Aberrant landscapes of maternal meiotic crossovers contribute to aneuploidies in human embryos.
Aberrant landscapes of maternal meiotic crossovers contribute to aneuploidies in human embryos.
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母体减数分裂交叉的异常景观导致人类胚胎的非整倍性。
DOI：
10.1101/2023.06.07.543910
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
McCoy,RajivC
中科院分区：
文献类型：
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作者：
Ariad,Daniel;Madjunkova,Svetlana;Madjunkov,Mitko;Chen,Siwei;Abramov,Rina;Librach,Clifford;McCoy,RajivC
减数分裂重组对人类遗传多样性和染色体分离的准确性至关重要。了解它在个体之间的变异以及它出错的过程是人类遗传学的长期目标。目前的方法推断重组景观依赖于人口遗传模式的连锁不平衡（LD）捕捉时间平均的观点，或直接检测的配子或多代系谱，这限制了数据集的规模和可用性的交叉。在这里，我们介绍了一种方法推断性别特异性重组景观使用数据植入前遗传检测非整倍体（PGT-A）。该方法依赖于体外受精（IVF）胚胎活检的低覆盖率（<0.05×）全基因组测序。为了克服数据稀疏性，我们的方法利用其固有的相关性结构，来自外部群体参考面板的单倍型知识，以及胚胎中频繁发生的单体性，从而默认对剩余染色体进行定相。大量的模拟表明，我们的方法的高精度，即使在覆盖率低至0.02×。将该方法应用于来自18，967个胚胎的PGT-A数据，我们绘制了70，660个分辨率为150 kbp的重组事件，复制了已建立的性别特异性重组模式。我们观察到减少总长度的女性遗传图谱的三体与二体性相比，以及染色体特异性改变的交叉分布。基于近着丝粒区域的单倍型构型，我们的数据表明不同机制的减数分裂错误的染色体特异性倾向。我们的研究结果提供了一个全面的观点，异常减数分裂重组的作用，在人类非整倍性的起源，并提供了一个通用的工具，映射交叉低覆盖测序数据从多个兄弟姐妹。
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.