Despite their critical role in encoding genetic information, chromosomes frequently mis-segregate during human meiosis, producing abnormalities in chromosome number—a phenomenon termed aneuploidy. Aneuploidy is the leading cause of human pregnancy loss, as well as the cause of genetic conditions such as Klinefelter, Turner and Down syndromes1,2. It is estimated that only approximately half of human conceptions survive to birth, primarily because of the abundance of aneuploidies that are inviable in early gestation5,6.
Work in humans and model organisms has established that one risk factor for aneuploidy involves variation in the number and location of meiotic crossover recombination events, especially in the female germline3,4. Notably, female meiosis initiates in fetal development, when replicated homologous chromosomes (homologues) pair and establish crossovers, which, together with cohesion between sister chromatids, hold homologues together in a ‘bivalent’ configuration. Homologues segregate (meiosis I) upon ovulation after the onset of puberty, whereas sister chromatids segregate (meiosis II) after fertilization. The physical linkages formed by meiotic crossovers help stabilize paired chromosomes during this prolonged period of female meiotic arrest7. Cohesin complexes, loaded in developing fetal oocytes, link sister chromatids and are crucial for chromosome synapsis and crossover formation8,9. Failure to form bivalents due to lack of crossovers10 or their suboptimal placement11, as well as age-related cohesin deterioration12, can lead to premature separation of sister chromatids and the related phenomenon of reverse segregation, which together represent the predominant mechanisms of maternal meiotic aneuploidy13.
Although producing sex-specific recombination maps and revealing associations with crossover phenotypes at meiosis-related genes, the largest studies of crossovers in living human families lacked aneuploid participants and only speculated about such relationships14,15. Much of current knowledge about the connection between human recombination and aneuploidy, as well as their genetic bases, thus comes from smaller samples of people living with survivable aneuploidies, limiting statistical power. By contrast, recent advances in single-cell sequencing have enabled simultaneous discovery of crossovers and aneuploidies in sperm and eggs, but are typically relegated to small numbers of gametes (in the case of oocytes) or small numbers of donors, hindering understanding of variability and potential shared genetic architecture of these phenotypes16,17,18.
Clinical genetic data from pre-implantation genetic testing (PGT) of in vitro fertilized (IVF) embryos help overcome these limitations and offer an ideal resource for characterizing aneuploidy and mapping meiotic crossovers at scale. Here we used single nucleotide polymorphism (SNP) array-based PGT data from 139,416 blastocyst-stage embryo biopsies and 22,850 sets of biological parents to (1) map recombination and aneuploidy, (2) test their relationship quantitatively and (3) discover genetic factors that modulate their incidence and features. Our analysis revealed an overlapping genetic basis of female recombination and aneuploidy formation involving common variation in key meiotic machinery. Together, our work offers a more complete view of the sources of variation in the fundamental molecular processes that generate genetic diversity while impacting human fertility.