Abstract
The work presented in this thesis shows that mutations arise constantly, between one generation and the next but also throughout life. This continuous occurrence of mutations leads to extraordinary genetic diversity between individuals but is also at the origin of the existence of genetically different populations of cells within a single human being. While the occurrence of novel mutations represents an important biological phenomenon in humans with a role on prenatal development, physiology and evolution, novel mutations also contribute to different forms of human disease ranging from rare and severe developmental disorders to adult-onset diseases such as cancer. The work in this thesis supports that in addition to the detection of mutations, NGS can be used as a tool to identify the timing of mutations in order to include the dimension of time in the interpretation of mutations and their possible consequences. De novo mutations have different recurrence risks depending on the exact timing at which they occurred, which can be determined by meticulous analysis with NGS methods. Indeed, genetic mosaicism resulting from mutations occurring during embryogenesis is common and, depending on their timing, postzygotic mutations can be transmitted to the next generation. Additionally, somatic mutations arise in stem cells throughout life and can be detected using highly sensitive sequencing methods. Furthermore, the timing of a mutation can also shape the resulting phenotype, as the same mutation can be involved in different disorders depending on its timing. For instance, overlapping germline and somatic mutations in SETBP1, leading to Schinzel-Giedion syndrome and to myeloid leukemia, respectively. Future work focusing on the role of timing of somatic and germline mutations will provide us with a better understanding of the effect of the expression of a mutation in the dynamic context of a cell, a tissue and a whole organism.
