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Breuss, Martin W; Yang, Xiaoxu; Schlachetzki, Johannes C M; Antaki, Danny; Lana, Addison J; Xu, Xin; Chung, Changuk; Chai, Guoliang; Stanley, Valentina; Song, Qiong; Newmeyer, Traci F; Nguyen, An; O'Brien, Sydney; Hoeksema, Marten A; Cao, Beibei; Nott, Alexi; McEvoy-Venneri, Jennifer; Pasillas, Martina P; Barton, Scott T; Copeland, Brett R; Nahas, Shareef; Van Der Kraan, Lucitia; Ding, Yan; Glass, Christopher K; Gleeson, Joseph G
Nature, 04/2022, Volume: 604, Issue: 7907Journal Article
The structure of the human neocortex underlies species-specific traits 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 . 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 clade 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.
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