AbstractPre-implantation genetic testing for aneuploidy (PGT-A) is used in approximately half of in vitro fertilization cycles. Given the limited understanding of the genetics of human embryos, the current use of PGT-A is based on biologically uncertain assumptions and unvalidated guidelines, leading to the possibility of disposing of embryos with pregnancy potential.

摘要植入前非整倍体基因检测（PGT-A）用于大约一半的体外受精周期。鉴于对人类胚胎遗传学的了解有限，目前使用PGT-A是基于生物学上不确定的假设和未经验证的指南，导致有可能处理具有怀孕潜力的胚胎。

We isolated and sequenced all single cells (1133) from in vitro cultured 20 human blastocysts. We found that all blastocysts exhibited mosaicism with mitotic-induced aneuploid cells and showed an ~25% aneuploidy rate per embryo. Moreover, 70% (14/20) of blastocysts contained ‘chromosome-complementary’ cells, suggesting genetic mosaicism is underestimated in routine PGT-A.

我们从体外培养的20个人类胚泡中分离并测序了所有单细胞（1133）。我们发现，所有胚泡均表现出与有丝分裂诱导的非整倍体细胞的镶嵌性，并且每个胚胎的非整倍体率约为25%。此外，70%（14/20）的囊胚含有“染色体互补”细胞，这表明在常规PGT-A中遗传镶嵌被低估了。

Additionally, the analysis of 20,945 single cells from day 8–14 embryos (in vitro cultured) and embryonic/fetal organs showed that 97% of the analyzed embryos/organs were mosaic. Over 96% of their aneuploid cells harbored ≤ 2 chromosome errors. Our findings have revealed a high prevalence of mosaicism in human embryos..

此外，对第8-14天胚胎（体外培养）和胚胎/胎儿器官的20945个单细胞的分析表明，97%的分析胚胎/器官是镶嵌的。超过96%的非整倍体细胞具有≤2个染色体错误。我们的研究结果表明，人类胚胎中镶嵌症的患病率很高。。

IntroductionPre-implantation genetic testing for aneuploidy (PGT-A) is widely applied in clinical practice, and approximately half of in vitro fertilization cycles undergo PGT-A in the United States1. PGT-A is a genetic screening approach for deselecting affected embryos, improving rates of implantation and live birth2.

引言非整倍体植入前基因检测（PGT-A）在临床实践中得到广泛应用，在美国约有一半的体外受精周期经历了PGT-A 1。PGT-A是一种基因筛查方法，用于取消选择受影响的胚胎，提高植入率和活产率2。

Several PGT-A studies have shown that 2%–90% of embryos were diagnosed as having chromosomal mosaicism2,3,4,5. These studies mostly determined mosaic embryos via intermediate copy number strategy (20%–80% or 30–70%). However, some studies point out that this strategy can cause false positives of mosaic embryos, and that the reported mosaic embryos were actually uniform aneuploid/euploid embryos6.

几项PGT-A研究表明，2%–90%的胚胎被诊断出具有染色体镶嵌性2,3,4,5。这些研究主要通过中间拷贝数策略（20%–80%或30–70%）确定镶嵌胚胎。然而，一些研究指出，这种策略可能会导致镶嵌胚胎的假阳性，并且报道的镶嵌胚胎实际上是均匀的非整倍体/整倍体胚胎6。

This may result in the misguided disposal of potentially viable embryos and unnecessary termination of pregnancies7. Although multiple studies evaluated mosaicism in human embryos via various methods8,9,10,11, single cell genetic characteristic of the whole embryo is still unclear. Studies of both fetal and placental tissues reported a low incidence of mosaicism during first- and second-trimester pregnancies via cytogenetic chromosome analysis of chorion villus sampling (CVS) or amniocentesis sampling12,13.

这可能导致对潜在可行胚胎的错误处理和不必要的终止妊娠7。尽管多项研究通过各种方法评估了人类胚胎中的镶嵌性8,9,10,11，但整个胚胎的单细胞遗传特征仍不清楚。对胎儿和胎盘组织的研究报道，通过绒毛膜绒毛取样（CVS）或羊膜穿刺术取样的细胞遗传学染色体分析，妊娠早期和中期的镶嵌发生率较低12,13。

However, such a small proportion of cells obtained from CVS or amniocentesis sampling cannot reveal the genetic status of the whole fetus at different developmental stages. Considering the limited access to multiple tissues from the fetus, the dynamic mosaicism alterations during human fetal development remain largely unknown.In this study, we performed single-cell sequencing and data analysis to explore, for the first time, human embryo/fetus chromosomal mosaicism throughout multiple consecutive developmental stages spanning from the blastocyst stage to 26 w.

然而，从CVS或羊膜穿刺术取样获得的如此小比例的细胞不能揭示整个胎儿在不同发育阶段的遗传状态。考虑到从胎儿获得多种组织的途径有限，人类胎儿发育过程中的动态镶嵌变化在很大程度上仍然未知。。

Data availability

数据可用性

All data and protocols in this manuscript are available upon request from the lead contact. The raw sequencing data were deposited in the GSA-human database (HRA003384). The code used in this study is available on github (https://github.com/yzqheart/scBlastocystSeq).

