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Backtracking Cell Phylogenies in the Human Brain with Somatic Mosaic Variants
1Sorbonne Université, Institut du Cerveau (Paris Brain Institute) ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, Paris, France. sara.bizzotto@inserm.fr.
Methods in Molecular Biology (Clifton, N.J.)
|January 2, 2025
Summary
Somatic single nucleotide variants (sSNVs) in the developing human brain act as unique cell markers. This workflow uses whole-genome sequencing and targeted sequencing to trace cell lineages and understand brain development.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Somatic mosaic variants, particularly somatic single nucleotide variants (sSNVs), are frequent in developing human brain progenitor cells.
- These variants serve as permanent, unique, and cumulative markers of cell divisions and clonal expansion.
Purpose of the Study:
- To describe an experimental workflow for conducting lineage studies in the human brain utilizing somatic variants.
- To enable the deciphering of cell phylogeny and clonal architecture within the developing brain.
Main Methods:
- Whole-genome sequencing (WGS) of bulk DNA from human fresh-frozen tissue biopsies for sSNV calling.
- Single nuclei whole-genome amplification (WGA) followed by targeted sequencing of sSNV loci for validation and phylogenetic analysis.
Main Results:
- The described workflow successfully identifies and validates sSNVs in human brain tissue.
- The method allows for the reconstruction of cell lineages and the study of clonal dynamics during human brain development.
Conclusions:
- This workflow provides a robust method for lineage tracing in the human brain using naturally occurring somatic variants.
- Understanding cell division patterns and clonal expansion is crucial for comprehending human brain development and potential neurological disorders.
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