Aberrant landscapes of maternal meiotic crossovers contribute to aneuploidies in human embryos.

Autor:	Ariad D; Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA; daniel@ariad.org rajiv.mccoy@jhu.edu., Madjunkova S; CReATe Fertility Centre, Toronto, Ontario M5G 1N8, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada., Madjunkov M; CReATe Fertility Centre, Toronto, Ontario M5G 1N8, Canada., Chen S; CReATe Fertility Centre, Toronto, Ontario M5G 1N8, Canada., Abramov R; CReATe Fertility Centre, Toronto, Ontario M5G 1N8, Canada., Librach C; CReATe Fertility Centre, Toronto, Ontario M5G 1N8, Canada.; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario M5G 1E2, Canada.; Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada.; Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada., McCoy RC; Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA; daniel@ariad.org rajiv.mccoy@jhu.edu.
Jazyk:	angličtina
Zdroj:	Genome research [Genome Res] 2024 Feb 07; Vol. 34 (1), pp. 70-84. Date of Electronic Publication: 2024 Feb 07.
DOI:	10.1101/gr.278168.123
Abstrakt:	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 rely either on population genetic patterns of linkage disequilibrium (LD)-capturing a time-averaged view-or on direct detection of crossovers in gametes or multigeneration pedigrees, which limits data set 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 (<0.05×) 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, and the frequent occurrence of monosomies in embryos, whereby the remaining chromosome is phased by default. Extensive simulations show our method's high accuracy, even at coverages as low as 0.02×. 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 with disomies, as well as chromosome-specific alterations in crossover distributions. Based on haplotype configurations in pericentromeric regions, our data indicate chromosome-specific propensities for different mechanisms of meiotic error. Our results provide a comprehensive view of the role of aberrant meiotic recombination in the origins of human aneuploidies and offer a versatile tool for mapping crossovers in low-coverage sequencing data from multiple siblings. (© 2024 Ariad et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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