Prenatal Life is the Predominant Source of Somatic Mosaicism Across Tissues and Aging

Despite the well-known rise in somatic mutations with age, their true impact on aging—and the origins of mosaicism—has remained elusive. Here we present a powerful new framework that reconstructs the timing of somatic mutations across the entire lifespan using only adult tissues, integrating single-cell transcriptomics with high-resolution variant calling. Applying this framework to human and mouse tissues, we find that the vast majority of somatic mutations do not accumulate gradually with age but instead arise in a dramatic burst during embryonic development, concentrated in the first weeks of life. These early mutations seed long-lived clonal lineages that span tissues and persist for decades, defining the mosaic architecture of the body far more than previously appreciated. Our findings overturn the conventional view of mutation accrual in aging and highlight prenatal development as the dominant origin of lifelong somatic mosaicism.