Yang Qingya, Carioscia Sara A, Isada Matthew, McCoy Rajiv C
Department of Biology, Johns Hopkins University, Baltimore, MD, USA 21218.
bioRxiv. 2024 Dec 2:2024.11.26.625484. doi: 10.1101/2024.11.26.625484.
Chromosome mis-segregation is common in human meiosis and mitosis, and the resulting aneuploidies are the leading cause of pregnancy loss. Preimplantation genetic testing for aneuploidy (PGT-A) seeks to prioritize chromosomally normal embryos for transfer based on genetic analysis of a biopsy of approximately five trophectoderm cells from blastocyst-stage fertilized (IVF) embryos. While modern PGT-A platforms classify these biopsies as aneuploid, euploid, or mosaic (possessing a mixture of normal and aneuploid cells), the underlying incidences of aneuploid, euploid, and mosaic embryos and the rates of meiotic and mitotic error that produced them remain largely unknown. To address this knowledge gap, we paired a recent method for embryo simulation with approximate Bayesian computation (ABC) to infer rates of meiotic and mitotic error that best explain published PGT-A data. By simulating from these posterior distributions, we also evaluated the chromosomal status of entire embryos. For a published clinical sample, we estimated a 39-43% probability of meiotic error per meiosis, as well as a 1.0-3.0% probability of mitotic error per mitosis, depending on assumptions about spatial clustering of aneuploid cells within mosaic embryos. In addition, our analyses suggest that less than 1% of blastocysts are fully euploid, and that many embryos possess low-level mosaic clones that are not captured during biopsy. These broad conclusions were relatively insensitive to potential misclassification of mosaic biopsies. Together, our work helps overcome the limitations of embryo biopsies to estimate the fundamental rates of cell division errors that are the main causes of human pregnancy loss.
染色体错分离在人类减数分裂和有丝分裂中很常见，由此产生的非整倍体是妊娠丢失的主要原因。胚胎植入前非整倍体基因检测（PGT-A）旨在根据对囊胚期体外受精（IVF）胚胎约5个滋养外胚层细胞活检的基因分析，优先选择染色体正常的胚胎进行移植。虽然现代PGT-A平台将这些活检样本分类为非整倍体、整倍体或嵌合体（含有正常细胞和非整倍体细胞的混合物），但非整倍体、整倍体和嵌合胚胎的潜在发生率以及产生它们的减数分裂和有丝分裂错误率在很大程度上仍然未知。为了填补这一知识空白，我们将一种最新的胚胎模拟方法与近似贝叶斯计算（ABC）相结合，以推断最能解释已发表的PGT-A数据的减数分裂和有丝分裂错误率。通过从这些后验分布进行模拟，我们还评估了整个胚胎的染色体状态。对于一个已发表的临床样本，根据对嵌合胚胎中非整倍体细胞空间聚类的假设，我们估计每次减数分裂的减数分裂错误概率为39%-43%，每次有丝分裂的有丝分裂错误概率为1.0%-3.0%。此外，我们的分析表明，不到1%的囊胚是完全整倍体，而且许多胚胎拥有在活检过程中未被捕获的低水平嵌合克隆。这些广泛的结论对嵌合活检潜在的错误分类相对不敏感。总之，我们的工作有助于克服胚胎活检的局限性，以估计作为人类妊娠丢失主要原因的细胞分裂错误的基本发生率。
