Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain

• 成果类型: Article
• 署名作者: Chung, Changuk; Yang, Xiaoxu; Hevner, Robert F.; Kennedy, Katie; Vong, Keng Ioi; Liu, Yang; Patel, Arzoo; Nedunuri, Rahul; Barton, Scott T.; Noel, Geoffroy; Barrows, Chelsea; Stanley, Valentina; Mittal, Swapnil; Breuss, Martin W.; Schlachetzki, Johannes C. M.; Kingsmore, Stephen F.; Gleeson, Joseph G.
• 署名单位: University of California System; University of California San Diego; Utah System of Higher Education; University of Utah; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; University of Colorado System; University of Colorado Anschutz Medical Campus; University of California System; University of California San Diego
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3732
• DOI: 10.1038/s41586-024-07292-5
• 发表日期: 2024-05-09
• 关键词: fate mapping reveals; gabaergic neurons; cerebral-cortex; basal ganglia; single-cell; expression; mutations; migration; origins; neocortex

摘要

Debate remains around the anatomical origins of specific brain cell subtypes and lineage relationships within the human forebrain1-7. Thus, direct observation in the mature human brain is critical for a complete understanding of its structural organization and cellular origins. Here we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific mosaic variant barcode analysis. From four hemispheres and two different human neurotypical donors, we identified 287 and 780 mosaic variants, respectively, that were used to deconvolve clonal dynamics. Clonal spread and allele fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted than resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome transcriptome analysis at both a cell-type-specific and a single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1+ inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of mosaic variants across 17 locations within one parietal lobe reveals that restriction of clonal spread in the anterior-posterior axis precedes restriction in the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain. Using mosaic variant barcode analysis, clonal dynamics of specific cell types are deconvolved in the human forebrain.