Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells
Abstract Background Mitochondrial DNA (mtDNA) variants hold promise as endogenous barcodes for tracking human cell lineages, but their efficacy as reliable lineage markers are hindered by the complex dynamics of mtDNA in somatic tissues. Results Here, we use computational modeling and single-cell ge...
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BMC
2025-03-01
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| Series: | Genome Biology |
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| Online Access: | https://doi.org/10.1186/s13059-025-03540-7 |
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| author | Xin Wang Kun Wang Weixing Zhang Zhongjie Tang Hao Zhang Yuying Cheng Da Zhou Chao Zhang Wen-Zhao Zhong Qing Ma Jin Xu Zheng Hu |
| author_facet | Xin Wang Kun Wang Weixing Zhang Zhongjie Tang Hao Zhang Yuying Cheng Da Zhou Chao Zhang Wen-Zhao Zhong Qing Ma Jin Xu Zheng Hu |
| author_sort | Xin Wang |
| collection | DOAJ |
| description | Abstract Background Mitochondrial DNA (mtDNA) variants hold promise as endogenous barcodes for tracking human cell lineages, but their efficacy as reliable lineage markers are hindered by the complex dynamics of mtDNA in somatic tissues. Results Here, we use computational modeling and single-cell genomics to thoroughly interrogate the origin and clonal dynamics of mtDNA variants across various biological settings. Our findings reveal that the majority of mtDNA variants which are specifically present in a cell subpopulation, termed subpopulation-specific variants, are pre-existing heteroplasmies in the first cell instead of de novo somatic mutations during divisions. Moreover, subpopulation-specific variants demonstrate limited discriminatory power among different genuine lineages under weak clonal expansion; however, certain subpopulation-specific variants with consistently high frequencies among a subpopulation are capable of faithfully labeling cell lineages in scenarios of stringent clonal expansion, such as strongly expanded T cell populations in diseased conditions and clonal hematopoiesis in aged individuals. Inspired by our simulations, we introduce a lineage informative score, facilitating the identification of reliable mitochondrial lineage tracing markers across different modalities of single-cell genomic data. Conclusions Combining computational modeling and single-cell sequencing, our study reveals that the performance of mitochondrial lineage tracing is highly dependent on the extent of clonal expansion, which thus should be considered when applying mitochondrial lineage tracing. |
| format | Article |
| id | doaj-art-2c22fa3de73340d0ba268dfc11daa931 |
| institution | DOAJ |
| issn | 1474-760X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
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| series | Genome Biology |
| spelling | doaj-art-2c22fa3de73340d0ba268dfc11daa9312025-08-20T02:49:30ZengBMCGenome Biology1474-760X2025-03-0126112010.1186/s13059-025-03540-7Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cellsXin Wang0Kun Wang1Weixing Zhang2Zhongjie Tang3Hao Zhang4Yuying Cheng5Da Zhou6Chao Zhang7Wen-Zhao Zhong8Qing Ma9Jin Xu10Zheng Hu11State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesSchool of Mathematical Sciences, Xiamen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityState Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesState Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesSchool of Mathematical Sciences, Xiamen UniversityGuangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityGuangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityState Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityState Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesAbstract Background Mitochondrial DNA (mtDNA) variants hold promise as endogenous barcodes for tracking human cell lineages, but their efficacy as reliable lineage markers are hindered by the complex dynamics of mtDNA in somatic tissues. Results Here, we use computational modeling and single-cell genomics to thoroughly interrogate the origin and clonal dynamics of mtDNA variants across various biological settings. Our findings reveal that the majority of mtDNA variants which are specifically present in a cell subpopulation, termed subpopulation-specific variants, are pre-existing heteroplasmies in the first cell instead of de novo somatic mutations during divisions. Moreover, subpopulation-specific variants demonstrate limited discriminatory power among different genuine lineages under weak clonal expansion; however, certain subpopulation-specific variants with consistently high frequencies among a subpopulation are capable of faithfully labeling cell lineages in scenarios of stringent clonal expansion, such as strongly expanded T cell populations in diseased conditions and clonal hematopoiesis in aged individuals. Inspired by our simulations, we introduce a lineage informative score, facilitating the identification of reliable mitochondrial lineage tracing markers across different modalities of single-cell genomic data. Conclusions Combining computational modeling and single-cell sequencing, our study reveals that the performance of mitochondrial lineage tracing is highly dependent on the extent of clonal expansion, which thus should be considered when applying mitochondrial lineage tracing.https://doi.org/10.1186/s13059-025-03540-7Lineage tracingmtDNA variantsClonal dynamicsSingle-cell genomics |
| spellingShingle | Xin Wang Kun Wang Weixing Zhang Zhongjie Tang Hao Zhang Yuying Cheng Da Zhou Chao Zhang Wen-Zhao Zhong Qing Ma Jin Xu Zheng Hu Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells Genome Biology Lineage tracing mtDNA variants Clonal dynamics Single-cell genomics |
| title | Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells |
| title_full | Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells |
| title_fullStr | Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells |
| title_full_unstemmed | Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells |
| title_short | Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells |
| title_sort | clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells |
| topic | Lineage tracing mtDNA variants Clonal dynamics Single-cell genomics |
| url | https://doi.org/10.1186/s13059-025-03540-7 |
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