Aberrant landscapes of maternal meiotic crossovers contribute to aneuploidies in human embryos [METHOD]

Meiotic recombination is crucial for human genetic diversity and chromosome segregation accuracy. Understanding its variation across individuals and the processes by which it goes awry are long-standing goals in human genetics. Current approaches for inferring recombination landscapes either rely on population genetic patterns of linkage disequilibrium (LD)—capturing a time-averaged view or direct detection of crossovers in gametes or multi-generation pedigrees, which limits dataset scale and availability. Here, we introduce an approach for inferring sex-specific recombination landscapes using data from preimplantation genetic testing for aneuploidy (PGT-A). This method relies on low-coverage <0.05x whole-genome sequencing of in vitro fertilized (IVF) embryo biopsies. To overcome the data sparsity, our method exploits its inherent relatedness structure, knowledge of haplotypes from external population reference panels, as well as the frequent occurrence of monosomies in embryos, whereby the remaining chromosome is phased by default. Extensive simulations demonstrate our method's high accuracy, even at coverages as low as 0.02x. Applying this method to PGT-A data from 18,967 embryos, we mapped 70,660 recombination events with ~150 kbp resolution, replicating established sex-specific recombination patterns. We observed a reduced total length of the female genetic map in trisomies compared to disomies, as well as chromosome-specific alterations in crossover distribution...

Source: Genome Research - December 1, 2023 Category: Genetics & Stem Cells Authors: Ariad, D., Madjunkova, S., Madjunkov, M., Chen, S., Abramov, R., Librach, C., McCoy, R. C. Tags: METHOD Source Type: research