Longitudinal assessment of clonal mosaicism in human hematopoiesis via mitochondrial mutation tracking
Open accessAbstract
Our ability to track cellular dynamics in humans over time in vivo has been limited. Here, we demonstrate how somatic mutations in mitochondrial DNA (mtDNA) can be used to longitudinally track the dynamic output of hematopoietic stem and progenitor cells in humans. Over the course of 3 years of blood sampling in a single individual, our analyses reveal somatic mtDNA sequence variation and evolution reminiscent of models of hematopoiesis established by genetic labeling approaches. Furthermore, we observe fluctuations in mutation heteroplasmy, coinciding with specific clinical events, such as infections, and further identify lineage-specific somatic mtDNA mutations in longitudinally sampled circulating blood cell subsets in individuals with leukemia. Collectively, these observations indicate the significant potential of using tracking of somatic mtDNA sequence variation as a broadly applicable approach to systematically assess hematopoietic clonal dynamics in human health and disease.
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Leveraging the high rate of mitochondrial mutations can track clonal dynamics within an unperturbed hematopoietic system in humans.
“In order to truly reflect cell behavior during steady state hematopoiesis, one promising alternative in humans involves leveraging the high rate of mitochondrial mutations to track clonal dynamics within an unperturbed hematopoietic system (Lareau et al., 2019; Ludwig et al., 2019a; Xu et al., 2019).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Lareau et al., 2019
Cites
The Sequence Alignment/Map format and SAMtools
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., & 1000 Genome Project Data Processing Subgroup (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp352 · Cited by 62,041 · see citing works
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400 · see citing works
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709 · see citing works
Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications
Krueger, F., & Andrews, S. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr167 · Cited by 5,161 · see citing works
Population dynamics of normal human blood inferred from somatic mutations
Lee-Six, H., Øbro, N. F., Shepherd, M. S., Grossmann, S., Dawson, K., Belmonte, M., Osborne, R. J., Huntly, B. J. P., Martincorena, I., Anderson, E., et al. (2018) · Nature · doi:10.1038/s41586-018-0497-0 · Cited by 604 · see citing works
Clonal analysis of lineage fate in native haematopoiesis
Rodriguez-Fraticelli, A. E., Wolock, S. L., Weinreb, C. S., Panero, R., Patel, S. H., Jankovic, M., Sun, J., Calogero, R. A., Klein, A. M., & Camargo, F. D. (2018) · Nature · doi:10.1038/nature25168 · Cited by 596 · see citing works
Somatic mutation in single human neurons tracks developmental and transcriptional history
Lodato, M. A., Woodworth, M. B., Lee, S., Evrony, G. D., Mehta, B. K., Karger, A., Lee, S., Chittenden, T. W., D’Gama, A. M., Cai, X., et al. (2015) · Science · doi:10.1126/science.aab1785 · Cited by 570 · see citing works
Lineage Tracing in Humans Enabled by Mitochondrial Mutations and Single-Cell Genomics
Ludwig, L. S., Lareau, C. A., Ulirsch, J. C., Christian, E., Muus, C., Li, L. H., Pelka, K., Ge, W. H., Oren, Y., Brack, A., et al. (2019) · Cell · doi:10.1016/j.cell.2019.01.022 · Cited by 534 · see citing works
Polylox barcoding reveals haematopoietic stem cell fates realized in vivo
Pei, W., Feyerabend, T. B., Rößler, J., Wang, X., Postrach, D., Busch, K., Rode, I., Klapproth, K., Dietlein, N., Quedenau, C., et al. (2017) · Nature · doi:10.1038/nature23653 · Cited by 412 · see citing works
Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age
Elson, J. L., Samuels, D. C., Turnbull, D. M., & Chinnery, P. F. (2001) · The American Journal of Human Genetics · doi:10.1086/318801 · Cited by 340 · see citing works
Biasco, L., Pellin, D., Scala, S., Dionisio, F., Basso-Ricci, L., Leonardelli, L., Scaramuzza, S., Baricordi, C., Ferrua, F., Cicalese, M. P., et al. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.04.016 · Cited by 243 · see citing works
Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells
Yu, V. W. C., Yusuf, R. Z., Oki, T., Wu, J. W., Sáez, B., Wang, X., Cook, C., Baryawno, N., Ziller, M. J., Lee, E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.02.010 · Cited by 233 · see citing works
Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells
Yu, V. W. C., Yusuf, R. Z., Oki, T., Wu, J. W., Sáez, B., Wang, X., Cook, C., Baryawno, N., Ziller, M. J., Lee, E., et al. (2016) · Cell · doi:10.1016/j.cell.2016.10.045 · Cited by 197 · see citing works
Qu, K., Zaba, L. C., Satpathy, A. T., Giresi, P. G., Li, R., Jin, Y., Armstrong, R. J., Chen, J., Schmitt, N., Rahbar, Z., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.05.008 · Cited by 178 · see citing works
Xu, J., Nuno, K. A., Litzenburger, U. M., Qi, Y., Corces, M. R., Majeti, R., & Chang, H. Y. (2019) · eLife · doi:10.7554/elife.45105 · Cited by 150 · see citing works
Haematopoiesis in the era of advanced single-cell technologies
Jacobsen, S. E. W., & Nerlov, C. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0227-8 · Cited by 127 · see citing works
Scala, S., Ricci, L. B., Dionisio, F., Pellin, D., Giannelli, S., Salerio, F. A., Leonardelli, L., Cicalese, M. P., Ferrua, F., Aiuti, A., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0195-3 · Cited by 111 · see citing works
