Abstract
Aneuploidy, the presence of an abnormal number of chromosomes, is a major cause of early pregnancy loss in humans. Yet, the developmental consequences of specific aneuploidies remain unexplored. Here, we determine the extent of post-implantation development of human embryos bearing common aneuploidies using a recently established culture platform. We show that while trisomy 15 and trisomy 21 embryos develop similarly to euploid embryos, monosomy 21 embryos exhibit high rates of developmental arrest, and trisomy 16 embryos display a hypo-proliferation of the trophoblast, the tissue that forms the placenta. Using human trophoblast stem cells, we show that this phenotype can be mechanistically ascribed to increased levels of the cell adhesion protein E-CADHERIN, which lead to premature differentiation and cell cycle arrest. We identify three cases of mosaicism in embryos diagnosed as full aneuploid by pre-implantation genetic testing. Our results present the first detailed analysis of post-implantation development of aneuploid human embryos.
Highlights
Aneuploidy, the presence of an abnormal number of chromosomes, is a major cause of early pregnancy loss in humans
Our results show that monosomy 21 embryos are 10 times more likely to arrest in culture than euploid embryos, and trisomy 16 embryos present a hypoproliferation defect specific of the trophoblast
We focused our attention on particular aneuploidies that are common and cause minimal impact on preimplantation development, and selected those human embryos that reached the blastocyst stage with the correct morphology and at the appropriate timing
Summary
Aneuploidy, the presence of an abnormal number of chromosomes, is a major cause of early pregnancy loss in humans. Recent technical advances have allowed human embryos to develop beyond day 7 and up to day 12/13 in vitro, in the absence of maternal tissues[11,12] Embryos cultured in this system recapitulate the major morphological transformations of in vivo developing embryos, such as separation of the inner cell mass (ICM) into the epiblast that will give rise to the embryo proper and the hypoblast that will give rise to the yolk sac, formation of the amniotic and yolk sac cavity, and differentiation of the trophoblast, the tissue that will form the placenta[11,12]. We uncovered three cases of mosaicism in embryos that were initially diagnosed by PGT-A as fully aneuploid, highlighting the potential of our human embryo platform to determine the extent of genetic mosaicism, and its influence on post-implantation human development
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