Somatic mutation is a natural process in healthy human tissues but has significant implications in a range of disorders and diseases with cancer being the most prominent example. In the last decade, genomics research generated big data resources that contributed tremendously to our understanding how genetic mutations and evolutionary processes shape cancer initiation and progression. More recently, sequencing efforts have shifted towards normal human tissues to explore their somatic mutational landscapes in order to understand the processes before cancer initiation. Here, data from large-scale cancer sequencing efforts is utilized as well as new data is generated to explore somatic mutation in healthy human tissues. Firstly, a mutational process that associates translocations with long-ranging epigenetic silencing is discovered in pan-cancer data. After somatic translocations involving the naturally inactivated X-chromosome in women, the RNA expression pattern of the partner chromosome indicated the spread of X-inactivation onto the autosomal partner in glioblastoma and bladder cancer. This recurrent finding highlights a novel rare mechanism how translocations contribute to genome instability and gene expression modulation in cancer. Secondly, G&T-seq, a single cell multiomics technique, is extended to single nucleotide variant analysis. When applied to cortical neurons, it suggested a substantial level of technical artefacts in previously published mutational spectra. Thus, this multiomic approach offers an alternative method in a field that is still under active development and identifies a basic but refined mutational spectrum in individual cortical neurons. Thirdly, hundreds of targeted microdissections of prostate epithelium were sequenced to investigate the lineage relationships and clonal dynamics within prostatic ductal structures. Through combination of genetic and morphological relationship between the epithelial microdissections, long-ranging developmental clones could be detected throughout the ductal structures. A secondary, more spatially confined expansion was indicated during puberty followed by tissue maintenance through local progenitor proliferation. This is the most comprehensive insight into the somatic point mutation landscape of healthy human prostate and generates valuable insight into the clonal dynamics of prostatic ductal epithelium. Collectively, this thesis contributes to the characterisation and our understanding of somatic mutational processes in health and disease.