Nature: Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain
In this video introduction, Drs. Changuk Chung, Xiaoxu Yang, and Joseph Gleeson are presenting their recent discoveries in human neural development using mosaic variant barcoding. Cortical inhibitory neurons were demonstrated to derive from the ventral forebrain during mammalian development, according to previous animal models and in vitro experiments, debates remain around the anatomical origins of specific brain cell subtypes, such as inhibitory neurons, and lineage relationships within the human forebrain. Thus, direct observation of 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. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain. For more information, please visit the original publication at https://doi.org/10.1038/s41586-024-07....