Somatic Mosaicism of the Brain: The Functional Implications of Post‐Zygotic Mutations to Neural Circuits

Abstract

The human brain is a genomic mosaic shaped by post‐zygotic mutations that accumulate from the earliest embryonic divisions through aging. This review synthesizes current evidence on the origins, detection, functional consequences and disease relevance of neural somatic mosaicism. We find that somatic variants—including single‐nucleotide variants, copy‐number variations, mobile element insertions, structural rearrangements and aneuploidies—arise through distinct molecular mechanisms such as replication errors, oxidative stress, defective DNA repair and transposable element activity, each leaving characteristic mutational signatures. The developmental timing of mutations is the primary determinant of their clonal distribution and functional impact: early mutations generate widespread clones, whereas later events produce localized or single‐cell mosaics. We demonstrate that even small populations of mutant neurons can disrupt network dynamics when key signalling pathways are affected, as shown in mTOR‐related cortical malformations where non‐cell‐autonomous mechanisms drive epileptogenesis. Our analysis reveals that somatic mosaicism provides a unifying explanation for diverse neurological conditions, from focal epilepsies and neurodevelopmental disorders to late‐onset neurodegenerative diseases, including mechanisms invisible to conventional blood‐based genetic testing. We conclude that understanding the brain as a dynamic mosaic of billions of distinct genomes—rather than a single‐genome organ—is essential for accurate disease modelling, diagnostics and the development of targeted therapies.