Early mouse embryos are prone to DNA replication errors

During the first cell divisions of mouse embryos a period of instability has been uncovered, which translates into chromosomal errors.

Researchers from the RIKEN Centre fror Biosystems Dynamics Research in Kobe, Japan, aimed to understand why aneuploidy is relatively common in early mammalian development (see BioNews 1056 and 1076). The authors developed a new analysis technique to generate a single-cell high resolution and genome-wide DNA replication atlas of pre-implantation mouse embryos.

'We found that at certain points, genomic DNA is temporarily unstable and chromosomal aberrations are elevated' said Dr Ichiro Hiratani, corresponding author of the paper published in Nature.

DNA replication is key during early development to guarantee conservation of the genomic material. Following fertilisation, the zygote undergoes a series of cell divisions into two, four, eight and 16 cells before differentiation into distinct cell types begins. During each division, the DNA is replicated before being equally divided into the two daughter cells.

Genomic DNA is organised in chromosomes. During replication, the chromosomes and DNA untangle forming a structure that looks like a fork moving down the DNA strands. The fork rezips DNA after replication and unzips the sections that will be replicated next.

By carefully characterising the DNA replication mechanism at the single-cell level, Dr Hiratani's team discovered that the fork speed increases abruptly at the four to eight-cell stage. Moreover, before the four-cell stage, DNA replication happens gradually and uniformly, unlike adult cells that do so in specific sequences. These results agreed with mouse totipotent cells showing a slower DNA replication mechanism (see BioNews 1136).

As the replication mechanism changes and the speed of the fork increases, division from four into eight-cell is unstable and prone to chromosomal errors varying from extra copies, missing copies, breaks or incomplete sections.

'Given these observations, it is all the more surprising that the erroneous transitional four-cell... was not eliminated during evolution' the authors wrote in the paper. The team also highlighted that these results raise more questions than answers.

'... are these series of phenomena evolutionarily conserved in other species, including human embryos? And what are the subsequent fates of cells with chromosomal aberrations?' said Dr Hiratani.

This stage of development, the division from four into eight cells, takes place in IVF clinics before embryo transfer. 'Moreover, [these observations] provide insights for future clinical applications in IVF clinics regarding strategies to minimise chromosome aberrations common in early embryos', the authors wrote in the paper.