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Aneuploidy in mammalian oocytes and the impact of maternal ageing

Abstract

During fertilization, the egg and the sperm are supposed to contribute precisely one copy of each chromosome to the embryo. However, human eggs frequently contain an incorrect number of chromosomes — a condition termed aneuploidy, which is much more prevalent in eggs than in either sperm or in most somatic cells. In turn, aneuploidy in eggs is a leading cause of infertility, miscarriage and congenital syndromes. Aneuploidy arises as a consequence of aberrant meiosis during egg development from its progenitor cell, the oocyte. In human oocytes, chromosomes often segregate incorrectly. Chromosome segregation errors increase in women from their mid-thirties, leading to even higher levels of aneuploidy in eggs from women of advanced maternal age, ultimately causing age-related infertility. Here, we cover the two main areas that contribute to aneuploidy: (1) factors that influence the fidelity of chromosome segregation in eggs of women from all ages and (2) factors that change in response to reproductive ageing. Recent discoveries reveal new error-causing pathways and present a framework for therapeutic strategies to extend the span of female fertility.

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Fig. 1: Meiosis of human oocytes.
Fig. 2: Chromosome segregation in mammalian oocytes.
Fig. 3: Assembly of the meiotic spindle in mammalian oocytes.
Fig. 4: Domains and components of the mammalian meiotic spindle.
Fig. 5: Age-associated defects in chromosome segregation in mammalian oocytes.
Fig. 6: Factors implicated in mammalian oocyte ageing.

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Acknowledgements

The authors intended to write an accessible article for a wide audience, while introducing as many new findings as possible. We would like to apologize to all the authors whose work could not be cited here due to space constraints. M.S., A.W. and C.C. have received financial support from the Max Planck Society, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) by a DFG Leibniz Prize (SCHU 3047/1-1), an EMBO Post-Doctoral Long-Term Fellowship to A.W., and a Boehringer Ingelheim Fonds PhD Fellowship to C.C. Work was further supported by the DFG under Germany’s Excellence Strategy (EXC 2067/1-390729940).

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Correspondence to Melina Schuh.

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Glossary

Oxidative stress

Arises due to an imbalance between the production of reactive oxygen species (ROS) and the detoxification of ROS through antioxidant pathways. Excessive levels of ROS can lead to an accumulation of damage to macromolecules, including DNA within cells.

Primordial germ cells

(PGCs). An immature germline cell that is established during fetal development, which eventually matures through meiosis into a gamete.

Homologous chromosomes

Maternally and paternally inherited chromosomes similar in genetic content and size, and however not identical as they contain different alleles.

Sister chromatids

An identical chromosome copy of a single homologous chromosome formed through DNA replication. Both sister chromatids are comprised of identical DNA sequences and alleles.

Cohesin complexes

A tripartite ring-like protein complex that can simultaneously link two strands of DNA and can organize chromosomes into bivalent structures in meiosis.

Meiotic recombination

A DNA repair process specific to germ cells where homologous chromosomes exchange strands of DNA and form chiasmata structures. Meiotic recombination creates new gene allele combinations, increasing genetic diversity in the offspring. Structurally, meiotic recombination also links homologous chromosomes together via chiasmata to form bivalent chromosomes that promote accurate chromosome segregation during meiosis I.

Non-crossover

The repair of DNA double-strand breaks through meiotic recombination without reciprocal exchange of large genomic DNA sequences between homologous chromosomes.

Chiasmata

A DNA-protein assembly located at DNA lesions formed by meiotic recombination.

Telomeres

The protected ends of chromosomes that consist of repetitive DNA sequences and associated shelterin protein complexes.

Bivalent chromosome

Chromosome assemblies consisting of two pairs of homologous sister chromatids joined together by cohesin after formation of chiasmata.

Follicular atresia

The degeneration and re-absorption of oocyte-containing follicles within the ovary. A wave of follicular atresia during fetal development reduces follicle numbers before birth and is followed by gradual atresia that occurs continuously throughout reproductive life.

Gap junctions

Inter-cellular membrane channels that connect the oocyte to somatic follicle cells. These channels are used to transfer small molecules from the follicle cells to the oocyte.

Graafian follicle

A large ovarian follicle produced by the later stages of folliculogenesis. At this follicle stage, the prophase-arrested oocyte resumes meiosis.

Luteinizing hormone

A gonadotropin that triggers germ cell maturation in both males and females, triggering ovulation in females.

Pituitary gland

An organ of the endocrine system located at the base of the brain responsible for the release of luteinizing hormone, among other hormones.

Nuclear envelope breakdown

(NEBD). The stage when the oocyte nucleus breaks down and condensed chromosomes are released into the cytoplasm. Also termed germinal vesicle breakdown in oocytes.

REC8

The meiosis-specific α-kleisin subunit of a cohesin complex that is cleaved by separase during anaphase.

