High-resolution, noninvasive single-cell lineage tracing in mice and humans based on DNA methylation epimutations [scBS-seq]

In vivo lineage tracing holds great potential to reveal fundamental principles of tissue development and homeostasis. However, lineage tracing in humans relies on DNA mutations that are extremely rare. In mice, the improved genetic labeling approach has low resolution over cell division histories. Here, we demonstrated for the first time that frequent epimutations on DNA methylation can be exploited to infer lineage histories in normal cells, enabled by our newly developed computational method MethyTree. Using both in-house and public sparse single-cell DNA methylation datasets with known lineage labels, MethyTree reconstructed lineage histories at high resolution and accuracy across different cell types, stages, and species. Applying MethyTree, we identified the first fate decision in human embryo development and pinpointed in total ~230 clones of hematopoietic stem cells in mice. Our study opens the door for high-resolution, noninvasive lineage tracing in mice, humans and beyond. Overall design: In this study, we generate single-cell bisulfite sequence datasets for the HEK 293T cell line to evaluate the performance of MethyTree.