Somatic mosaicism occurs when cells within the same person carry different genomes because of mutations that arise after fertilization. This intrapersonal genetic diversity can be present in a few cells or expand to large tissue patches, and it affects both normal physiology and disease susceptibility. Leslie G. Biesecker National Human Genome Research Institute and Nancy B. Spinner Johns Hopkins University reviewed how postzygotic mutations create diagnostic and therapeutic challenges, because a pathogenic variant may be absent from blood but present in affected tissues, altering detection and clinical interpretation. Recognition of mosaicism is therefore central to accurate genetic diagnosis and risk assessment.
Mechanisms and sources of variation
Mutations that produce mosaicism come from errors in DNA replication, failure of DNA repair, and exposure to environmental mutagens. Inigo Martincorena Wellcome Sanger Institute and colleagues demonstrated that normal adult tissues accumulate large numbers of somatic mutations and that exposures such as ultraviolet light drive mutation patterns in skin. Clonal expansion of mutated cells—when a cell with a selective advantage divides more than its neighbors—can turn a rare event into a sizable cellular population. Clonal expansion is a mechanistic bridge between neutral mosaic change and clinically important lesions, because it increases the cellular fraction carrying a mutation and therefore its functional impact.
Consequences for disease risk and tissue function
When mosaic mutations affect critical genes or cell types, they can cause focal or systemic disease. Examples include localized developmental malformations, some forms of epilepsy and neurodevelopmental disorders, and many cancers where somatic driver mutations accumulate. Biesecker and Spinner emphasize that mosaicism complicates genotype–phenotype correlations: the same mutation may be benign at low cellular fraction but pathogenic after clonal expansion. Tissue context matters: a mutation in a small population of neurons may disrupt networks, whereas the same change in a nonessential cell type may be clinically silent.
Environmental and cultural factors influence mosaic outcomes. Sun-exposed lifestyles increase skin mutation burden; smoking and pollution similarly raise mutation rates in respiratory tissues, altering local disease risk and public-health patterns. Aging also increases mosaicism and is linked to clonal hematopoiesis, which raises risks of hematologic malignancy and cardiovascular disease. Clinically, improved deep sequencing and tissue sampling make detection more reliable, but variable sampling and low allele fractions still limit interpretation. Understanding somatic mosaicism therefore requires integrating genomic evidence, tissue biology, exposure history, and rigorous clinical correlation to assess risk and guide care.