Aneuploidy in human eggs: contributions of the meiotic spindle

Abstract

Human eggs frequently contain an incorrect number of chromosomes, a condition termed aneuploidy. Aneuploidy affects ∼10–25% of eggs in women in their early 30s, and more than 50% of eggs from women over 40. Most aneuploid eggs cannot develop to term upon fertilization, making aneuploidy in eggs a leading cause of miscarriages and infertility. The cellular origins of aneuploidy in human eggs are incompletely understood. Aneuploidy arises from chromosome segregation errors during the two meiotic divisions of the oocyte, the progenitor cell of the egg. Chromosome segregation is driven by a microtubule spindle, which captures and separates the paired chromosomes during meiosis I, and sister chromatids during meiosis II. Recent studies reveal that defects in the organization of the acentrosomal meiotic spindle contribute to human egg aneuploidy. The microtubules of the human oocyte spindle are very frequently incorrectly attached to meiotic kinetochores, the multi-protein complexes on chromosomes to which microtubules bind. Multiple features of human oocyte spindles favour incorrect attachments. These include spindle instability and many age-related changes in chromosome and kinetochore architecture. Here, we review how the unusual spindle assembly mechanism in human oocytes contributes to the remarkably high levels of aneuploidy in young human eggs, and how age-related changes in chromosome and kinetochore architecture cause aneuploidy levels to rise even higher as women approach their forties.

Human embryos arrest in a quiescent-like state characterized by metabolic and zygotic genome activation problems

“…Around 30% of cells were predicted to be aneuploid (Supplementary Fig. 2A, B), which agrees with previous data that aneuploidy is common in human embryos (Thomas et al, 2021). We notice that chromosomal defects become particularly evident at the 8-cell stage, and reach around 30% at the morula/E3 stage (14/48 cells, 29%) and persist to the E7-stage (late blastocyst) at similar rates (116/321 cells, 36%) (Supplementary Fig.…”

Parental genome unification is highly error-prone in mammalian embryos

“…Our data also show that the SAC is not stringent enough to block anaphase when only a few chromosomes are unattached, as in the case of unclustered zygotes. A low stringency of the SAC has also been reported for mouse and human oocytes and for mouse embryos ( Thomas et al., 2021 ; Vázquez-Diez et al., 2019 ). The low stringency of the SAC might explain why 17% of the zygotes with clustered genomes display chromosome segregation errors.…”

Next Generation Sequencing Detects Premeiotic Errors in Human Oocytes

“…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 ].…”