Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos

Abstract

The high incidence of aneuploidy in early human development, arising either from errors in meiosis or postzygotic mitosis, is the primary cause of pregnancy loss, miscarriage, and still birth following natural conception as well asin vitrofertilization (IVF). Preimplantation genetic testing for aneuploidy (PGT-A) has confirmed the prevalence of meiotic and mitotic aneuploidies among blastocyst-stage IVF embryos that are candidates for transfer. However, only about half of normally fertilized embryos develop to the blastocyst stagein vitro, while the others arrest at cleavage to late morula or early blastocyst stages. To achieve a more complete view of the impacts of aneuploidy, we applied a validated method of PGT-A to a large series (n = 909) of arrested embryos and trophectoderm biopsies. We then correlated observed aneuploidies with abnormalities of the first two cleavage divisions using time lapse imaging (n = 843). The combined incidence of meiotic and mitotic aneuploidies was strongly associated with blastocyst morphological grading, with the proportion ranging from 20% to 90% for the highest to lowest grades, respectively. In contrast, the incidence of aneuploidy among arrested embryos was exceptionally high (94%), dominated by mitotic aneuploidies affecting multiple chromosomes. In turn, these mitotic aneuploidies were strongly associated with abnormal cleavage divisions, such that 51% of abnormally dividing embryos possessed mitotic aneuploidies compared to only 23% of normally dividing embryos. We conclude that the combination of meiotic and mitotic aneuploidies drives arrest of human embryosin vitro, as development increasingly relies on embryonic gene expression at the blastocyst stage.

Simultaneous genome-wide haplotyping and copy number detection enables universal equine preimplantation genetic testing

“…In contrast, the two aneuploid blastocysts contained errors of meiotic origin on smaller chromosomes, and one of them additionally contained mitotic aneuploidies in a small proportion of the embryo, as they were detected in the TE biopsy only. These ndings corroborate the human observation that especially genomic aberrations that affect a large part of the genome in a large proportion of the embryo, such as (complex) aneuploidy resulting from mitotic errors at the earliest embryonic divisions, combinations of meiotic and mitotic aneuploidies, or ploidy aberrations seem detrimental to embryonic development while meiotic errors or low-grade mosaicism do not necessarily prohibit embryo development to the blastocyst stage 24,28,32,33,66,67 . In horses, meiotic monosomies of smaller autosomal chromosomes have been reported in aborted equine specimens (e.g., chromosome 26, 27 and 31), but never in live born horses 11,20 .…”

“…Considering this is a bit lower compared to the frequencies of human arrested cleavage-stage embryos (93-94% in 32,33 ), this is likely a realistic estimate. At the blastocyst-stage, errors were detected in 14% of samples.…”

“…In human and cows, aneuploidy occurs frequently throughout early embryo development [21][22][23][24][25][26][27][28] and contributes also to pregnancy loss before the clinical detection of pregnancy. The latter is known from transfers of aneuploid cow and human blastocysts 25,[29][30][31] and the analysis of in vitro-produced human embryos that arrest before reaching the blastocyst stage 32,33 . In addition, IVEP may increase the incidence of genomic instability as shown by studies in different livestock species 22,27,34 .…”

CHK1‐CDC25A‐CDK1 regulate cell cycle progression and protect genome integrity in early mouse embryos

“…Infertility rates worldwide are increasing (Carson & Kallen, 2021 ; Gruhn & Hoffmann, 2022 ). About 50% of human embryos do not develop to the blastocyst stage due to a high incidence of aneuploidy (preprint: McCoy et al , 2022 ). Also, almost 95% of human arrested embryos show chromosome segregation errors (preprint: McCoy et al , 2022 ), and even in blastocysts, 20% show mosaicism when disaggregated (Capalbo et al , 2021 ) or 30% when a biopsy is analyzed (preprint: McCoy et al , 2022 ).…”

A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

“…Understanding this stage is paramount for discerning causes of infertility, implantation failure and spontaneous abortion, as well as developmental disorders. Although counter-intuitive, human preimplantation embryos are highly prone to chromosomal instability (CIN), not only following in vitro fertilisation (IVF) [1][2][3][4][5] , but also after natural conception [6][7][8][9][10] . Chromosomal gains and losses may arise during meiosis, affecting the whole embryo after fertilisation 1,2,[6][7][8][9][10][11][12] .…”