TY - JOUR
T1 - Somatic mosaicism reveals clonal distributions of neocortical development
AU - Breuss, Martin W.
AU - Yang, Xiaoxu
AU - Schlachetzki, Johannes C. M.
AU - Antaki, Danny
AU - Lana, Addison J.
AU - Xu, Xin
AU - Chung, Changuk
AU - Chai, Guoliang
AU - Stanley, Valentina
AU - Song, Qiong
AU - Newmeyer, Traci F.
AU - Nguyen, An
AU - O'Brien, Sydney
AU - Hoeksema, Marten A.
AU - Cao, Beibei
AU - Nott, Alexi
AU - McEvoy-Venneri, Jennifer
AU - Pasillas, Martina P.
AU - Barton, Scott T.
AU - Copeland, Brett R.
AU - Nahas, Shareef
AU - van der Kraan, Lucitia
AU - Ding, Yan
AU - NIMH Brain Somatic Mosaicism Network
AU - Glass, Christopher K.
AU - Gleeson, Joseph G.
N1 - Funding Information: We thank the individuals who donate their bodies and tissues for the advancement of research; S. Lee, C. Zhu and I. Tang for feedback; D. Weinberger, J. Kleinman, T. Hyde and R. Narukar for the samples; and R. Sinkovits, A. Majumdar and S. Strande at the San Diego Supercomputer Center. Sequencing is supported by the Rady Children’s Institute for Genomic Medicine and the UCSD Institute for Genomic Medicine. M.W.B. was supported by an EMBO Long-Term Fellowship (no. ALTF 174-2015), the Marie Curie Actions of the European Commission (nos LTFCOFUND2013 and GA-2013-609409) and an Erwin Schrödinger Fellowship by the Austrian Science Fund (no. J 4197-B30). This study was supported by grants to J.G.G. from the Howard Hughes Medical Institute, NIMH (1U01 MH108898, R01 MH124890 and R21 AG070462), and to C.K.G. from NIA (RF1 AG061060-02, R01 AG056511-02, R01 NS096170-04), and the UC San Diego IGM Genomics Center (S10 OD026929). A.N. was supported by the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/4/28
Y1 - 2022/4/28
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85129779690&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/35444276
U2 - https://doi.org/10.1038/s41586-022-04602-7
DO - https://doi.org/10.1038/s41586-022-04602-7
M3 - Article
C2 - 35444276
SN - 0028-0836
VL - 604
SP - 689
EP - 696
JO - NATURE
JF - NATURE
IS - 7907
ER -