Analyses stratified by maternal age and recombination further characterize genes associated with maternal nondisjunction of chromosome 21

Chernus, Jonathan M.; Sherman, Stephanie L.; Feingold, Eleanor

doi:10.1002/pd.5919

Cited by 5 publications

(3 citation statements)

References 77 publications

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“…Meanwhile, patterns of SPH chromosome-wide indicate a potential mitotic origin of trisomy (or MII error without recombination). Although previous studies have noted that the attribution of centromere-spanning BPH and SPH patterns to MI and MII errors is imperfect owing to alternative mechanisms by which the signatures may originate ( Chernus et al 2021 ), our results support the hypothesis that chromosomes possess unique propensities for various forms of segregation error (χ 2 [21, N = 1911] = 393.3, P = 2.3 × 10 −70 ) ( Fig. 5 ; Supplemental Table S2 ).…”

Section: Resultssupporting

confidence: 83%

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

Ariad,

Madjunkova,

Madjunkov

et al. 2023

Genome Res.

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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 <0.05× 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, 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 0.02×. 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 to 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.

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Section: Resultssupporting

confidence: 83%

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

Ariad,

Madjunkova,

Madjunkov

et al. 2023

Genome Res.

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show abstract

“…Meanwhile, patterns of SPH chromosome-wide indicate a potential mitotic origin of trisomy (or MII error without recombination). While previous studies have noted that the attribution of centeromere-spanning BPH and SPH patterns to MI and MII errors is imperfect due to alternative mechanisms by which the signatures may originate [39], our results support the hypothesis that chromosomes possess unique propensities for various forms of segregation error ( 2 [2, N = 2540] = 489.2, P = 1.6 ⇥ 10 77 ; Figure 5; Table S2). The vast majority (> 81%) of trisomies of chromosomes 15, 16, 19, 21, and 22 exhibited haplotypic patterns consistent with errors in MI, while chromosomes 11, 13, and 14 exhibited more modest excesses (⇠70%) of MI errors (binomial test, Bonferroni adjusted-P < 0.05 for all noted chromosomes).…”

Section: Chromosome-specific Propensities For Various Mechanisms Of T...supporting

confidence: 85%

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

Ariad

Madjunkova

Madjunkov

et al. 2023

Preprint

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Meiotic recombination is a fundamental source of human genetic diversity and is also critical for ensuring the accuracy of chromosome segregation. Understanding the landscape of meiotic recombination, its variation across individuals, and the processes by which it goes awry are long-standing goals in human genetics. Current approaches for inferring the landscape of recombination 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, limiting the scale and availability of relevant datasets. Here, we introduce an approach for inferring sex-specific landscapes of recombination from retrospective analysis of data from preimplantation genetic testing for aneuploidy (PGT-A) based on low-coverage (<0.05×) whole-genome sequencing of biopsies from in vitro fertilized (IVF) embryos. To overcome the sparsity of these data, our method exploits its inherent relatedness structure, knowledge of haplotypes from external population reference panels, as well as the frequent occurrence of chromosome loss in embryos, whereby the remaining chromosome is phased by default. Based on extensive simulation, we show that our method retains high accuracy down to coverages as low as 0.02×. Applying this method to low-coverage PGT-A data from 18,967 embryos, we mapped 70,660 recombination events at an average resolution of ~150 kbp, replicating key features of sex-specific recombination maps from the literature. We observed that the total length of the female genetic map is reduced for trisomies compared to disomies, while the genomic distribution of crossovers is also altered in a chromosome-specific manner. Based on haplotype configurations detected in regions surrounding the centromeres, our data additionally indicate that individual chromosomes possess unique propensities for different mechanisms of meiotic error. Together, our results provide a detailed view of the role of aberrant meiotic recombination in the origins of human aneuploidies, as well as a flexible tool for mapping crossovers in low-coverage sequencing data from multiple siblings.

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“…Churnus et al. extend their earlier studies to identify specific genes that may affect recombination and meiotic error 20 . Using a genome‐wide association study approach on families with a Down syndrome child, they identify a number of candidate genes that may affect recombination and segregation.…”

Section: Special Issuementioning

confidence: 99%

The origins of aneuploidy research consortium

2021

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The presence of high levels of aneuploidy in oocytes and early embryos and their fate is of considerable scientific and clinical importance. The Origins of Aneuploidy Research Consortium (OARC) was established to promote interdisciplinary communication and collaborative research into this topic. Under the umbrella of OARC, a series of papers has now been published in this Special Issue of Prenatal Diagnosis. Recent studies have transformed the view that aneuploidy is usually attributable to meiotic non‐disjunction. The molecular basis for the association between meiotic error and maternal age is becoming understood. The clinical significance of mitotic instability in the earliest cells divisions of the embryo is also becoming clearer. An error in the segregation of one or more whole chromosomes from a parent does not invariably result in a non‐viable pregnancy or an abnormal outcome. Epidemiologic data allows an assessment of in utero viability, the effect of maternal age, and secondary factors that may affect aneuploidy prevalence. We advocate careful use of nomenclature and revision of educational materials to more accurately explain the complex and often nuanced mechanisms. OARC plans to hold additional workshops, promote additional publications and offer educational resources.

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Analyses stratified by maternal age and recombination further characterize genes associated with maternal nondisjunction of chromosome 21

Cited by 5 publications

References 77 publications

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

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

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

The origins of aneuploidy research consortium

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