Rendeiro, A. F., Krausgruber, T., Fortelny, N., Zhao, F., Penz, T., Farlik, M., Schuster, L. C., Nemc, A., Tasnády, S., Réti, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14081-6 · Cited by 96 · see citing works
Longitudinal personal DNA methylome dynamics in a human with a chronic condition
Chen, R., Lin, X., Tu, K., Duan, M., Kukurba, K. R., Li‐Pook‐Than, J., Xie, D., & Snyder, M. P. (2018) · Nature Medicine · doi:10.1038/s41591-018-0237-x · Cited by 61 · see citing works
In vivo dynamics of human hematopoietic stem cells: novel concepts and future directions
Scala, S., & Aiuti, A. (2019) · Blood Advances · doi:10.1182/bloodadvances.2019000039 · Cited by 47 · see citing works
Rendeiro, A. F., Krausgruber, T., Fortelny, N., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/597005 · Cited by 6 · see citing works
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Mimitou, E. P., Lareau, C. A., Chen, K. Y., Zorzetto-Fernandes, A. L., Hao, Y., Takeshima, Y., Luo, W., Huang, T.-S., Yeung, B. Z., Papalexi, E., et al. (2021) · Nature Biotechnology · doi:10.1038/s41587-021-00927-2 · Cited by 529 · see citing works
Massively parallel single-cell mitochondrial DNA genotyping and chromatin profiling
Lareau, C. A., Ludwig, L. S., Muus, C., Gohil, S. H., Zhao, T., Chiang, Z., Pelka, K., Verboon, J. M., Luo, W., Christian, E., et al. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0645-6 · Cited by 290 · see citing works
Unraveling Hematopoiesis through the Lens of Genomics
Liggett, L. A., & Sankaran, V. G. (2020) · Cell · doi:10.1016/j.cell.2020.08.030 · Cited by 163 · see citing works
Sanchez-Contreras, M., Sweetwyne, M. T., Tsantilas, K. A., Whitson, J. A., Campbell, M. D., Kohrn, B. F., Kim, H. J., Hipp, M. J., Fredrickson, J., Nguyen, M. M., et al. (2023) · eLife · doi:10.7554/elife.83395 · Cited by 71 · see citing works
Mitochondrial genetics through the lens of single-cell multi-omics
Nitsch, L., Lareau, C. A., & Ludwig, L. S. (2024) · Nature Genetics · doi:10.1038/s41588-024-01794-8 · Cited by 52 · see citing works
Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy
Rosanwo, T. O., & Bauer, D. E. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.10.002 · Cited by 27 · see citing works
Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells
Wang, X., Wang, K., Zhang, W., Tang, Z., Zhang, H., Cheng, Y., Zhou, D., Zhang, C., Zhong, W., Ma, Q., et al. (2025) · Genome biology · doi:10.1186/s13059-025-03540-7 · Cited by 21 · see citing works
Natural Barcodes for Longitudinal Single Cell Tracking of Leukemic and Immune Cell Dynamics
Penter, L., Gohil, S. H., & Wu, C. J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.788891 · Cited by 20 · see citing works
Scalable, multimodal profiling of chromatin accessibility and protein levels in single cellsPreprint
Mimitou, E. P., Lareau, C. A., Chen, K. Y., Zorzetto-Fernandes, A. L., Takeshima, Y., Luo, W., Huang, T.-S., Yeung, B. Z., Thakore, P. I., Wing, J. B., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.09.08.286914 · Cited by 18 · see citing works
Stein, C. M., Hablesreiter, R., Christen, F., Löwe, P., Torre, C. F., Kopp, K., Locher, B. N., Nitsch, L., Altwasser, R., Kerschbaum, J. F., et al. (2025) · Leukemia · doi:10.1038/s41375-025-02823-z · Cited by 6 · see citing works
Ludwig, L. S., & Lareau, C. A. (2023) · Methods in molecular biology · doi:10.1007/978-1-0716-2899-7_14 · Cited by 6 · see citing works
Computational approaches for multimodal lineage tracing
Wang, K., He, X., & Hu, Z. (2026) · Nature Reviews Genetics · doi:10.1038/s41576-026-00969-9 · Cited by 5 · see citing works
Mitochondrial genetic variations in leukemia: a comprehensive overview
Zhang, A., Liu, W., & Qiu, S. (2024) · Blood Science · doi:10.1097/bs9.0000000000000205 · Cited by 3 · see citing works
The landscape of cell lineage tracing
Ye, F., Guang, L., Li, H., & Cheng, L. (2025) · Science China Life Sciences · doi:10.1007/s11427-024-2751-6 · Cited by 1 · see citing works
Katsuda, T. (2022) · Bioinformation · doi:10.6026/97320630018053 · Cited by 1 · see citing works
Heterogeneity in platelet differentiation pathways
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Chang, R., Tsai, A. P., Wang, B., Tsui, K., Pang, C., & Li, C. (2026) · Aging Cell · doi:10.1111/acel.70718
- Authors
- Lareau, C. A., Ludwig, L. S., & Sankaran, V. G.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Lareau, Caleb A.
- Ludwig, Leif S.
- Venue
- Blood Advances
- Publisher
- American Society of Hematology
- Published
- 2019-12-16
- Volume
- 3
- Issue
- 24
- Pages
- 4161-4165
- ISSN
- 2473-9529 (ISSN-L)
- 2473-9537
- PMC
- PMC6929387
- OpenAlex
- W2996033296
- Cited by
- 17
- References
- 20
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 3
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Blood Advances (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R33HL120791)
- National Cancer Institute (F31CA232670)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103794)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- clonal mosaicism, hematopoiesis, mitochondrial DNA mutations, hematopoietic stem and progenitor cells, clonal dynamics, long-term tracking, leukemia, infection
- MeSH terms
- DNA, Mitochondrial, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mitochondria, Mosaicism, Mutation, Clonal Evolution
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