Lineage Tracing in Humans Enabled by Mitochondrial Mutations and Single-Cell Genomics

Area of Science:

• Genomics
• Cell Biology
• Biotechnology

Background:

• Lineage tracing is crucial for understanding cell fate in complex organisms.
• Current human lineage tracing methods using nuclear somatic mutations are error-prone, limited in scale, and lack cell state information.

Purpose of the Study:

• To develop a scalable and accurate method for human cell lineage tracing.
• To leverage somatic mutations in mitochondrial DNA (mtDNA) as natural genetic barcodes.

Main Methods:

• Tracking somatic mutations in mtDNA using single-cell RNA sequencing and assay for transposase accessible chromatin (ATAC) sequencing.
• Utilizing mtDNA mutations as clonal markers to infer cellular relationships.
• Analyzing native human cells both in vitro and in vivo.

Main Results:

• Somatic mtDNA mutations serve as highly accurate clonal markers.
• The approach enables lineage tracking at a 1,000-fold greater scale than nuclear genome sequencing.
• Simultaneous information on gene expression and chromatin accessibility is captured.

Conclusions:

• Somatic mtDNA mutation tracking is a powerful tool for human cell lineage analysis.
• This method opens new avenues for charting cellular dynamics in human health and disease.
• The approach integrates clonal dynamics with cell state information for comprehensive insights.