Maternal age and genome-wide failure of meiotic recombination are associated with triploid conceptions in humans

Abstract Triploid and haploid conceptions are not viable and are a common occurrence in humans, where they account for 10% of all pregnancy losses. Despite the parent-of-origin being important in the etiology of the pregnancy, our knowledge of their causes is limited, especially at the point of conception. Using a dataset of 96,660 biopsies and a validation dataset of 44,324 from human blastocysts embryos generated by intra-cytoplasmic sperm injection (ICSI), we estimate that 1.1% of human conceptions (n=1,063) contain extra or missing chromosome sets in zygotes. We identify a maternal age effect, with a 1.059 per year increased risk in triploidy/haploidy (p=0.0008). In 0.03% of couples, we identified three or more triploid/haploid embryos, suggesting a personal risk effect (p=0.03). Genotype analysis of 55 triploid embryo biopsies and their parents show that one third of maternal triploid conceptions originate in meiosis I and two thirds in meiosis II. Seven of these embryos are inferred to have entirely failed to initiate meiotic recombination genome-wide, suggesting that human oocytes with pervasive meiotic recombination failure that are formed during fetal development are capable of ovulation in adult life. Finally, we identify a new type of genome-wide maternal isodiploidy (two maternal chromosome sets) in 0.05% of embryos (41 of 74,009). Collectively, our findings shed light on the biology of meiosis and the formation of human oocytes with the number of chromosome sets.