Stem Cell Chronicles: Autobiographies Within Genomes Darryl Shibata & Simon Tavaré Published online: 3 July 2007 # Humana Press Inc. 2007 Abstract Human stem cell studies are difficult because many of the powerful experimental approaches that mark and follow stem cells and their progeny are impractical. Moreover, humans are long-lived, and it would literally take a lifetime to follow stem cell fates prospectively. Consider- ing these hurdles, an ideal method would not require prior experimental manipulations but still allow “observations” of human stem cells from birth to death. The purpose of this review is to outline how histories or fates are likely to be surreptitiously recorded within somatic cell genomes by replication errors (molecular clock hypothesis). It may be possible to reconstruct stem cell lifetimes by measuring the random somatic changes that accumulate within their genomes, or the genomes of their more-easy-to-identify progeny. Keywords Stem cell . Molecular clock . Genealogy Life involves the replication and transfer of information between generations. Information is stored within genomes, which also record ancestry because genomes are almost exact copies of copies. Replication errors inevitably occur, allowing for variation or evolution, and these changes may subsequently be copied and passed from cell to cell. Ancestry is recorded by such random changes, and it is possible to infer intervals since genomes shared a common ancestor by counting differences—the greater the differ- ences between two genomes, the greater, on average, the interval since they shared a common ancestor (“molecular clock” hypothesis [1]). Sequences are commonly used to infer species phylogeny [1]. By analogy, it should be possible to reconstruct a somatic cell tree (Fig. 1a) because all cells within an individual are related, with the zygote as the ultimate common ancestor [2]. Somatic cell genomes represent nearly exact copies of the genome in the zygote. Somatic cells with greater mitotic ages (total numbers of divisions since the zygote) should accumulate greater numbers of replication errors. All cells within an individual have identical chronological ages (years since birth), but their mitotic ages may differ. Stem Cell Genealogies Before dwelling on the complexities of “molecular clocks,” it is useful to outline how stem cell biology is logically encoded by mitotic age and genealogy (the changes in phenotype between the zygote and a present day cell). The genealogy and genome of every cell starts from the zygote. The genealogy of many cells can be divided into three sequential phenotypic phases: development from the zygote, a stem cell phase, and differentiation (Fig. 1b). Development and differentiation are programmed and restricted to specific times and numbers of divisions. For many cell types, development only occurs during the first few months or years after conception, and differentiation from a stem cell also typically requires a set amount of time from several days to weeks. Numbers of divisions during these phases are pre-programmed or “constant” regardless Stem Cell Rev (2007) 3:94–103 DOI 10.1007/s12015-007-0022-6 D. Shibata (*) Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA e-mail: dshibata@usc.edu S. Tavaré Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA S. Tavaré Department of Oncology, University of Cambridge, Cambridge, UK