The first mitotic division of human embryos is highly error prone

Abstract

Human beings are made of ~50 trillion cells which arise from serial mitotic divisions of a single cell - the fertilised egg. Remarkably, the early human embryo is often chromosomally abnormal, and many are mosaic, with the karyotype differing from one cell to another. Mosaicism presumably arises from chromosome segregation errors during the early mitotic divisions, although these events have never been visualised in living human embryos. Here, we establish live cell imaging of chromosome segregation using normally fertilised embryos from an egg-share-to-research programme, as well as embryos deselected during fertility treatment. We reveal that the first mitotic division has an extended prometaphase/metaphase and exhibits phenotypes that can cause nondisjunction. These included multipolar chromosome segregations and lagging chromosomes that lead to formation of micronuclei. Analysis of nuclear number and size provides evidence of equivalent phenotypes in 2-cell human embryos that gave rise to live births. Together this shows that errors in the first mitotic division can be tolerated in human embryos and uncovers cell biological events that contribute to preimplantation mosaicism.

A pluripotent developmental state confers a low fidelity of chromosome segregation

“…Extending our results to human preimplantation development suggests that lagging chromosomes are primarily responsible for mitotic errors in early embryonic cells, thus providing a mechanism for the whole-chromosome aneuploidy observed in preimplantation embryos ( Figure S5 E) ( McCoy et al., 2015 ; Starostik et al., 2020 ; Vanneste et al., 2009 ). In support, lagging chromosomes occur during the first mitotic division in human embryos ( Cavazza et al., 2021 ; Currie et al., 2022 ). In contrast, during mouse preimplantation development, unaligned chromosomes are the most frequent mitotic error ( Vázquez-Diez et al., 2019 ).…”

Cell fragmentation in mouse preimplantation embryos induced by ectopic activation of the polar body extrusion pathway

“…During mitosis, ectopic activation of the PBE pathway is more pronounced when the spindle suffers from poor anchoring (Fig 2). Since human embryos show frequent issues with spindle and chromosome capture (Kalatova et al, 2015;Cavazza et al, 2021;Currie et al, 2022), we propose that fragmentation may result from hyper-activation of the PBE pathway due to problems during chromosome separation. Importantly, ectopic activation of the PBE pathway occurs in control embryos without causing much fragmentation (Figs 3 and 4).…”

The embryo mosaicism profile of next-generation sequencing PGT-A in different clinical conditions and their associations

“…Chromosomal mosaicism likely originates during the first embryonic cleavages by mitotic errors after fertilization ( 15 ), while whole aneuploidies originate from chromosome segregation errors during meiotic division for gamete formation ( 16 ). Maternal age alone may not represent the only factor associated with mosaicism; however, in the analysis of interaction and the logistic regression analysis, adjusted for all clinical characteristics, proved that age can have an isolated effect and for each 1-year increase in maternal age, the chance of low and high mosaic in relation to whole aneuploidy is reduced.…”

“…Mosaicism occurs due to mitotic errors during the first embryonic cleavages ( 19 ). Studies have revealed that IVF laboratory conditions can increase mosaicism rates due to exposure to environmental, mechanical, and chemical stressors ( 15 , 20 , 21 ). The higher occurrence of mitoses during the blastocyst stage prompts an increased error rate.…”