Somatic mutations in human ontogenesis and their impact on health.

Abstract

Somatic mosaicism originates from postzygotic errors and creates a unique genomic landscape in every cell and individual. The health impacts of somatic mutations range from neutral to severe, responsible for most cancers and contributing to neurodevelopmental, neurodegenerative and other multifactorial diseases. The molecular mechanisms driving this variability are diverse, dominated by replication errors of DNA polymerase ε in CpG contexts and by spontaneous cytosine deamination followed by error-prone base excision repair. Duplex and single-cell sequencing now permit accurate quantification of low-frequency variants. These methods reveal that somatic mutations accumulate approximately linearly with age across tissues, from a few hundred per cell at birth to several thousand in old age. Rates differ several-fold between cell types, and the accumulating mutations carry specific clock-like signatures. We examine puberty, a period of intense hormone-dependent proliferation that confers reproductive capacity, as a plausible but understudied window of vulnerability for accelerated mutagenesis. Reconstructed phylogenies place driver alterations in normal breast and prostate epithelium within the pubertal window, but the few available datasets show only a small, statistically non-significant excess of mutation burden during puberty. Evolutionary theories, such as the disposable soma hypothesis, provide a framework for understanding the interplay between germline and somatic mutation rates, reproduction and their relationship with lifespan. Major unresolved questions persist: direct measurement of mutation rates across ontogeny, particularly childhood, puberty and young adulthood in longitudinal studies; the establishment of pathogenicity thresholds; and the development of evidence-based interventions to mitigate the health impacts of somatic mutations across the human lifespan.