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

TY - JOUR

T1 - Single-cell DNA sequencing reveals a high incidence of chromosomal abnormalities in human blastocysts

AU - Chavli, Effrosyni A

AU - Klaasen, Sjoerd J

AU - Van Opstal, Diane

AU - Laven, Joop Se

AU - Kops, Geert Jpl

AU - Baart, Esther B

PY - 2024/1/4

Y1 - 2024/1/4

N2 - 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.

AB - 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.

KW - Pregnancy

KW - Female

KW - Humans

KW - Preimplantation Diagnosis/methods

KW - Incidence

KW - Blastocyst

KW - Aneuploidy

KW - Mosaicism

KW - Sequence Analysis, DNA

KW - DNA

U2 - 10.1172/JCI174483

DO - 10.1172/JCI174483

M3 - Article

C2 - 38175717

SN - 0021-9738

VL - 134

JO - The journal of clinical investigation

JF - The journal of clinical investigation

IS - 6

ER -