Efficient reconstruction of cell lineage trees for cell ancestry and cancer

Mosaic mutations can be used to track cell ancestries and reconstruct high-resolution lineage trees during cancer progression and during development, starting from the first cell divisions of the zygote. However, this approach requires sampling and analyzing the genomes of multiple cells, which can be redundant in lineage representation, limiting the scalability of the approach. We describe a strategy for cost- and time-efficient lineage reconstruction using clonal induced pluripotent stem cell lines from human skin fibroblasts. The approach leverages shallow sequencing coverage to assess the clonality of the lines, clusters redundant lines and sums their coverage to accurately discover mutations in the corresponding lineages. Only a fraction of lines needs to be sequenced to high coverage. We demonstrate the effectiveness of this approach for reconstructing lineage trees during development and in hematologic malignancies. We discuss and propose an optimal experimental design for reconstructing lineage trees.

Automated summary

Mosaic mutations can be used to track cell ancestries and reconstruct lineage trees during cancer progression and development. However, analyzing multiple cells' genomes can be redundant and limit scalability. This study presents a cost- and time-efficient strategy using clonal induced pluripotent stem cell lines to reconstruct lineage trees. Shallow sequencing coverage is leveraged to assess clonality, cluster redundant lines, and accurately discover mutations. Only a fraction of lines needs to be sequenced at high coverage.