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Related Experiment Video

Updated: Jan 11, 2026

Lineage Tracing and Clonal Analysis in Developing Cerebral Cortex Using Mosaic Analysis with Double Markers MADM
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Combined somatic mutation and transcriptome analysis reveals region-specific differences in clonal architecture in

Vinayak V Viswanadham1, Sonia N Kim2, Emre Caglayan3

  • 1Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Bioinformatics and Integrative Genomics Program, Harvard Medical School, Boston, MA, USA.

Cell Reports
|November 15, 2025
PubMed
Summary

Human brain development reveals unique cellular lineage patterns. Researchers mapped somatic single-nucleotide variants (sSNVs) in over 72,000 cells, uncovering regional differences in clonal dispersion and late divergence of neuron types.

Keywords:
CP: genomicsCP: neurosciencecortical developmentglutamatergic neuronsinterneuronslineage tracingsingle-cell transcriptomicssomatic mutationsspatial genomicsvisual cortex

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Genomics

Background:

  • The human cerebral cortex exhibits regional specialization, but the role of cellular lineages in shaping this variation and neuronal cell-type distribution during development is poorly understood.
  • Investigating human cortical development requires methods to trace cellular origins and their spatial distribution.

Purpose of the Study:

  • To map single-cell lineages within human cortical regions and identify neuronal subtypes.
  • To understand how cellular lineages contribute to regional variation and neuronal diversity in the developing human brain.

Main Methods:

  • Utilized over 1,000 somatic single-nucleotide variants (sSNVs) identified from deep bulk whole-genome sequencing.
  • Analyzed sSNVs across more than 25 cortical regions and over 72,000 single cells.
  • Performed single-nucleus sSNV and whole-transcriptome analysis.

Main Results:

  • In the fronto-parietal cortex, sSNVs showed limited restriction, with neuron-generating clones dispersing into adjacent regions.
  • The primary visual cortex contained 30%-70% more sSNVs than the secondary visual cortex, with clones at this border exhibiting restricted dispersion, suggesting late lineage segregation.
  • Glutamatergic neuron clones displayed modest regional restrictions and shared low-mosaic sSNVs with some GABAergic neurons, indicating a recent dorsal cortical progenitor.

Conclusions:

  • The study reveals human-specific patterns of cortical lineage development.
  • Significant regional differences in clonal patterns were observed across the human cortex.
  • Evidence suggests a late divergence between some glutamatergic and GABAergic neuronal lineages.