Mutational Spectra Provide Insight into the Mechanisms Bridging DNA Damage to Genetic Disease
With every replication, mammalian genomes accumulate point mutations in patterns that reflect the local chemical activity of intrinsic and extrinsic mutagenic processes. Over generations of cell replications, these patterns become a historical record of the identity and duration of past and ongoing chemical and biochemical perturbations capable of leaving mutational scars, such as environmental agent exposure, pathogen infection, inflammation or metabolic stress. Decoding these mutational records can provide insight into the causes and mechanisms of genetic diseases. Moreover, this record can provide clinically relevant information such as biomarkers of exposure, of disease progression, and of response to therapy. Furthermore, the records can also help to identify novel, actionable targets for intervention. Mechanistically, point mutations accumulate in sequence context-dependent patterns known as mutational spectra that reflect: 1) patterns of DNA damage formation; 2) activity of DNA repair; and 3) the aftermath of replication across DNA damage. Most individual forms of DNA damage lead to characteristic mutational spectra. This Chapter provides a summary of the mutational signatures extracted from large scale sequencing efforts in human cancer, and a closer look at the mutational patterns induced by several environmental carcinogens, highlighting the mechanistic steps that contribute to the observed mutational distributions.