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Single-cell DNA sequencing reveals a high incidence of chromosomal abnormalities in human blastocysts
Effrosyni A. Chavli, … , Geert J.P.L. Kops, Esther B. Baart
Effrosyni A. Chavli, … , Geert J.P.L. Kops, Esther B. Baart
Published January 4, 2024
Citation Information: J Clin Invest. 2024;134(6):e174483. https://doi.org/10.1172/JCI174483.
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Research Article Genetics Reproductive biology Article has an altmetric score of 12

Single-cell DNA sequencing reveals a high incidence of chromosomal abnormalities in human blastocysts

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Abstract

Aneuploidy, a deviation from the normal chromosome copy number, is common in human embryos and is considered a primary cause of implantation failure and early pregnancy loss. Meiotic errors lead to uniformly abnormal karyotypes, while mitotic errors lead to chromosomal mosaicism: the presence of cells with at least 2 different karyotypes within an embryo. Knowledge about mosaicism in blastocysts mainly derives from bulk DNA sequencing (DNA-Seq) of multicellular trophectoderm (TE) and/or inner cell mass (ICM) samples. However, this can only detect an average net gain or loss of DNA above a detection threshold of 20%–30%. To accurately assess mosaicism, we separated the TE and ICM of 55 good-quality surplus blastocysts and successfully applied single-cell whole-genome sequencing (scKaryo-Seq) on 1,057 cells. Mosaicism involving numerical and structural chromosome abnormalities was detected in 82% of the embryos, in which most abnormalities affected less than 20% of the cells. Structural abnormalities, potentially caused by replication stress and DNA damage, were observed in 69% of the embryos. In conclusion, our findings indicated that mosaicism was prevalent in good-quality blastocysts, whereas these blastocysts would likely be identified as normal with current bulk DNA-Seq techniques used for preimplantation genetic testing for aneuploidy.

Authors

Effrosyni A. Chavli, Sjoerd J. Klaasen, Diane Van Opstal, Joop S.E. Laven, Geert J.P.L. Kops, Esther B. Baart

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Figure 5

Examples of mitotic error events leading to chromosomal mosaicism observed in different embryos.

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Examples of mitotic error events leading to chromosomal mosaicism observ...
(A–E) Copy number of the affected chromosome in all daughter cells within each embryo. (F and G) Every row represents the scKaryo-Seq result of a single cell and every column represents a different chromosome. The black and gray bars on the left indicate the cell origin (TE or ICM). The colors portray copy number states. The embryo numbers refer to Supplemental Table 3. (A) Embryo 9: Reciprocal gain and loss of chr21 in different daughter cells. (B) Embryo 34: The reciprocal gain and loss of the same segment of chr20 distributed over the daughter cells implies the occurrence of chromosome breakages. (C) Embryo 3: Whole chromosome and partial loss of chr19. The partial losses are of a different length and belong to cells that passed the quality control. (D) Embryo 22: There are cells with a whole chromosome or partial loss of chr8 possibly originating from 1 mitotic error. (E) Embryo 9: Chr5 is lost with the exception of the pericentromeric region, suggesting (peri) centromeric breakage events. (F) Complex abnormal cells within embryo 22 with related chromosomal abnormalities, as in all cells the same chromosomes are affected. One complex abnormal cell also contains multiple copies of a partial gain of chr8, which is most likely the reciprocal product of the partial losses of chr8 observed in other daughter cells (see arrow). (G) Embryo 42: Mixoploid chromosomal constitution in which fully triploid cells are present next to diploid cells. The TE and ICM were not analyzed separately in this embryo.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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