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Massively parallel single-cell mitochondrial DNA genotyping and chromatin profiling

Item Type:Article
Title:Massively parallel single-cell mitochondrial DNA genotyping and chromatin profiling
Creators Name:Lareau, C.A. and Ludwig, L.S. and Muus, C. and Gohil, S.H. and Zhao, T. and Chiang, Z. and Pelka, K. and Verboon, J.M. and Luo, W. and Christian, E. and Rosebrock, D. and Getz, G. and Boland, G.M. and Chen, F. and Buenrostro, J.D. and Hacohen, N. and Wu, C.J. and Aryee, M.J. and Regev, A. and Sankaran, V.G.
Abstract:Natural mitochondrial DNA (mtDNA) mutations enable the inference of clonal relationships among cells. mtDNA can be profiled along with measures of cell state, but has not yet been combined with the massively parallel approaches needed to tackle the complexity of human tissue. Here, we introduce a high-throughput, droplet-based mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), a method that combines high-confidence mtDNA mutation calling in thousands of single cells with their concomitant high-quality accessible chromatin profile. This enables the inference of mtDNA heteroplasmy, clonal relationships, cell state and accessible chromatin variation in individual cells. We reveal single-cell variation in heteroplasmy of a pathologic mtDNA variant, which we associate with intra-individual chromatin variability and clonal evolution. We clonally trace thousands of cells from cancers, linking epigenomic variability to subclonal evolution, and infer cellular dynamics of differentiating hematopoietic cells in vitro and in vivo. Taken together, our approach enables the study of cellular population dynamics and clonal properties in vivo.
Keywords:Cell Differentiation, Clonal Evolution, Clone Cells, Cultured Cells, DNA Sequence Analysis, Genetic Epigenesis, Genotyping Techniques, Hematopoiesis, High-Throughput Nucleotide Sequencing, Mitochondria, Mitochondrial DNA, Mutation, Neoplasms, Single-Cell Analysis
Source:Nature Biotechnology
Publisher:Nature Publishing Group
Page Range:451-461
Date:April 2021
Official Publication:https://doi.org/10.1038/s41587-020-0645-6
PubMed:View item in PubMed

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