Somatic mosaicism reveals clonal distributions of neocortical development

The structure of the human neocortex underlies species-specifictraits and reflects intricate developmental programs. Here we sought to reconstruct processes that occur during early development by sampling adult human tissues. We analysed neocortical clones in a post-mortem human brain through a comprehensive assessment of brain somatic mosaicism, acting as neutral lineage recorders(1,2). We combined the sampling of 25 distinct anatomic locations with deep whole-genome sequencing in a neurotypical deceased individual and confirmed results with 5 samples collected from each of three additional donors. We identified 259 bona fide mosaic variants from the index case, then deconvolved distinct geographical, cell-type and Glade organizations across the brain and other organs. We found that clones derived after the accumulation of 90-200 progenitors in the cerebral cortex tended to respect the midline axis, well before the anterior-posterior or ventral-dorsal axes, representing a secondary hierarchy following the overall patterning of forebrain and hindbrain domains. Clones across neocortically derived cells were consistent with a dual origin from both dorsal and ventral cellular populations, similar to rodents, whereas the microglia lineage appeared distinct from other resident brain cells. Our data provide a comprehensive analysis of brain somatic mosaicism across the neocortex and demonstrate cellular origins and progenitor distribution patterns within the human brain.

Automated summary

The structure of the human neocortex and its developmental processes were investigated through the assessment of brain somatic mosaicism. Samples from adult human tissues were analyzed, revealing distinct geographical, cell-type, and Glade organizations in the brain and other organs. The findings suggest that the clones in the cerebral cortex respect the midline axis and have dual origins from both dorsal and ventral cellular populations.