Somatic mutations and mosaicism

Somatic mutations are DNA changes arising post-zygotically in body cells rather than the germline, affecting only descendants of the cell where they occur. Every cell division carries a small replication-error probability, and exogenous mutagens (UV radiation, tobacco carcinogens, reactive oxygen species) further damage DNA throughout life; mutational burden thus rises roughly linearly with age — ~40 single-nucleotide substitutions per year in intestinal and hepatic stem cells (Blokzijl et al., 2016, Nature). When the resulting patchwork of genetically distinct lineages becomes detectable, the state is called somatic mosaicism. If a mutation confers even a modest replicative advantage, the clone can expand beyond random drift — clonal expansion. The best-characterised example is clonal hematopoiesis (CH): mutations in DNMT3A, TET2, and ASXL1 drive replacement of normal blood cells by one expanded clone. Jaiswal et al. (2014, NEJM) found CH in fewer than 1% of individuals under 40, rising to ~9–18% after age 70, associated with 11-fold elevated haematological-malignancy risk, 2-fold increased coronary heart disease risk, and 40% higher all-cause mortality. This link is associational in humans; mouse models support a causal inflammatory mechanism through which mutant leukocytes exacerbate atherosclerosis. Somatic mutations contribute to genomic instability, listed among the primary hallmarks of aging by López-Otín et al. (2023, Cell), though whether they directly drive organismal aging versus co-occurring with it remains under investigation.