How developmental signals may contribute to genomic mosaicism

Certain developmental signals not only shape the human embryo, but also play an important role in maintaining our genetic blueprints. They prevent alterations in the genome, called mosaicism.

An international research team led by scientists from the Center for Organismal Studies at Heidelberg University made the discovery while studying stem cells. The underlying biological mechanism allows DNA to produce an identical copy of itself during cell division using the original genetic template. But it may also contribute to genomic mosaicism during nerve cell development, according to the researchers, who analyzed tens of thousands of stem cell divisions.

The work is published in the journal Nature Communications.

The human body is made up of billions of cells that all have the same genetic blueprint and replicate from a single fertilized egg, that is, they replicate and separate division after division.

“During our lifetime, cellular mutations or other genomic alterations can occur due to errors in underlying processes or the effect of mutagens in certain cells. This creates a mosaicism in our body,” explains Dr. Anchel de Jaime-Soguero, postdoctoral researcher in the team led by Prof. Dr. Sergio P. Acebrón at the Center for Organism Studies at Heidelberg University.

This genomic mosaicism describes the existence of cell lines with different genetic information, which can lead to serious disorders or diseases.

“In embryonic development, there are two critical bottlenecks for genome maintenance,” explains Dr. de Jaime-Soguero.

Early human embryos often accumulate major alterations in their genome, including loss or gain of entire chromosomes, which is the leading cause of miscarriage. In addition, explosive neurogenesis in the developing brain can be accompanied by widespread genomic alterations that can contribute to neurodevelopmental disorders. The biological processes underlying the temporal and spatial formation of mosaicism remain largely unknown.

For their research, the researchers used pluripotent stem cells, which are capable of developing into almost any type of cell in the body. Using high-resolution imaging methods, they analyzed tens of thousands of stem cell divisions.

Professor Acebrón’s team was able to demonstrate that molecular signals that contribute to embryonic development and protect against errors in the genome of stem cells can also trigger mosaicism. According to the researchers, whether these different developmental signals, especially WNT, BMP and FGF, assume one or another function depends on where they are active in the early stages of embryonic development.

The researchers also determined that the underlying regulatory mechanism functions as a brake or accelerator pedal for DNA replication dynamics. Beyond pluripotency, most embryonic cell types are “insensitive” to this mechanism, with the exception of neural stem cells, which generate nerve cells. In their experiments on human and mouse neural stem cells, the researchers found that the same signal that induces neurogenesis is also responsible for high levels of chromosome segregation errors.

“We believe that this biological mechanism is a key piece of the puzzle to understand how mosaicism arises during early embryonic development,” says Professor Acebrón.