Quantitative analysis of clonal architecture across the human cerebral cortex using somatic mutations
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Kim, Sonia Nan
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CitationKim, Sonia Nan. 2021. Quantitative analysis of clonal architecture across the human cerebral cortex using somatic mutations. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.
AbstractThe human cerebral cortex shows remarkable functional specialization into regions devoted to motor, sensory, or visual functions, and these functional areas correlate with dramatic differences in cellular composition, or cytoarchitecture. Furthermore, the human cortex is subject to clonal mutations, occasionally leading to a predisposition to focal epilepsies and tumors. Here we use naturally occurring somatic mutations, typically functionally neutral, to provide the first map of clonal structure of the human cortex in relation to major cytoarchitectonic regions. We show that a combination of whole-genome sequencing of single cell and bulk brain DNA discovers clones with diverse mosaic distribution patterns across the cortical hemisphere. Neuron-generating clones show a degree of regional restriction but only when present at ultra-low mosaicism (≤1%), while clones comprising ≈1-2% or greater in the cellular population are rarely restricted to single cytoarchitectonic areas. Integration of lineage and cell-type analyses in single cells demonstrates that clones identified in excitatory and inhibitory neurons disperse across multiple brain regions at a low mosaicism in the cellular population. Our results demonstrate that clones generated early during cerebral cortical neurogenesis show wide dispersion in the cortex, with later generated clones showing modest restriction, contrasting sharply with previously described clonal patterns in non-primates. These data suggest that mechanisms acting after neurogenesis play important roles in defining cortical cell architecture, and suggest that damaging neuronal mutations in human epileptic disorders may distribute far more widely than is accounted for in current neurosurgical approaches.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37368521
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