DNA from the mother and father are handled differently in the newly formed embryo

Infertility and involuntary childlessness pose a great burden on women and couples and is a considerable challenge to society. Assisted reproductive technologies, like in vitro fertilization (IVF), can help individuals facing fertility challenges.

For couples without fertility challenges, the likelihood of conceiving is approximately one in four or one in five per cycle. Furthermore, data from the Norwegian Institute of Public Health (FHI) indicate that roughly one in eight pregnancies end in miscarriage, with the risk being higher in the earliest stages of pregnancy.

What accounts for these statistics, and what can go wrong during the initial phases of pregnancy??

Researchers at Centre for Embryology and Healthy Development (CRESCO) are seeking answers to why many embryos are lost. In a recent study on mice, they have examined how DNA from the mother and father are copied in the early embryo.

¡°This study is a step forward in understanding the development of early embryos. With more knowledge, we might be able to improve human fertility in the future,¡± Mads Lerdrup, researcher at CRESCO and Associate Professor at the University of Copenhagen, says.

Miscarriages often stem from chromosomal abnormalities

The risk of complications is at its peak during the first hours or days after fertilisation.

¡°These embryos that are lost very early in pregnancy, are never implanted in the uterus. They simply don¡¯t manage to get that far in their development. The same issue can arise with embryos fertilised in the lab through IVF,¡± Lerdrup explains. ??

One reason for this is damage of the DNA within the embryo, which can result in too few or too many chromosomes.

¡°Chromosomal damage in embryos is quite common, leading to their loss. However, we do not yet understand the underlying reasons. This is something that we aim to uncover,¡± he says.

A precarious process in early embryonic development

During the initial stages of pregnancy, embryos develop from a single cell to multiple cells through a process known as cell division. Each time a cell divides, the DNA, which contains the genetic codes in the cells, must be replicated.

This process occurs constantly within the human body throughout life.

¡°This cell division process is usually impressively efficient and error-free. Considering the many trillions of cells in our body, it is remarkable how robust this process is,¡± the Associate Professor points out.

However, the first cell divisions in an early embryo are not as straightforward.

¡°The egg cell and the sperm cell are highly specialised cells within which the DNA is packed up in a very confined space. Hence, the DNA must be unpacked and made accessible. The whole genome undergoes a lot of transitions in this first embryonic cell,¡± Lerdrup explains.

Researchers believe this induces significant "stress" within the embryo, studied extensively by Professor Eva Hoffman at the University of Copenhagen.?

¡°You can imagine these as stressful situations taking place at the same time in the early embryo. We know that this is a very special moment in our life cycle,¡± Lerdrup says.

Discovered that maternal and paternal DNA replication patterns were different

In their new study, the researchers studied the DNA replication patterns in early embryos.

"We discovered differences in the replication mechanisms of maternal and paternal DNA during the initial cell divisions," first author Jason Alexander Halliwell, Associate Professor at the University of Copenhagen, says.

The study was conducted on embryos from mice and is published in Nature Communications.?By using advanced sequencing technologies, they were able to separately analyse the replication patterns of the maternal and paternal genomes in single early embryos.?This process occurs in a quite similar manner in embryos from humans as it does in embryos from mice.

In certain regions, maternal DNA replicated much later than paternal DNA, whereas in other regions, maternal DNA replicated first.

¡°Our study was among the first studies where we were able to see in which part of the genome the DNA is copied first, and in which part of the genome it is copied last,¡± Lerdrup says.

¡°It is fascinating that maternal and paternal DNA replication occurs at different ¡®speeds¡¯,¡± the Associate Professor adds.

May improve IVF success rates in the future

The researchers anticipate that gaining more insight into stress factors in the early embryo could influence how fertility issues are addressed in the future.

¡°This new knowledge may lead us closer to understanding the potential underlying causes of DNA replication stress and errors leading to the loss of embryos,¡± Halliwell says.?

¡°Potentially, this could improve success rates of IVF-treatments and reduce developmental defects in the future,¡± the Assistant Professor adds.?
He underscores the remarkable fact that all human life begins from a single cell.

¡°What we really are studying is the process of how an embryo goes from one cell to trillions of cells that are within the human body,¡± he says.

¡°We want to understand the basic processes that are required to do that and why it often goes wrong at the earliest stages.¡±?

Technological advances enable the study

Professor Arne Klungland, Centre Director at CRESCO, highlights the technological advances that have made the study possible.

"This work demonstrates the technological progress made in molecular analysis. Now we can analyse dynamic processes in DNA from both the father and the mother within a single cell," the Professor says.

"Such methods could significantly impact our ability to investigate and understand the genetic causes of abnormal embryo development," Klungland continues.?

A sister centre for CRESCO in Copenhagen

This spring, a Danish centre of excellence named Center for Fertility and Inheritance (CFI) will be established. The centre will be lead by Professor Eva Hoffmann.?

¡°Both CRESCO and CFI share a vision of improving human and animal fertility, and it is our intent that researchers within these centres will team up in Norwegian-Danish collaborations. These big and ambitious questions require a lot of bright minds working together and state-of-the-art technology,¡± Lerdrup says.?

¡°The centres are a fantastic opportunity to strengthen already great scientific environments,¡± he adds.

Reference

Halliwell, J. A., Martin-Gonzalez, J., Hashim, A., Dahl, J. A., Hoffmann, E. R., & Lerdrup, M. (2024). Sex-specific DNA-replication in the early mammalian embryo. Nature Communications, 15(1), 6323.?https://doi.org/10.1038/s41467-024-50727-w

Contact

• Mads Lerdrup
• Arne Klungland
• Centre for Embryology and Healthy Development (CRESCO)

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