Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells


Although mitochondrial DNA (mtDNA) variants hold promise as endogenous barcodes for tracking human cell lineages, their efficacy as reliable lineage markers is hindered by the complex dynamics of mtDNA in somatic tissues. Here, we utilized computational modeling and single-cell genomics to thoroughly interrogate the origin and clonal dynamics of mtDNA lineage markers across various biological settings. Our findings revealed the majority of purported “clone informative variants (CIVs)” were pre-existing heteroplamies in the first cell instead of de novo somatic mutations during divisions. Moreover, CIVs demonstrated limited discriminatory power among different lineages during normal development; however, certain CIVs with consistently high allele frequencies proved capable of faithfully labeling cell lineages in scenarios of stringent clonal expansion. Inspired by our simulations, we introduced a lineage informative (LI) score, facilitating the identification of reliable mitochondrial lineage markers across different modalities of single-cell genomic data.

BioRxiv, 2024
Click the Cite button above to demo the feature to enable visitors to import publication metadata into their reference management software.

Supplementary notes can be added here, including code and math.