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

• Published in: The Journal of clinical investigation Vol. 134; no. 6; pp. 1 - 11
• Main Authors: Chavli, Effrosyni A, Klaasen, Sjoerd J, Van Opstal, Diane, Laven, Joop S.E, Kops, Geert J.P.L, Baart, Esther B
• Format: Journal Article
• Language: English
• Published: Ann Arbor American Society for Clinical Investigation 15.03.2024
• Subjects: Aneuploidy; Biopsy; Blastocyst; Blastocysts; Cells; Chromosome aberrations; Chromosomes; Copy number; Diagnosis; DNA; DNA biosynthesis; DNA damage; DNA sequencing; Embryonic development; Embryos; Genetic aspects; Genetic screening; Genetic testing; Genomes; Genomics; Health aspects; Human reproductive technology; Implantation; Karyotypes; Methods; Mosaicism; Nucleotide sequencing; Obstetrical research; Scientific equipment and supplies industry; Trophectoderm; Whole genome sequencing; United States; Netherlands
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI174483.

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.