de Quadros Elaine, Xu Jia, Treff Nathan, Marin Diego, Freedman Arielle, Milevski Cristian, Miller Kathleen, Bian Minglei
Department of Reproductive Clinical Science, Embryology & Andrology, Eastern Virginia Medical School (part of Macon & Joan Brock Virginia Health Sciences at Old Dominion University), Norfolk, VA, USA.
Reproductive Specialists of the Carolinas Embryology Laboratory, Charlotte, NC, USA.
Hum Reprod. 2025 Jul 30. doi: 10.1093/humrep/deaf151.
Are segmental aneuploidies identified in human embryos more likely to occur within known fragile sites of the genome?
Segmental breaks in the autosomes of human preimplantation embryos occur more frequently in known fragile areas of the genome.
Fragile sites represent specific loci in the genome characterized by inhibition of DNA synthesis when exposed to known inhibitors and are particularly sensitive to replication stress and instability.
STUDY DESIGN, SIZE, DURATION: This was a retrospective analysis of single nucleotide polymorphism (SNP) array-based preimplantation genetic testing data from biopsies performed on 2066 human blastocysts in 98 assisted reproduction laboratories around the world from September 2019 to January 2023.
PARTICIPANTS/MATERIALS, SETTING, METHODS: This multicenter study included eligible patients undergoing IVF with preimplantation genetic testing (PGT), in which at least one embryo was diagnosed with a segmental aneuploidy. The mean maternal age was 36.4 years (SD 4.1), ranging from 25 to 44 years. These samples were processed on high-density SNP arrays. Chromosome level copy number and B allele frequency (BAF) plots from these embryos were used to determine segmental aneuploidy breakpoints. Known fragile sites catalogued by the HumCFS database were used for correlation analyses.
Overall, a side-by-side pairing of observed breakpoints and known fragile sites demonstrated a strong concordance (r = 0.81, 95% CI [0.6, 0.92]). A chi-square test for independence for stratified groups showed a highly significant correlation between all observed breakpoints and known fragile sites (597 expected vs. 848 observed; P < 0.001) and for telomeric breaks alone (521 expected vs. 784 observed; P < 0.001). Observed interstitial breaks alone were not correlated to expected breakpoints (75 expected vs. 64 observed; P > 0.05).
LIMITATIONS, REASONS FOR CAUTION: These findings should be interpreted with caution, as limitations in genomic resolution may bias detection and classification of smaller segmental aneuploidies. Additionally, this study touched upon the distribution of meiotic to mitotic breakpoints in human blastocysts as they relate to known fragile sites. Since meiotic aneuploidies increase with advanced maternal age and many IVF patients undergoing PGT-A testing fall in this category, a sampling bias should be considered for this specific metric.
Demonstrating that segmental aneuploidies significantly correlate with known fragile sites highly susceptible to replication stress offers insight into the origin of subchromosomal imbalances and hints at the influence of stressors on reproductive success.
STUDY FUNDING/COMPETING INTEREST(S): This study received no external funding and was fully supported by the participating authors and their affiliated institutions. The authors declare no conflicts of interest related to this study.
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在人类胚胎中检测到的节段性非整倍体是否更有可能出现在基因组中已知的脆性位点内？
人类植入前胚胎常染色体中的节段性断裂在基因组中已知的脆性区域更频繁地发生。
脆性位点代表基因组中的特定位点，其特征是在暴露于已知抑制剂时DNA合成受到抑制，并且对复制应激和不稳定性特别敏感。
研究设计、规模、持续时间：这是一项回顾性分析，分析了2019年9月至2023年1月期间全球98个辅助生殖实验室对2066个人类囊胚活检进行的基于单核苷酸多态性（SNP）阵列的植入前基因检测数据。
参与者/材料、环境、方法：这项多中心研究纳入了接受体外受精并进行植入前基因检测（PGT）的符合条件的患者，其中至少有一个胚胎被诊断为节段性非整倍体。母亲的平均年龄为36.4岁（标准差4.1），年龄范围为25至44岁。这些样本在高密度SNP阵列上进行处理。这些胚胎的染色体水平拷贝数和B等位基因频率（BAF）图用于确定节段性非整倍体断点。由HumCFS数据库编目的已知脆性位点用于相关性分析。
总体而言，观察到的断点与已知脆性位点的并排配对显示出很强的一致性（r = 0.81，95%可信区间[0.6, 0.92]）。分层组的独立性卡方检验显示，所有观察到的断点与已知脆性位点之间存在高度显著的相关性（预期597个与观察到的848个；P < 0.001）以及仅端粒断点之间（预期521个与观察到的784个；P < 0.001）。单独观察到的间质断点与预期断点不相关（预期75个与观察到的64个；P > 0.05）。
局限性、谨慎原因：这些发现应谨慎解释，因为基因组分辨率的局限性可能会使较小节段性非整倍体的检测和分类产生偏差。此外，本研究涉及人类囊胚中减数分裂至有丝分裂断点的分布与已知脆性位点的关系。由于减数分裂非整倍体随着母亲年龄的增加而增加，并且许多接受PGT-A检测的体外受精患者属于这一类别，因此对于这一特定指标应考虑抽样偏差。
证明节段性非整倍体与高度易受复制应激影响的已知脆性位点显著相关，这为亚染色体不平衡的起源提供了见解，并暗示了应激源对生殖成功的影响。
研究资金/利益冲突：本研究未获得外部资金，完全由参与的作者及其附属机构支持。作者声明与本研究无关的利益冲突。
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