Abstract:
:Elucidating the lineage relationships among different cell types is key to understanding human brain development. Here we developed parallel RNA and DNA analysis after deep sequencing (PRDD-seq), which combines RNA analysis of neuronal cell types with analysis of nested spontaneous DNA somatic mutations as cell lineage markers, identified from joint analysis of single-cell and bulk DNA sequencing by single-cell MosaicHunter (scMH). PRDD-seq enables simultaneous reconstruction of neuronal cell type, cell lineage, and sequential neuronal formation ("birthdate") in postmortem human cerebral cortex. Analysis of two human brains showed remarkable quantitative details that relate mutation mosaic frequency to clonal patterns, confirming an early divergence of precursors for excitatory and inhibitory neurons, and an "inside-out" layer formation of excitatory neurons as seen in other species. In addition our analysis allows an estimate of excitatory neuron-restricted precursors (about 10) that generate the excitatory neurons within a cortical column. Inhibitory neurons showed complex, subtype-specific patterns of neurogenesis, including some patterns of development conserved relative to mouse, but also some aspects of primate cortical interneuron development not seen in mouse. PRDD-seq can be broadly applied to characterize cell identity and lineage from diverse archival samples with single-cell resolution and in potentially any developmental or disease condition.
journal_name
Proc Natl Acad Sci U S Aauthors
Huang AY,Li P,Rodin RE,Kim SN,Dou Y,Kenny CJ,Akula SK,Hodge RD,Bakken TE,Miller JA,Lein ES,Park PJ,Lee EA,Walsh CAdoi
10.1073/pnas.2006163117subject
Has Abstractpub_date
2020-06-23 00:00:00pages
13886-13895issue
25eissn
0027-8424issn
1091-6490pii
2006163117journal_volume
117pub_type
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