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

## TL;DR

The study finds that maternal age and genome-wide meiotic recombination failure are linked to triploid conceptions in humans, which are a common cause of pregnancy loss.

## Contribution

The study identifies a maternal age effect on triploidy/haploidy and reports genome-wide meiotic recombination failure in human oocytes.

## Key findings

- 1.1% of human conceptions have extra or missing chromosome sets in zygotes.
- Triploidy/haploidy risk increases by 1.046 per year of maternal age (p < 0.001).
- Seven embryos showed genome-wide meiotic recombination failure, indicating defective meiotic checkpoints.

## 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 blastocyst embryos generated by intracytoplasmic sperm injection, we estimate that 1.1% of human conceptions (n = 1,063) contain extra or missing chromosome sets in zygotes. In our cohort of intracytoplasmic-sperm-injection-derived embryos, where the risk of polyspermy is inherently lower compared to natural conception, we identify for the first time a maternal age effect, with a 1.046-per-year increased risk in triploidy/haploidy (p < 0.001). In 0.03% of couples, we identified three or more triploid/haploid embryos, suggesting a personal risk effect (p = 0.03). Genotype analysis of 41 triploid embryo biopsies and their parents shows that around 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, a surprising finding 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 type of genome-wide maternal isodiploidy (two maternal chromosome sets) in 0.05% of embryos (41/74,009). Collectively, our findings shed light on the biology of meiosis and the formation of human oocytes with the number of chromosome sets.

Ploidy abnormalities affect over 1% of human embryos. Haploidy typically results from absent sperm DNA, while triploidy mainly arises from maternal meiosis II errors. Triploidy also shows a linear maternal age effect and can be characterized by genome-wide recombination failure, indicative of defective meiotic checkpoints during fetal development.