Simultaneous brain cell type and lineage determined by scRNA-seq reveals stereotyped cortical development

Area of Science:

• Genomics
• Developmental Biology
• Computational Biology

Background:

• Cellular genomes record a history of cell divisions through acquired mutations.
• Loss of heterozygosity (LOH) is a common genomic alteration that accumulates across the genome.
• LOH provides a substantial capacity for inferring cell lineage and developmental history.

Purpose of the Study:

• To develop a method for inferring cell lineage and developmental timing using only single-cell RNA sequencing (scRNA-seq) data.
• To identify loss of heterozygosity (LOH) events as markers of cell lineage and developmental progression.
• To demonstrate the applicability of this retrospective analysis in mouse brain development.

Main Methods:

• Utilized single-cell RNA sequencing (scRNA-seq) on mouse brain cells.
• Identified loss of heterozygosity (LOH) events by detecting tracts of monoallelically expressed heterozygous single-nucleotide variants (SNVs).
• Simultaneously inferred cell lineage, developmental time points (via X chromosome inactivation and LOH counts), and cell types (via gene expression).

Main Results:

• Loss of heterozygosity (LOH) events were detected as monoallelic expression of heterozygous single-nucleotide variants (SNVs).
• Cell lineage and developmental timing were successfully inferred from scRNA-seq data by analyzing LOH patterns and X chromosome inactivation.
• The findings support a model of progenitor cells generating diverse cortical cell types through defined expansion and neurogenesis waves.

Conclusions:

• Retrospective lineage tracing is feasible using LOH analysis from scRNA-seq data.
• This approach allows for the simultaneous inference of cell identity, lineage, and developmental progression.
• The method is applicable to various model organisms and potentially humans, even where genetic engineering is not feasible.