Most of us assume that when a cell divides, it creates two daughter cells identical to the parent cell, but the reality is more like a genetic game of telephone. With almost every cell division, a mutational event becomes fixed in the daughter cells. Normally, cells can repair any mutations by the time the next cell division occurs. However, when this mutation is carried forward to the next generation of cells, a clone of mutated cells can emerge. As a result, humans can emerge as complex mosaics, each cell genetically distinct from the other. Mosaic mutations consist of a mixture of normal and mutated cells, leading to competition and dynamic changes in proportions over time
Embryonic development
In the process of embryonic development, things are just getting started. Unlike their specialized counterparts like muscle or skin cells, embryos are made of pluripotent stem cells—cells with the potential to develop into any tissue type. But here's the catch: a mutation in these cells creates a genetic domino effect, with consequences across multiple tissues as development continues. This is especially important to understand risks of passing on genetic disease. Mutations can trigger abnormal cell function, paving the way for disease to progress. It begs the question: just how early can these mutations occur?
Mosaicism is defined by the timing and lineage of the mutation (Walvogel et al, 2024).
Understanding phylogenetics
One method scientists use to answer this question is phylogenetics. Phylogeny refers to the evolutionary development of a species or group of organisms. It's like tracing the family tree from dinosaurs to chickens. Now, shrink it down to the cellular level. When combined with genetics, phylogenetics can refer to the evolutionary development of cells within an organism. By spotting mutations that overlap, scientists figure out when mutations were acquired. For example, if most cells have a certain mutation, it most likely showed up early in development. When scientists built genetic family trees (phylogenies), they discovered something intriguing: those first cell divisions in embryos are most susceptible to mutational events. This could be explained by the rapid division that occurs in early development with not many cell cycle checkpoints to make sure everything's accurate.
The shared mutations between the clonal genomes are used to construct a phylogeny (Walvogel et al, 2024).
Implications on genetic risk assessment
Despite its clinical significance, current clinical guidelines frequently miss detecting mosaicism which is a critical oversight. The evolving research on genetic mosaicism shines a spotlight on its important role in genetic risk assessment, especially for parents carrying mosaic mutations. The increased risk of passing on genetic disorders to their children shows the need for accurate genetic counseling and well-informed decision-making. As our understanding of genetic inheritance continues to expand, it becomes increasingly important for researchers to access reliable testing methods specifically designed to identify mosaic mutations.
References
Waldvogel, S. M., Posey, J. E., & Goodell, M. A. (2024). Human embryonic genetic mosaicism and its effects on development and disease. Nature Reviews Genetics, 1-17.
Serb, J. M., & Oakley, T. H. (2005). Hierarchical phylogenetics as a quantitative analytical framework for evolutionary developmental biology. Bioessays, 27(11), 1158-1166. Assessed and Endorsed by the MedReport Medical Review Board