Early development of balstomeres with whole-genome abnormalities

Whole-genome (WG) abnormalities, like uniparental diploidy or triploidy, affect fetal development and occasionally co-exist with biparental diploid cells, resulting in chimerism or mixoploidy. We recently discovered WG abnormalities originate via “heterogoneic division” of the first zygotic cleavage. To explore the developmental potential of blastomeres harboring WG abnormalities, we split each totipotent blastomere from bipolar and multipolar first cleavage embryos and cultured them to three preimplantation stages. Outgrowths were haplotyped and single-cell transcriptome profiled. We not only confirmed an enrichment of heterogoneic divisions in multipolar cleaving zygotes, but also demonstrated its occurrence in bipolar cleaving zygotes. Blastomeres with WG abnormalities showed impaired developmental potential, attributed to stress responses induced during embryonic genome activation (EGA). Nonetheless, some blastomeres survived these stress responses and reached the blastocyst stage. This study reveals the origin and early development of WG abnormal blastomeres and has significant clinical implications, as they might constitute an important contingent of embryos resulting in abnormal development.