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

Abstract

Debate remains around anatomic origins of specific brain cell subtypes and lineage relationships within the human forebrain. Thus, direct observation in the mature human brain is critical for a complete understanding of the 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 from two different human neurotypical donors, we identified 287 and 780 mosaic variants (MVs), respectively that were used to deconvolve clonal dynamics. Clonal spread and allelic fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted compared with resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome-transcriptome analysis at both a cell-type-specific and 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 MVs across 17 locations within one parietal lobe reveals restrictions of clonal spread in the anterior-posterior axis precedes that of 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.

Human Brain Ancestral Barcodes

“…Tangential excitatory neuron migration was also detected, albeit related excitatory neurons were more localized than inhibitory neurons. Tangential migration is also seen with sequencing studies that find neurons with specific mutations in multiple brain regions (14)(15)(16)(17).…”

Single-cell genotyping and transcriptomic profiling in focal cortical dysplasia

“…In addition to glutamatergic neurons and astrocytes, a small subset of cells from other lineages are also mutated, including GABAergic neurons and microglia. Most GABAergic neurons in the cortex originate from the ganglionic eminences, although recent studies have suggested that a portion of interneurons may have a dorsal origin [27][28][29][30] , while microglia derive from the mesoderm. This finding implies that FCDII lesions (at least the more extended ones, with high VAF) would originate from mutations that presumably occurred prior to the separation of these cell types into different lineages (i.e.…”

Molecular and cellular dynamics of the developing human neocortex at single-cell resolution

“…However, our spatial transcriptomic data demonstrate the presence of MEIS2 + PAX6 + INs in the white matter of both the prenatal and postnatal human brain, indicating their potential role as white matter interneurons. With recent reports of a shared origin between some cortical interneurons and ENs 87,88 , it remains to be determined whether INs derived from Tri-IPCs also differentiate into cortical interneurons.…”