Polar body

A cell that is produced during the meiotic divisions of the oocyte. One polar body is produced during each of the two asymmetric meiotic divisions, finally generating a large egg and two small polar bodies. Polar bodies receive chromosomes from the oocyte and are later degraded.

Pronuclei

Transient nuclear membrane structures that form following fertilization to separately hold the chromosomes of the sperm and the meiosis II egg.

Zygotic genome activation

The stage in embryonic development where the genes of the embryo are first transcribed, marking the maternal-to-zygote transition.

Phthalates

A compound used to make plastic more flexible and durable.

Bisphenol A

(BPA). A monomeric compound that is polymerized to produce polycarbonate plastics and resins.

Centrosomes

Organelles comprised of two centrioles surrounded by pericentriolar material that assembles the spindle machinery.

RAN-dependent microtubule assembly pathway

RAN bound to GTP (RAN–GTP) releases spindle-assembly factors bound to importins that are close to chromosomes. In turn, RAN–GTP activates the spindle-assembly factors, leading to local spindle microtubule assembly at chromosomes.

Importins

Proteins that bind to nuclear localization sequences on other proteins and mediate their transfer from the cytoplasm and into the nucleus via nuclear pores that span the nuclear membrane.

Kinetochores

Protein assemblies formed on the centromeres of chromosomes that bind to microtubules to form kinetochore fibres (k-fibres). Inner kinetochore proteins bind to centromeric repeat DNA, forming the constitutive centromeric associated network, while outer kinetochore proteins form the KMN network that engages microtubules.

Merotelic attachments

When a kinetochore is erroneously attached to two or more k-fibres originating from opposite spindle poles.

Lagging chromosomes

A chromosome whose segregation is delayed or that fails to segregate from the spindle mid-zone to the spindle poles during anaphase.

Fluorescence in situ hybridization

A diagnostic method where fluorescently labelled oligonucleotides are annealed onto chromosome regions containing sequence complementarity and analysed by fluorescence light microscopy.

Array comparative genome hybridization

A diagnostic method where fluorescently labelled chromosome fragments from a specimen are competitively annealed to a micro-array chip containing oligonucleotides of a reference genome.

Next-generation sequencing

A diagnostic method where thousands to millions of genomic fragments are annealed to a microarray chip and sanger-sequenced in parallel at single-base resolution.

Blastocoel fluid

Fluid within the blastocyst cavity that is released from the blastocyst during egg freezing.

Kinetochore fibres

(K-fibres). Bundles of microtubules stably attached to kinetochores responsible for pulling chromosomes to spindle poles during anaphase.

NDC80 complex

A component of the outer kinetochore found in all eukaryotes that is comprised of four subunits termed NDC80, NUF2, SPC24 and SPC25.

Spindle assembly checkpoint

(SAC). A cellular surveillance mechanism that prevents or delays entry into anaphase until kinetochores are stably attached to spindle microtubules.

Mitotic checkpoint complex

(MCC). A protein complex formed as part of the SAC that blocks the anaphase-promoting complex/cyclosome from interacting with its co-activator CDC20.

Anaphase-promoting complex/cyclosome

(APC/C). A protein ubiquitin ligase complex responsible for triggering degradation of cell-cycle and other proteins prior to anaphase onset, including cyclin B1 and securin.

Cyclin B1

A regulatory protein of the cell cycle that binds to CDK1, generating the cyclin B1–CDK1 complex that phosphorylates target proteins to promote cell cycle progression.

Securin

An inhibitory protein that binds to and inactivates the cohesin-cleaving enzyme separase. It is degraded by the APC/C prior to entry into anaphase, eventually allowing separase activity.

Metacentric chromosomes

A class of chromosomes with two long arms, with the kinetochore roughly equidistant from both telomeres.

Univalent chromosomes

A bivalent chromosome that has prematurely separated into two homologous chromosomes before anaphase I.

Gonadotropic hormones

Hormones that stimulate the gonads, including luteinizing hormone and follicle-stimulating hormone in females.

CHEK2

Gene encoding a tumour-suppressor serine/threonine kinase that responds to DNA damage by initiating repair, cell cycle arrest and apoptotic signalling.

Reactive oxygen species (ROS)

A class of free radical compounds including superoxide anions, hydrogen peroxide and hydroxyl radicals. At low levels, ROS promote a range of cellular functions but too high levels can cause damage to proteins, lipids and nucleic acids.

Corpus luteum

A compartment of the ovary formed after rupture of a follicle following ovulation. This structure secretes hormones that help establish and maintain pregnancy. If embryo implantation fails to occur, the corpus luteum undergoes degeneration and wound healing.

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Charalambous, C., Webster, A. & Schuh, M. Aneuploidy in mammalian oocytes and the impact of maternal ageing. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00517-3

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