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

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• The anatomical origins and lineage relationships of human forebrain cell subtypes remain debated.
• Direct observation in the mature human brain is crucial for understanding its cellular organization and origins.

Purpose of the Study:

• To investigate human forebrain cellular origins and lineage relationships.
• To utilize cell-type-specific somatic mosaicism as a tool to deconvolve clonal dynamics.

Main Methods:

• Employed cell-type-specific mosaic variant barcode analysis on human brain tissue from two donors.
• Analyzed mosaic variants across multiple brain regions and hemispheres.
• Performed simultaneous genome and transcriptome analysis at single-cell resolution.

Main Results:

• Identified hundreds of mosaic variants to deconvolve clonal dynamics.
• Found hippocampal excitatory neurons exhibit more lineage restriction than neocortical or basal ganglia neurons.
• Suggested a dorsal neocortical origin for a subset of DLX1+ inhibitory neurons, sharing an origin with excitatory neurons.
• Observed anterior-posterior clonal spread restriction precedes dorsal-ventral restriction.

Conclusions:

• Cell-type-resolved somatic mosaicism is a powerful method for uncovering human forebrain developmental lineage relationships.
• The findings provide critical insights into the structural organization and cellular origins of the human forebrain.