Aneuploidy triggers autophagy and p53-mediated apoptosis and impairs second lineage segregation in human preimplantation embryos

Aneuploidy is present in about 80% of human preimplantation embryos and is thought to largely explain our relatively low fertility. However, the percentage of aneuploid cells decreases progressively during the early cleavages and chromosomally mosaic human embryos have been shown to result in healthy newborns with normal karyotypes. These observations imply a selective loss of aneuploid cells, but the underlying mechanisms are not yet fully understood. Here, we show that, while aneuploid embryos had lower cell numbers in both trophectoderm (TE) and inner-cell-mass (ICM), the effect of aneuploidy was cell-type dependent. Aneuploid TE presented transcriptomic signatures of DNA-damage, p53-signalling and apoptosis. Immunostaining of whole embryos showed that aneuploidy results in increased proteotoxic stress, autophagy, DNA damage-mediated activated p53 and subsequent apoptosis in the TE only. In the ICM, aneuploidy impaired primitive endoderm differentiation. Our findings explain why fully aneuploid embryos fail to further develop and shed light on the mechanisms by which aneuploid cells are removed from mosaic embryos. ### Competing Interest Statement The authors have declared no competing interest.