Approximate Bayesian computation supports a high incidence of chromosomal mosaicism in blastocyst-stage human embryos.

Abstract

Chromosome mis-segregation is common in human meiosis and mitosis, and the resulting aneuploidies are the leading cause of pregnancy loss. Preimplantation genetic testing for aneuploidy (PGT-A) prioritizes chromosomally normal embryos for transfer based on analysis of a biopsy of ∼5 trophectoderm cells from blastocyst-stage in vitro fertilized embryos. While modern PGT-A platforms classify these biopsies as aneuploid, euploid, or mosaic (a mixture of normal and aneuploid cells), the underlying incidences of aneuploid, euploid, and mosaic embryos and the rates of meiotic and mitotic error that produced them remain largely unknown. To address this knowledge gap, we paired a method for embryo simulation with approximate Bayesian computation to infer rates of meiotic and mitotic error that explain published PGT-A data. Using simulation, we also evaluated the chromosomal status of entire embryos. For a published clinical sample, we estimated a 40% to 58% probability of meiotic error per meiosis and a 1.5% to 6.3% probability of mitotic error per mitosis, depending on assumptions about spatial organization. In addition, our analyses suggest that <1% of blastocysts are fully euploid and that many embryos possess low-level mosaic clones that are not captured during biopsy. These conclusions were relatively insensitive to misclassification of mosaic biopsies. Together, our findings imply that low-level mosaicism is a normal feature of embryogenesis and are consistent with clinical data demonstrating the developmental potential of mosaic-testing embryos. More broadly, our work helps overcome the limitations of embryo biopsies to estimate fundamental rates of chromosome mis-segregation in human development.