FIGURE 2.

Proposed model of the dynamics of somatic mutagenesis during life. Schematic overview depicting the distributions and rates of somatic mutations. (A) Mutations arising early in development can be propagated to many cells of multiple tissues, as indicated by the red cell lineage. Due to this wide distribution, mutations arising early in life can have a strong potential impact on development and disease. Mutations acquired later in life are usually only inherited by a small number of cells (the blue- and orange-colored cells). Some early mutations, depicted by the purple lineage here, may also end up in extra-embryonic cell lineages not contributing to the embryo proper. (B) The somatic mutation rate is especially high in the first embryonic cell divisions. After genome activation, the mutation rate decreases. It is unclear if this decrease is gradual (as depicted) or more abrupt, but the mutation rate probably remains relatively high compared to the postnatal mutation rate. After birth, the somatic mutation rate appears to stay remarkably constant during aging, leading to a gradual linear mutation accumulation. Variance in the mutation rate between tissues leads to a tissue-specific mutation burden. In some tissues (such as intestine), the tissue-specific mutation patterns already arise early in embryogenesis, whereas in others (such as liver) these patterns start to emerge only after birth.