Recently, lineage tracing technology using CRISPR/Cas9 genome editing has enabled simultaneous readouts of gene expressions and lineage barcodes, which allows for the reconstruction of the cell division tree and makes it possible to reconstruct ancestral cell types and trace the origin of each cell type. Meanwhile, trajectory inference methods are widely used to infer cell trajectories and pseudotime in a dynamic process using gene expression data of present-day cells. Here, we present TedSim (single-cell temporal dynamics simulator), which simulates the cell division events from the root cell to present-day cells, simultaneously generating two data modalities for each single cell: the lineage barcode and gene expression data. TedSim is a framework that connects the two problems: lineage tracing and trajectory inference. Using TedSim, we conducted analysis to show that (i) TedSim generates realistic gene expression and barcode data, as well as realistic relationships between these two data modalities; (ii) trajectory inference methods can recover the underlying cell state transition mechanism with balanced cell type compositions; and (iii) integrating gene expression and barcode data can provide more insights into the temporal dynamics in cell differentiation compared to using only one type of data, but better integration methods need to be developed.

Recently, the combined scRNA-seq and CRISPR/Cas9 genome editing technologies have enabled simultaneous readouts of gene expressions and lineage barcodes, which allows for the reconstruction of the cell division tree, and makes it possible to trace the origin of each cell type. Computational methods are emerging to take advantage of the jointly profiled scRNA-seq and lineage barcode data to better reconstruct the cell division history or to infer the cell state trajectories. Here, we present TedSim (single cell Temporal dynamics Simulator), a simulator that simulates the cell division events from the root cell to present-day cells, simultaneously generating the CRISPR/Cas9 genome editing lineage barcodes and scRNA-seq data. In particular, TedSim generates cells from multiple cell types through cell division events. TedSim can be used to benchmark and investigate computational methods which use either or both of the two types of data, scRNA-seq and lineage barcodes, to study cell lineages or trajectories. TedSim is available at: https://github.com/Galaxeee/TedSim.

Understanding how single cells divide and differentiate into different cell types in developed organs is one of the major tasks of developmental and stem cell biology. Recently, lineage tracing technology using CRISPR/Cas9 genome editing have enabled simultaneous readouts of gene expressions and lineage barcodes in single cells, which allows for the reconstruction of the cell division tree, and even the detection of cell types and differentiation trajectories at the whole organism level. While most state-of-the-art methods for lineage reconstruction utilize only the lineage barcode data, methods that incorporate gene expression data are emerging, aiming to improve the accuracy of lineage reconstruction. However, effectively incorporating the gene expression data requires a reasonable model on how gene expression data changes along generations of divisions. Here, we present LinRace (Lineage Reconstruction with asymmetric cell division model), a method that integrates the lineage barcode and gene expression data using the asymmetric cell division model and infers cell lineage under a framework combining Neighbor Joining and maximum-likelihood heuristics. On both simulated and real data, LinRace outputs more accurate cell division trees than existing methods for lineage reconstruction. Moreover, LinRace can output the cell states (cell types) of ancestral cells, which is rarely performed with existing lineage reconstruction methods. The information on ancestral cells can be used to analyze how a progenitor cell generates a large population of cells with various functionalities. LinRace is available at: https://github.com/ZhangLabGT/LinRace.

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Understanding how single cells divide and differentiate into different cell types in developed organs is one of the major tasks of developmental and stem cell biology. Recently, lineage tracing technology using CRISPR/Cas9 genome editing has enabled simultaneous readouts of gene expressions and lineage barcodes in single cells, which allows for the reconstruction of the cell division tree, and even the detection of cell types and differentiation trajectories at the whole organism level. While most state-of-the-art methods for lineage reconstruction utilize only the lineage barcode data, methods that incorporate gene expression data are emerging, aiming to improve the accuracy of lineage reconstruction. However, effectively incorporating the gene expression data requires a reasonable model of how gene expression data changes along generations of divisions. Here, we present LinRace (Lineage Reconstruction with asymmetric cell division model), a method that integrates the lineage barcode and gene expression data using the asymmetric cell division model and infers cell lineage under a framework combining Neighbor Joining and maximum-likelihood heuristics. On both simulated and real data, LinRace outputs more accurate cell division trees than existing methods for lineage reconstruction. Moreover, LinRace can output the cell states (cell types) of ancestral cells, which is rarely performed with existing lineage reconstruction methods. The information on ancestral cells can be used to analyze how a progenitor cell generates a large population of cells with various functionalities. LinRace is available at: https://github.com/ZhangLabGT/LinRace.