From DNA damage to mutations : a thorough characterization of somatic genomic instability in the human body
Keywords: Biology.

Little is known about somatic mutagenesis, which is the process of quasi random acquisition of mutations in somatic cells (i.e. non-gamete cells). While somatic mutations play an important role in disease and bodily processes such as cancer, ageing, and immune response, the process of mutation acquisition in humans is poorly understood. It is important to fill this gap in knowledge as fundamental questions on somatic evolution have remained elusive, for instance to name a few: What are the main sources of mutagenesis? Are those environmental or endogenous? What's the role of different tissue-specific developmental paths on the types and abundance of mutations? How are subject phenotypic features associated with somatic mutagenesis? What are the main forces of selection acting on somatic mutations? To what extent cancer-like genomic characteristics appear prior to cancer development? Answering these questions would move forward the field, it would solidify an organismal understanding of the human body, and it could inform future cancer research and therapies. The work presented in this thesis aims to first provide a brief summary of somatic mutagenesis as we understand it today (first chapter), including the origins of mutations, the main differences with germline mutagenesis, and what we understand from an evolutionary perspective from cancer research. Then the results of two projects are presented, these aim to elucidate some of the questions posed above. The third chapter specifically looks at the origins of one of the most ubiquitous types of mutation that can lead to skin cancer. These are Ultra Violet (UV)-induced mutations that originate from unrepaired DNA damage inflicted by UV light present in the sunlight. The results from this project provide evidence that DNA damage occurs non-randomly in the human genome, and while the process from DNA damage to mutation acquisition is long, the distribution of mutations in skin cancer mirrors that of DNA damage in healthy cells. Most importantly, the main factor associated with DNA damage and mutations is the 3D genome organization within the nucleus, whereby DNA positioned in the outer nuclear area is more prone to be damaged and to accumulate mutations. The fourth chapter presents the results on the creation and analysis of the largest catalogue to date of somatic mutations across different healthy organs and people. These analyses provide strong evidence on how somatic mutation load can be affected by genetic background, age, and in some cases sex. An inter-tissue comparison revealed that there is great variability on mutation abundance across tissues, with those more commonly exposed to the environment (e.g. skin, lung, esophagus) having high number of mutations, whereas those with low environmental exposure (e.g. brain, muscle) showing the opposite effect. Importantly, cancer mutations are enriched across all healthy tissues thus posing a challenge to genetically define a cancerous state. Finally, evidence of both positive and negative selection was found in different sets of somatic mutations, this in contrast to germline evolution where negative selection prevails on most mutations. Interestingly, cancer mutations are the ones under positive selection, whereas most other mutations are under negative selection. In conclusion, the work presented here provides a thorough characterization of mutageneis from DNA damage to the establishment and evolution of somatic mutations. These results shed light on fundamental evolutionary questions as well as providing results that further our understanding of cancer as a disease of the genome