Nature of spontaneously arising single base substitutions in normal cells

Abstract

Next-generation sequencing (NGS) of single cells and micro-dissected tissues has demonstrated that the number of somatic mutations in normal cells increases linearly with age. The majority of somatic mutations are single base substitutions (SBSs). NGS has revealed the mutagenic effect of various metabolic and environmental genotoxic agents on different cells, such as normal colonic epithelial cells, hematopoietic cells, hepatocytes, and neurons. NGS has also uncovered the clonal expansion of cells in normal tissues of the elderly driven by oncogenic mutations. There are two main mechanisms for the generation of mutations, namely, replication errors and DNA damage, with both being followed by inaccurate repair. NGS studies of normal tissues highlight the substantial contribution of the latter mechanism by revealing the significant accumulation of somatic mutations in mitotically inactive hepatocytes and neurons. This review describes the nature of spontaneously arising SBSs in normal tissues, the causes of mutagenesis, cellular pathways of the DNA damage response that suppress mutagenesis, as well as unsolved questions on the matter.

Funding

JSPS KAKENHI(16H06306); JSPS Core-to-Core Program, A. Advanced Research Networks; Program of the National Natural Science Foundation of China(41991314)