应主要联系人的要求，可以获得本手稿中的所有数据和协议。原始测序数据保存在GSA人类数据库（HRA003384）中。这项研究中使用的代码可以在github上找到(https://github.com/yzqheart/scBlastocystSeq)。

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Download referencesAcknowledgementsWe are grateful to Drs. Jie Yan, Qiang Liu, and Yidong Chen for kindly reviewing our manuscript. This study was funded by the China National Key R&D Program (2019YFA0801400, 2018YFC1004000) and the National Natural Science Foundation of China (82125013, 82288102, 82101741).Author informationAuthor notesThese authors contributed equally: Fan Zhai, Siming Kong, Shi Song, Qianying Guo.Authors and AffiliationsCenter for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, ChinaFan Zhai, Siming Kong, Shi Song, Qianying Guo, Ling Ding, Jiaqi Zhang, Nan Wang, Ying Kuo, Shuo Guan, Peng Yuan, Liying Yan, Zhiqiang Yan & Jie QiaoNational Clinical Research Center for Obstetrics and Gynecology, Beijing, ChinaFan Zhai, Siming Kong, Shi Song, Qianying Guo, Ling Ding, Jiaqi Zhang, Nan Wang, Ying Kuo, Shuo Guan, Peng Yuan, Liying Yan, Zhiqiang Yan & Jie QiaoKey Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, ChinaFan Zhai, Siming Kong, Shi Song, Qianying Guo, Ling Ding, Jiaqi Zhang, Nan Wang, Ying Kuo, Shuo Guan, Peng Yuan, Liying Yan, Zhiqiang Yan & Jie QiaoBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, ChinaFan Zhai, Siming Kong, Shi Song, Qianying Guo, Ling Ding, Jiaqi Zhang, Nan Wang, Ying Kuo, Shuo Guan, Peng Yuan, Liying Yan, Zhiqiang Yan & Jie QiaoResearch Units of Comprehensive Diagnosis and Treatment of Oocyte Maturation Arrest, Beijing, ChinaFan Zhai, Siming Kong, Shi Song, Qianying Guo, Ling Ding, Jiaqi Zhang, Nan Wang, Ying Kuo, Shuo Guan, Peng Yuan, Liying Yan, Zhiqiang Yan & Jie QiaoPeking-Tsinghua Center for Life Sciences, Peking University, Beijing, ChinaSiming Kong & Jie Qia.

下载参考文献致谢我们感谢Jie Yan，Qiang Liu和Yidong Chen博士审阅我们的稿件。本研究由中国国家重点研发计划（2019YFA0801400108YFC1004000）和国家自然科学基金（821250138228810282101741）资助。作者信息作者注意到这些作者做出了同样的贡献：范斋，孔思明，石松，郭千英。作者和附属机构北京大学第三医院妇产科生殖医学中心，北京，中国翟凡，孔思明，石松，郭千英，丁玲，张嘉琦，王楠，郭莹，关硕，袁鹏，严丽英，严志强，乔杰全国妇产科临床研究中心，北京，翟凡，孔思明，石松，郭千英，丁玲，张嘉琦，王楠，郭莹，关硕，袁鹏，严丽英，严志强，乔杰辅助生殖实验室（北京大学），教育部，翟凡，孔思明，石松，郭千英，凌丁，张嘉琪，王楠，郭英国，关硕，袁鹏，严丽英，严志强，严杰乔培京生殖内分泌与辅助生殖技术重点实验室，北京，中国樊斋，孔思明，石松，郭千英，凌丁，张嘉琪，王楠，郭英国，关硕，袁鹏、严丽英、严志强和乔杰卵母细胞成熟停滞综合诊断和治疗研究单位，北京，中国翟凡、孔思明、石松、郭千英、丁玲、张嘉琪、王楠、郭莹、关硕、袁鹏、严丽英、严志强和乔杰北京大学清华生命科学中心，北京，孔思明和乔杰。

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PubMed Google ScholarContributionsConceptualization: J.Q., Z.Y., L.Y., P.Y.; Methodology: F.Z., Q.G., L.D., N.W., Y.K., S.G.; Bioinformatics analysis: S.K., Z.Y., S.S.; Funding acquisition: J.Q., L.Y., Z.Y.; Supervision: J.Q., L.Y., Z.Y., P.Y.; Writing — original draft: F.Z., S.K., Z.Y., Q.G., S.S.; Writing — review & editing: F.Z., S.K., Z.Y., Q.G., S.S., J.Z., J.Q., L.Y., P.Y.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献概念：J.Q.，Z.Y.，L.Y.，P.Y。；方法学：F.Z.，Q.G.，L.D.，N.W.，Y.K.，S.G。；生物信息学分析：S.K.，Z.Y.，S.S。；资金获取：J.Q.，L.Y.，Z.Y。；监督：J.Q.，L.Y.，Z.Y.，P.Y。；写作-原稿：F.Z.，S.K.，Z.Y.，Q.G.，S.S。；写作-评论和编辑：F.Z.，S.K.，Z.Y.，Q.G.，S.S.，J.Z.，J.Q.，L.Y.，P.Y。通讯作者通讯。

Peng Yuan, Liying Yan, Zhiqiang Yan or Jie Qiao.Ethics declarations

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Reprints and permissionsAbout this articleCite this articleZhai, F., Kong, S., Song, S. et al. Human embryos harbor complex mosaicism with broad presence of aneuploid cells during early development.

转载和许可本文引用本文Zhai，F.，Kong，S.，Song，S。等人。人类胚胎具有复杂的镶嵌性，在早期发育过程中广泛存在非整倍体细胞。

Cell Discov 10, 98 (2024). https://doi.org/10.1038/s41421-024-00719-3Download citationReceived: 19 March 2024Accepted: 23 July 2024Published: 24 September 2024DOI: https://doi.org/10.1038/s41421-024-00719-3Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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