Parental genomes segregate into distinct blastomeres during multipolar zygotic divisions leading to mixoploid and chimeric blastocysts

Abstract

Background During normal zygotic division, two haploid parental genomes replicate, unite and segregate into two biparental diploid blastomeres. Results Contrary to this fundamental biological tenet, we demonstrate here that parental genomes can segregate to distinct blastomeres during the zygotic division resulting in haploid or uniparental diploid and polyploid cells, a phenomenon coined heterogoneic division. By mapping the genomic landscape of 82 blastomeres from 25 bovine zygotes, we show that multipolar zygotic division is a tell-tale of whole-genome segregation errors. Based on the haplotypes and live-imaging of zygotic divisions, we demonstrate that various combinations of androgenetic, gynogenetic, diploid, and polyploid blastomeres arise via distinct parental genome segregation errors including the formation of additional paternal, private parental, or tripolar spindles, or by extrusion of paternal genomes. Hence, we provide evidence that private parental spindles, if failing to congress before anaphase, can lead to whole-genome segregation errors. In addition, anuclear blastomeres are common, indicating that cytokinesis can be uncoupled from karyokinesis. Dissociation of blastocyst-stage embryos further demonstrates that whole-genome segregation errors might lead to mixoploid or chimeric development in both human and cow. Yet, following multipolar zygotic division, fewer embryos reach the blastocyst stage and diploidization occurs frequently indicating that alternatively, blastomeres with genome-wide errors resulting from whole-genome segregation errors can be selected against or contribute to embryonic arrest. Conclusions Heterogoneic zygotic division provides an overarching paradigm for the development of mixoploid and chimeric individuals and moles and can be an important cause of embryonic and fetal arrest following natural conception or IVF.

Embryo morphokinetics derived from fresh and vitrified bovine oocytes predict blastocyst development and nuclear abnormalities

“…With regard to abnormal cleavage events, we found lower developmental capacity in zygotes with multipolar cleavage or ruffling membrane, which is in line with human studies 29,37 and recent publications in human and bovine zygotes that showed how multipolar division leads to lower embryo development compared to normal cleavers 30,34 . As supported by the higher number of nuclear abnormalities following multipolar zygotic division, multipolar zygotic division seems to be associated with genome segregation errors in embryos leading to a higher frequency of mixoploidy, and chromosomal abnormalities in the resultant embryos 33,39,41 and embryonic arrest 30 . 31,36,38 .…”

“…Time-lapse technology enables non-invasive and continuous observation of embryo development from fertilization to transfer. This technology has been used in human studies to detect key events that predict blastocyst formation, ploidy, and embryo implantation potential and it is applied in some fertility clinics for its technical benefits and to select the best embryos for transfer (reviewed by Pennetta et al) 27,28. Morphokinetic parameters have been linked to embryo development and chromosomal or genome-wide errors 29,30 . For example, the pace of development of in vitro produced embryos can be linked to embryo quality, and embryos that cleave faster following fertilization are more developmentally competent than are those that cleave relatively late 31,32 .…”

“…On the other hand, cytokinetic events diverging from the normal division of mammalian zygotes in two equally sized blastomeres have been shown to relate to embryo quality 24,33,34 . Multipolar division-the first division of the embryo directly into three cells 29,30,33,35 , ruffling membranes-motility of the oolemma before the first division 36,37 , the occurrence of a resting period in between the divisions or so-called lag-phase, and heterogeneous size of the blastomeres following the first division can all affect embryo development and pregnancy rates 33,38 . Although some time-lapse studies in cows have reported on the prevalence of abnormal cleavage patterns and on the length of cell cycles and their correlation with developmental capacity 30,33,34,36,[39][40][41] , integration of the effect of all the morphokinetic events mentioned previously in one single study has not yet been performed.…”

Shape of the first mitotic spindles impacts nucleation in human embryos

“…Dual spindles were also observed in bovine embryos 34 . A study of bovine embryos showed that parental genomes segregated to distinct blastomeres during the rst division, resulting in haploid or uniparental diploid and polyploid cells 39 . This phenomenon is presumed to occur because parental chromosomes are segregated into two groups and can form heterogeneous cells 40 .…”

Insights into embryonic chromosomal instability: mechanisms of DNA elimination during mammalian preimplantation development

“…Unlike mitotic errors at the zygote stage ( Figure 1C ), a mitotic mis-segregation event that arises in 2-cell embryos or later in development can produce cells with diverse karyotypes known as chromosomal mosaicism ( Figure 1D ). Euploid-aneuploid mosaic embryos containing a mixture of both chromosomally normal and abnormal cells are the most common ( Chuang et al, 2020 ), but there are also reports of embryos with mixoploidy, whereby cells differ according to whether they are haploid, diploid, or polyploid ( Destouni et al, 2016 ; Carson et al, 2018 ; Daughtry et al, 2019 ; De Coster et al, 2022 ). However, these types of errors typically go undetected and/or are classified as euploid unless parental DNA is inputted to assign chromosomes as either maternal or paternal.…”