Scientists had thought aneuploidy arose in some embryos due to problems with the activity of microtubule spindles, the cell apparatus that pulls the two sets of chromosomes apart during mitosis. Now a study of human and mouse embryos and oocytes published in Cell shows most of these mistakes are not primarily due to the spindles, but spontaneous errors in DNA duplication occurring during the earliest stages of mitosis in the one-cell stage. These errors cause the spindles to malfunction and place the wrong number of chromosomes in each daughter cell, leading to aneuploidy.
'This has largely been overlooked in previous studies – because why would the embryo allow the integrity of the genome to be compromised when this is such a critical requirement for normal development?' said Dr Dieter Egli, assistant professor at Columbia University, New York and the study's lead author.
During IVF, only around 30 percent of human embryos make it to the blastocyst stage and most embryos stop growing within a few days of fertilisation. Identifying why this is could help researchers identify targets for predicting or even improving IVF success rates. A recent study looked at the reasons why some IVF embryos stop dividing, and found some go into a senescent-like state (see BioNews 1149). While PGT-A is used to identify aneuploid embryos before transfer, whether or not this screening can improve the likelihood of a live birth for women under the age of 35 is the subject of some controversy (see BioNews 1123).
In this latest study researchers found spontaneous DNA errors which caused asymmetric progression of the replication fork could lead to weaknesses and breaks in the DNA. This incomplete and inaccurate duplication of DNA led to breaks in the chromosomes which in turn caused dysregulation of the spindles and aneuploidy.
DNA methylation could be the cause of the slow progression of the replication fork, the authors hypothesised, along with inherited DNA damage. The areas of the chromosomes that were most likely to be affected by DNA strand breaks were mostly in non-protein coding regions of the genome.