On the origins and fate of chromosomal abnormalities in human preimplantation embryos: an unsolved riddle

Abstract

About 8 out of 10 human embryos obtained in vitro harbour chromosomal abnormalities of either meiotic or mitotic origin. Abnormalities of mitotic origin lead to chromosomal mosaicism, a phenomenon which has sparked much debate lately as it confounds results obtained through preimplantation genetic testing for aneuploidy (PGT-A). PGT-A in itself is still highly debated, not only on the modalities of its execution, but also on whether it should be offered to patients at all. We will focus on post-zygotic chromosomal abnormalities leading to mosaicism. First, we will summarize what is known of the rates of chromosomal abnormalities at different developmental stages. Next, based on the current understanding of the origin and cellular consequences of chromosomal abnormalities, which is largely based on studies on cancer cells and model organisms, we will offer a number of hypotheses on which mechanisms may be at work in early human development. Finally, and very briefly, we will touch upon the impact our current knowledge has on the practice of PGT-A. What is the level of abnormal cells that an embryo can tolerate before it loses its potential for full development? And is blastocyst biopsy as harmless as it seems?

Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos

“…Since then, with the introduction of comprehensive chromosome testing methods, numerous studies have confirmed this association (Fragouli et al , 2013; Capalbo et al , 2014; Qi et al , 2014; Maurer et al , 2015). However, all of these studies were limited by the use of earlier methodologies that did not discriminate between full and intermediate copy number changes for all chromosomes, limited sampling of embryo cells, or analysis of selected clinical-grade embryos only (reviewed by Regin et al , 2022).…”

Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

“…The mechanisms behind this selective clearance are thought to be mediated by two well-studied intracellular stress responses 10 . First, aneuploidy results in gene-dosage defects, leading to an unbalanced protein pool and proteotoxic stress.…”

“…If this remains unresolved by activation of autophagy, CASP8/LC3B/p62 will interact to activate the apoptosis cascade (Pan et al, 2011;Stingele et al, 2012;Dürrbaum et al, 2014). Second, aneuploidy results in replication stress that can lead to DNA-damage, resulting in p53 activation and ultimately to apoptosis (Zhu et al, 2018;Regin et al, 2022). Bolton et al (Bolton et al, 2016) showed that aneuploid cells are selectively cleared from chimeric mouse embryos generated from control blastomeres mixed with aneuploid blastomeres obtained using a treatment with the SAC inhibitor reversine.…”

“…Depending on the study, up to 80% of human cleavage stage embryos are found to be aneuploid, of which 70% show chromosomal mosaicism, i.e. the presence of at least two cell lineages with different genomic content (Regin et al ., 2022). The reasons behind this high rate of chromosomal abnormalities of mitotic origin is still largely unknown (McCoy, 2017) but could be a combination of a weak spindle assembly checkpoint (SAC) that is uncoupled of apoptosis until the blastocyst stage (Jacobs et al ., 2017; Vázquez-Diez et al ., 2019), in combination with an abundancy of transcripts of anti-apoptotic genes in cleavage-stage embryos (Yan et al ., 2013).…”

“…If this remains unresolved by activation of autophagy, CASP8/LC3B/p62 will interact to activate the apoptosis cascade (Pan et al ., 2011; Stingele et al ., 2012; Dürrbaum et al ., 2014). Second, aneuploidy results in replication stress that can lead to DNA-damage, resulting in p53 activation and ultimately to apoptosis (Zhu et al ., 2018; Regin et al ., 2022). Bolton et al .…”