Tripolar mitosis drives the association between maternal genotypes of PLK4 and aneuploidy in human preimplantation embryos
Aneuploidy is prevalent in human preimplantation embryos and is the leading cause of pregnancy loss. Many aneuploidies arise during oogenesis, increasing in frequency with maternal age. Superimposed on these meiotic aneuploidies are a range of errors occurring during early mitotic divisions of the embryo, contributing to widespread chromosomal mosaicism. Here we reanalyzed a published dataset comprising preimplantation genetic testing for aneuploidy in 24,653 blastomere biopsies from day-3 cleavage-stage embryos, as well as 17,051 trophectoderm biopsies from day-5 blastocysts. We focused on complex abnormalities that affected multiple chromosomes simultaneously, seeking to quantify their incidences and gain insight into their mechanisms of formation. In addition to well-described patterns such as triploidy and haploidy, we identified 4.7% of day-3 blastomeres possessing karyotypes suggestive of tripolar mitosis in normally-fertilized diploid zygotes or descendant diploid cells. We further supported this hypothesis using time-lapse data from an intersecting set of 77 cleavage-stage embryos. The diploid tripolar signature was rare among day-5 blastocyst biopsies (0.5%), suggesting that complex aneuploidy generated by tripolar mitosis impairs cellular and/or early embryonic survival. Strikingly, we found that the tripolar mitosis mechanism is responsible for the previously described association with common maternal genetic variants spanning PLK4. Our findings are consistent with the role of PLK4 as the master regulator of centriole duplication with a known capacity to induce tripolar mitosis when mutated or mis-expressed. Taken together, we propose that tripolar mitosis is a key mechanism generating karyotype-wide aneuploidy in cleavage-stage embryos and implicate PLK4-mediated centrosome abnormality as a factor influencing its occurrence.