Abstract
Simultaneous measurement of cell lineage and cell fates is a longstanding goal in biomedicine. Here we describe EMBLEM, a strategy to track cell lineage using endogenous mitochondrial DNA variants in ATAC-seq data. We show that somatic mutations in mitochondrial DNA can reconstruct cell lineage relationships at single cell resolution with high sensitivity and specificity. Using EMBLEM, we define the genetic and epigenomic clonal evolution of hematopoietic stem cells and their progenies in patients with acute myeloid leukemia. EMBLEM extends lineage tracing to any eukaryotic organism without genetic engineering.
Highlights
Resolving lineage relationships between cells is necessary to understand the fundamental mechanisms underlying normal development and the progression of disease
We examined whether any of the Mitochondrial DNA (mtDNA) variants present in leukemic stem cells (LSCs) can be seen in the pre-leukemic’ hematopoietic stem cell (pHSC), where the first leukemia-associated protein-coding mutations have already occurred in functional normal hematopoietic stem cells (Corces-Zimmerman et al, 2014; Corces et al, 2016)
We present a computational strategy to combine cell lineages tracing by endogenous mtDNA mutations and chromatin accessibility profiling in the same cell using single-cell ATAC-seq data
Summary
Resolving lineage relationships between cells is necessary to understand the fundamental mechanisms underlying normal development and the progression of disease. Genome editing of reporter constructs via CRISPR-Cas allowed synthetic reconstruction of cell lineage relationships in model organisms, and has been coupled with transcriptome profiling to inform cell fates (Spanjaard et al, 2018) These prospective ‘mutate-and-record’ methods provide powerful tools to resolve the developmental origin of cells in genetically engineered cells and organisms, but cannot be utilized in living humans, archival clinical samples, or any wild type organism (Woodworth et al, 2017). Regions with high mutation rates, such as microsatellite repeats, retrotransposons, and copy-number variants, has been used to resolve the lineage relationship for normal or cancerous tissue samples (Evrony et al, 2015; Biezuner et al, 2016). These methods reduce the cost of whole genome sequencing, but still lack information on cell phenotypes
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