Localized heterochrony integrates overgrowth potential of oncogenic clones

Abstract

ABSTRACT Somatic mutations occur frequently and can arise during embryogenesis, resulting in the formation of a patchwork of mutant clones. Such mosaicism has been implicated in a broad range of developmental anomalies; however, their etiology is poorly understood. Patients carrying a common somatic oncogenic mutation in either PIK3CA or AKT1 can present with disproportionally large digits or limbs. How mutant clones, carrying an oncogenic mutation that often drives unchecked proliferation, can lead to controlled and coordinated overgrowth is unknown. We use zebrafish to explore the growth dynamics of oncogenic clones during development. Here, in a subset of clones, we observed a local increase in proportion of the fin skeleton closely resembling overgrowth phenotypes in patients. We unravel the cellular and developmental mechanisms of these overgrowths, and pinpoint the cell type and timing of clonal expansion. Coordinated overgrowth is associated with rapid clone expansion during early pre-chondrogenic phase of bone development, inducing a heterochronic shift that drives the change in bone size. Our study details how development integrates and translates growth potential of oncogenic clones, thereby shaping the phenotypic consequences of somatic mutations.