A Phylogenetic Approach to Mapping Cell Fate

Recent, surprising, and controversial discoveries have challenged conventional concepts regarding the origins and plasticity of stem cells, and their contributions to tissue regeneration, and highlight just how little is known about mammalian development in comparison to simpler model organisms. In the case of the transparent worm, Caenorhabditis elegans, Sulston and colleagues used a microscope to record the birth and death of every cell during its life, and the compilation of this "fate map" represents a milestone achievement of developmental biology. Determining a fate map for mammals or other higher organisms is more complicated because they are opaque, take a long time to mature, and have a tremendous number of cells. Consequently, fate mapping experiments have relied on tagging a progenitor cell with a dye or genetic marker in order to later identify its descendants. This approach, however, extracts little information because it demonstrates that a population of cells, all having inherited the same label, shares a common ancestor, but it does not reveal how cells in that population are related to one another. To avoid that problem, as well as technical limitations of current methods for mapping cell fate, we, and others, have developed a new strategy for retrospectively deriving cell fate maps by using phylogenetics to infer the order in which somatic mutations have arisen in the genomes of individual cells during development in multicellular organisms. DNA replication inevitably introduces mutations, particularly at repetitive sequences, every time a cell divides. It is thus possible to deduce the history of cell divisions by cataloging somatic mutations and phylogenetically reconstructing cell lineage. This approach has the potential to produce a complete mammalian cell fate map that, in principle, could describe the developmental lineage of any cell and help resolve outstanding questions of stem cell biology, tissue repair and maintenance, and aging.