Fernandez, Thomas V

Abstract 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.

Genomic sleuthing spots early divergence After fertilization, the human zygote divides into two cells. Fasching et al. used genomic analysis from cellular samples taken much later in development to back-calculate the cell division trees that went before. Although the first cell division in human development looks symmetrical from the outside, the fates followed by daughter cells from each of those first two blastomeres are anything but the same. As much as 90% of blood cells are derived from just one of the first two blastomeres. Science , this issue p. 1245