The First Mitotic Division of the Human Embryo is Highly Error-prone

Abstract

Aneuploidy in human embryos is surprisingly prevalent and increases drastically with maternal age, resulting in miscarriages, infertility and birth defects. Frequent errors during the meiotic divisions cause this aneuploidy, while age-independent errors during the first cleavage divisions of the embryo also contribute. However, the underlying mechanisms are poorly understood, largely because these events have never been visualised in living human embryos. Here, using cell-permeable DNA dyes, we film chromosome segregation during the first and second mitotic cleavage divisions in human embryos from women undergoing assisted reproduction following ovarian stimulation. We show that the first mitotic division takes several hours to complete and is highly variable. Timings of key mitotic events were, however, largely consistent with clinical videos of embryos that gave rise to live births. Multipolar divisions and lagging chromosomes during anaphase were frequent with no maternal age association. In contrast, the second mitosis was shorter and underwent mostly bipolar divisions with no detectable lagging chromosomes. We propose that the first mitotic division in humans is a unique and highly error-prone event, which contributes to fetal aneuploidies.

Parental genome unification is highly error-prone in mammalian embryos

“…Altogether, these data establish that the unification of the parental chromosomes is a particularly critical and sensitive step in embryo development. Consistent with our results, a recent preprint demonstrates that chromosome segregation in human zygotes is highly error-prone, and the first mitotic division is more frequently abnormal than the second mitotic division ( Ford et al., 2020 ).…”

“…However, we were not able to analyze human zygotes after NEBD. Interestingly, human zygotes were reported to undergo multipolar divisions ( Ford et al., 2020 ; Ottolini et al., 2017 ), which are uncommon in bovine zygotes. There might thus also be differences between human and bovine zygotes.…”

Non-rodent mammalian zygotes assemble dual spindles despite the presence of paternal centrosomes

“…It will be very interesting in the future to understand the mechanism of chromosomal microtubule nucleation and spindle bipolarization in mouse and bovine zygotes and to carefully compare it to clinical data to infer whether a similar process occurs in human zygotes. Recent studies are pointing towards such a mechanism in human zygotes, especially the observation that the genomes frequently display a multipolar orientation in prometa- and metaphase and that chromosomes are frequently segregated in a uniparental conformation (Ford et al, 2020).…”

SAC during early cell divisions: Sacrificing fidelity over timely division, regulated differently across organisms

“…On the other hand, mammalian species such as human [ 11,76,77 ] non‐human primates [ 78,79 ] , farm animals [ 80–84 ] and murine [ 74 ] have been reported to have chromosomal mosaicism in pre‐implantation embryos. [ 85 ] Their reproductive strategy involves longer gestation times with fewer progeny.…”