Somatic mosaicism reveals clonal distributions of neocortical development

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  • dc.contributor.author Breuss, Martin W.
  • dc.contributor.author NIMH Brain Somatic Mosaicism Network
  • dc.contributor.author Gleeson, Joseph G.
  • dc.date.accessioned 2023-04-28T06:05:48Z
  • dc.date.available 2023-04-28T06:05:48Z
  • dc.date.issued 2022
  • dc.description.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.
  • dc.description.sponsorship 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.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Breuss MW, Yang X, Schlachetzki JCM, Antaki D, Lana AJ, Xu X, et al. Somatic mosaicism reveals clonal distributions of neocortical development. Nature. 2022;604(7907):689-96. DOI: 10.1038/s41586-022-04602-7
  • dc.identifier.doi http://dx.doi.org/10.1038/s41586-022-04602-7
  • dc.identifier.issn 0028-0836
  • dc.identifier.uri http://hdl.handle.net/10230/56608
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nature. 2022;604(7907):689-96
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/609409
  • dc.rights © Springer Nature Publishing AG Breuss MW, Yang X, Schlachetzki JCM, Antaki D, Lana AJ, Xu X, Chung C, Chai G, Stanley V, Song Q, Newmeyer TF, Nguyen A, O’Brien S, Hoeksema MA, Cao B, Nott A, McEvoy-Venneri J, Pasillas MP, Barton ST, Copeland BR, Nahas S, Van Der Kraan L, Ding Y, NIMH Brain Somatic Mosaicism Network, Glass CK, Gleeson JG. Somatic mosaicism reveals clonal distributions of neocortical development. Nature. 2022;604(7907):689-96. DOI: 10.1038/s41586-022-04602-7
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.subject.keyword Cell fate and cell lineage
  • dc.subject.keyword Development
  • dc.subject.keyword DNA sequencing
  • dc.subject.keyword Genetics of the nervous system
  • dc.title Somatic mosaicism reveals clonal distributions of neocortical development
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/acceptedVersion

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