained complex errors. We conclude that germinal mosaicism leading to premeiotic aneuploidy is a consistent finding affecting at least 10% of unselected oocytes from women undergoing egg collection for a variety of reasons. The importance of premeiotic aneuploidy lies in the fact that, for individual oocytes, it greatly increases the risk of an aneuploid mature oocyte irrespective of maternal age. As such, this may account for some cases of aneuploid conceptions in very young women.

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“…preimplantation mortality of fertilised or unfertilised eggs can all give rise to compensation). For example, while aneuploidy is common for the larger human chromosomes in oocytes [ 54 , 91 ], owing to early selection this is not reflected in early embryonic data [ 91 ]. Similarly, some methods (e.g., FISH) report exceptionally high rates (>70%) of nondisjunction in eggs [ 2 , 3 ], consistent with very early stage (oocyte to zygote) mortality.…”

Section: Further Predictions and Evidencementioning

confidence: 99%

Selfish centromeres and the wastefulness of human reproduction

Hurst

2022

PLoS Biol

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Many human embryos die in utero owing to an excess or deficit of chromosomes, a phenomenon known as aneuploidy; this is largely a consequence of nondisjunction during maternal meiosis I. Asymmetries of this division render it vulnerable to selfish centromeres that promote their own transmission, these being thought to somehow underpin aneuploidy. In this essay, I suggest that these vulnerabilities provide only half the solution to the enigma. In mammals, as in utero and postnatal provisioning is continuous, the costs of early death are mitigated. With such reproductive compensation, selection can favour a centromere because it induces lethal aneuploidy: if, when taken towards the polar body, it instead kills the embryo via aneuploidy, it gains. The model is consistent with the observation that reduced dosage of a murine drive suppressor induces aneuploidy and with the fact that high aneuploidy rates in vertebrates are seen exclusively in mammals. I propose further tests of this idea. The wastefulness of human reproduction may be a price we pay for nurturing our offspring.

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Origins and mechanisms leading to aneuploidy in human eggs

Cited by 45 publications

References 107 publications

Maternal Smc3 protects the integrity of the zygotic genome through DNA replication and mitosis

Maternal Smc3 protects the integrity of the zygotic genome through DNA replication and mitosis

Next Generation Sequencing Detects Premeiotic Errors in Human Oocytes

Selfish centromeres and the wastefulness of human reproduction

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