Abstract: Multicellular organisms develop by way of a lineage tree, a series of cell divisions that give rise to cell types, tissues, and organs. However, our knowledge of the cell lineage and its determinants remains extremely fragmentary for nearly all species. This includes all vertebrates and arthropods such as Drosophila, wherein cell lineage varies between individuals; embryos and organs are often visually inaccessible, and progenitor cells disperse by long-distance migration. We recently pioneered a novel paradigm for recording cell lineage and other aspects of developmental history that has the potential to fundamentally transform our understanding of vertebrate biology. In brief, we engineer cells to stochastically introduce mutations at specific locations in the genome during development. The resulting patterns of mutations, which can be efficiently queried by massively parallel sequencing, can be used to reconstruct lineage and, more generally, to determine the molecular histories of individual cells on an organism-wide scale. Here we demonstrate our technique at the single-cell level on a variety of model organisms, including zebrafish and fly, tracing the lineage of tens of thousands of cells within individual organisms and organ systems.
Aaron McKenna is a Senior Fellow in the Shendure Lab at the University of Washington and the Howard Hughes Medical Institute. His work focuses on the computational and experimental methods for lineage tracing and signal recording in both normal development as well as in cancer. Before completing his Ph.D. at the University of Washington, he worked as a computational biologist at the Broad Institute of Harvard and MIT, where he helped to develop the Genome Analysis Toolkit and led the analysis of the TCGA's glioblastoma tumor type project.