Abstract
Humans are diploid organisms, and triploidy in human embryos is responsible for ∼10% of spontaneous miscarriages. Surprisingly, some pregnancies proceed to triploid newborns that suffer from many neuro-developmental disorders. To investigate the impact of triploidy on human development, we generate triploid human embryonic stem cells (hESCs) by fusing isogenic haploid and diploid hESCs. Comparison of the transcriptome, methylome, and genome-wide replication timing shows general similarity between diploid and triploid hESCs. However, triploid cells have a larger volume than diploid cells, demonstrating decreased surface-area-to-volume ratio. This leads to a significant downregulation of cell surface ion channel genes, which are more essential in neural progenitors than in undifferentiated cells, leading to inhibition of differentiation, and it affects the neuronal differentiation ability of triploid hESCs, both in vitro and in vivo. Notably, our research establishes a platform to study triploidy in humans and points to their pathology as observed in triploid embryos.