Missed connections: recombination and human aneuploidy

Hassold, Terry; Hunt, Patricia A.

doi:10.1002/pd.5910

Cited by 10 publications

(7 citation statements)

References 47 publications

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“…Chromosomes 7, 14, and 16 showed significant differences in crossover landscapes between disomic and trisomic chromosomes ( p -value <0.05; although note the small sample sizes for Chromosomes 7 and 14), whereas Chromosome 22 fell just above this threshold ( p -value = 0.051) ( Supplemental Table S3 ). Our observations reveal that on Chromosome 16, trisomies lacked a pair of hotspots in the vicinity of the centromere—one on each arm—broadly consistent with the previous observation that distal crossovers were enriched among a smaller sample of 62 cases of trisomy 16 ( Hassold et al 1995 ; Hassold and Hunt 2021 ). Meanwhile, trisomies of Chromosome 22 appeared relatively enriched for crossovers near the center of the q-arm.…”

Section: Resultssupporting

confidence: 91%

“…On a per-chromosome basis, the depletion was observed across all chromosomes but was largest for Chromosome 16 (54%) and smallest for Chromosome 4 (17%). Although these observations are consistent with the hypothesis that a reduced rate (or absence; i.e., “exchangeless homologs”) of recombination contributes to aneuploidy risk ( Hassold and Hunt 2021 ; Hassold et al 2021 ), we note that they may be partially driven by a failure of our method to detect crossovers on reciprocal recombinant chromosomes—a limitation that uniquely applies to trisomies but not disomies and affects nearly all previous genotype-based studies (see Discussion).…”

Section: Resultssupporting

confidence: 88%

“…Abnormal number or location of meiotic crossovers between homologous chromosomes may predispose oocytes to aneuploidy, as shown by several previous studies (for review, see Hassold and Hunt 2021 ). Our published method, LD-PGTA ( Ariad et al 2021 ), facilitates the mapping of crossovers on trisomic chromosomes, which can then be compared to the crossover map for disomic chromosomes obtained via LD-CHASE.…”

Section: Resultsmentioning

confidence: 76%

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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: 91%

Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 76%

See 1 more Smart Citation

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

Ariad,

Madjunkova,

Madjunkov

et al. 2023

Genome Res.

View full text Add to dashboard Cite

show abstract

“…Chromosomes 7, 14, and 16 exhibited significant differences in crossover landscapes between disomic and trisomic chromosomes (p-value < 0.05; though note small sample sizes for chromosomes 7 and 14), whereas chromosome 22 fell just above this threshold (p-value = 0.051; Table S3). Our observations reveal that on chromosome 16, trisomies lacked a pair of hotspots in the vicinity of the centromere-one on each arm-broadly consistent with the previous observation that distal crossovers were enriched among a smaller sample of 62 cases of Trisomy 16 [13,40].…”

Section: An Altered Landscape Of Crossovers Among Aneuploid Versus Di...supporting

confidence: 91%

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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“…Hassold and Hunt review the patterns of atypical recombination seen for different aneuploidies 19 . Recombination occurs during fetal development while meiotic segregation errors arise only once the egg is ovulated (mostly 15–45 years later).…”

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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Missed connections: recombination and human aneuploidy

Cited by 10 publications

References 47 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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