Somatic mosaicism reveals clonal distributions of neocortical development

Martin W. Breuss, Xiaoxu Yang, Johannes C. M. Schlachetzki, Danny Antaki, Addison J. Lana, Xin Xu, Changuk Chung, Guoliang Chai, Valentina Stanley, Qiong Song, Traci F. Newmeyer, An Nguyen, Sydney O’Brien, Marten A. Hoeksema, Beibei Cao, Alexi Nott, Jennifer McEvoy-Venneri, Martina P. Pasillas, Scott T. Barton, Brett R. Copeland, Shareef Nahas, Lucitia Van Der Kraan, Yan Ding, Christopher K. Glass and Joseph G. Gleeson ()
Additional contact information
Martin W. Breuss: University of California, San Diego
Xiaoxu Yang: University of California, San Diego
Johannes C. M. Schlachetzki: University of California, San Diego
Danny Antaki: University of California, San Diego
Addison J. Lana: University of California, San Diego
Xin Xu: University of California, San Diego
Changuk Chung: University of California, San Diego
Guoliang Chai: University of California, San Diego
Valentina Stanley: University of California, San Diego
Qiong Song: University of California, San Diego
Traci F. Newmeyer: University of California, San Diego
An Nguyen: University of California, San Diego
Sydney O’Brien: University of California, San Diego
Marten A. Hoeksema: University of California, San Diego
Beibei Cao: University of California, San Diego
Alexi Nott: Imperial College London
Jennifer McEvoy-Venneri: University of California, San Diego
Martina P. Pasillas: University of California, San Diego
Scott T. Barton: University of California, San Diego
Brett R. Copeland: University of California, San Diego
Shareef Nahas: Rady Children’s Institute for Genomic Medicine
Lucitia Van Der Kraan: Rady Children’s Institute for Genomic Medicine
Yan Ding: Rady Children’s Institute for Genomic Medicine
Christopher K. Glass: University of California, San Diego
Joseph G. Gleeson: University of California, San Diego

Nature, 2022, vol. 604, issue 7907, 689-696

Abstract: Abstract 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 recorders1,2. 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 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.

Date: 2022
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DOI: 10.1038/s41586-022-04602-7

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