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Updated: Sep 11, 2025

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Mitochondrial clone tracing within spatially intact human tissues.

Sydney A Bracht1, Jiazhen Rong2, Rodrigo A Gier1,3

  • 1Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.

Biorxiv : the Preprint Server for Biology
|August 12, 2025
PubMed
Summary

SUMMIT is a new technology for tracing cell clones in tissues using mitochondrial mutations. This spatially resolved lineage tracing method integrates with spatial omics to reveal tissue development and evolution.

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Area of Science:

  • Cell Biology
  • Genomics
  • Biotechnology

Background:

  • Understanding tissue development and evolution requires lineage tracing within intact tissues.
  • Current lineage tracing tools are incompatible with spatial omics, limiting spatial context.
  • Endogenous mutations are preferable for lineage tracing in human tissues.

Purpose of the Study:

  • To develop a spatially-resolved lineage tracing technology integrating gene expression profiling with mitochondrial mutation identification.
  • To enable lineage tracing in human tissues using endogenous mutations.
  • To characterize cell type composition and spatial configuration within identified clones.

Main Methods:

  • SUMMIT (Spatially Unveiling Mitochondrial Mutations In Tissues) integrates gene expression profiling with mitochondrial mutation-based clone identification.
  • A statistical framework addresses cell type mixing within spatial spots, assigning variants to subpopulations.
  • Information pooling across neighboring spots enhances power for detecting spatially localized clones.

Main Results:

  • SUMMIT was validated in a controlled mouse tumor model and applied to human tissues (Barrett's esophagus, gastric cardia, small bowel, colorectal cancer).
  • Distinguished between global mutations and mutations marking locally restricted clones.
  • Characterized cell type composition and spatial configuration within clones using coupled transcriptomic data.

Conclusions:

  • SUMMIT provides a novel framework for spatially-resolved lineage tracing in human tissues.
  • This technology integrates endogenous mitochondrial mutations with spatial transcriptomics.
  • Enables detailed characterization of spatially-defined clonal evolution in various human tissues.