Discovery of somatic mutations in the first stage of human life
A longstanding fundamental question in biological/medicinal research has encompassed the various events that occur in very early human development. To explore this research area, direct experiments are clearly not applicable for probing the human embryo as such.
In this work, researchers at KAIST observed the earliest mutations of human life, for example mutations acquired at a cell that is at the 2-, 4- or 8-cell stage, using whole-genome sequences of blood samples collected from 279 individuals with breast cancer.
Overall, this human embryo study involves the discovery of 163 early embryonic mutations seen in adult cells, which enables the tracking of human embryo development.
Somatic mutations of early embryonic stages can be distinguished from inherited polymorphisms from parents as they will be present in not all, but in a fraction of adult cells (known as somatic mosaicism).
Somatic mutations, for example, arising in one of the two cells in two-cell stage embryos will be present in approximately 50% of adult cells, if the two cells contribute equally to the adult tissues.
By applying careful bioinformatics algorithms on publicly accessible population-scale genome sequencing data set, the researchers can accurately identify a number of mosaic mutations for the first time.
Using the mutations, the researchers at KAIST statistically calculated which proportion of adult cells resulted from each of the first two cells in the embryo.
We found that these first two cells contribute differently to the whole body of adult individuals.
One cell gives rise to approximately 70% of adult tissues (dominant cell), whereas the other cell has a minor contribution, ~30% of tissues.
The skewed contribution continued for early cells in the later stages, i.e., 4-cell and 8-cell stages.
During this study, the researchers were also able to measure the rate of mutation in early human development for the first time, up to the earliest three cell-generations.
Contrary to conventional wisdom with ~1 mutation per cell per cell division, this study measured ~3 mutations for each cell doubling in every daughter cell.
Finally, this study also identified the mutational processes attributed to the 163 earliest mutations, known as mutational signatures 1 and 5.
These mutations are fairly randomly distributed throughout the human genome; functionally, the vast majority of the mutations are not likely to have remarkable or harmful consequences in individuals.
However, early mutations frequently occur in the human embryo.
Therefore, if an important gene is stochastically inactivated by early mutations, diseases such as developmental disorders could be caused.
This work was published in the journal Nature this March.
Ju YS, Martincorena I, Gerstung M, Petljak M, Alexandrov LB et al., “Somatic mutations reveal asymmetric cellular dynamics in the early human embryo”. Nature. 2017 Mar 30;543(7647):714-718.
Including website for more information:
* lab webpage : http://julab.kaist.ac.kr