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<jats:p>Canine transmissible venereal tumor (CTVT) is the oldest known somatic cell lineage. It is a transmissible cancer that propagates naturally in dogs. We sequenced the genomes of two CTVT tumors and found that CTVT has acquired 1.9 million somatic substitution mutations and bears evidence of exposure to ultraviolet light. CTVT is remarkably stable and lacks subclonal heterogeneity despite thousands of rearrangements, copy-number changes, and retrotransposon insertions. More than 10,000 genes carry nonsynonymous variants, and 646 genes have been lost. CTVT first arose in a dog with low genomic heterozygosity that may have lived about 11,000 years ago. The cancer spawned by this individual dispersed across continents about 500 years ago. Our results provide a genetic identikit of an ancient dog and demonstrate the robustness of mammalian somatic cells to survive for millennia despite a massive mutation burden.</jats:p>

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<jats:p>Listen to stories on the genome of a transmissible tumor, an update from Opportunity on Mars, and more.</jats:p>

<jats:p> <jats:bold>Background:</jats:bold> Differentiated cells can be reprogrammed to switch identities from one cell type to another under the direction of powerful transcription factors. In the mammalian central nervous system, this approach has been used experimentally to generate new categories of neuronal cells. The protocols are inspired by what we have learned from normal development, but the applications lie outside of normal embryogenesis. The research is changing how scientists think about regeneration of lost neurons and modeling of neuronal function in the central nervous system. The approaches also allow for new ways to study human neuronal development, a process that cannot be studied in vivo. <jats:bold>Advances:</jats:bold> Neurons are a highly specialized cell type, with their ability to transmit electrical signals. Beyond that, though, neurons also specialize into an astonishing diversity of classes. Although reprogramming with known transcription factors is a comparatively blunt tool, researchers have used knowledge of normal neuronal development to identify suites of factors that can convert mouse or human non-neuronal cells into induced neuronal cells showing class-specific features. These protocols have provided a renewable source of neuronal cells for high-throughput studies, which is particularly useful when source tissue is rare or unavailable. One exciting application of lineage reprogramming has been the generation of new neurons in situ by the direct conversion of other cell types already resident within the brain. Astrocytes have been converted into neurons in vivo. Even neurons have been changed from one subtype to another in young animals, indicating that postmitotic neurons may not be as immutable as once thought. These provocative results may foster the development of strategies for neuronal replacement that rely on “code-switching” of neuronal identity on the spot. <jats:bold>Outlook:</jats:bold> Direct lineage reprogramming is a nascent but promising field. Although both unspecialized and specialized neuronal cells have already been generated by these methods, we still need more refined understanding of how reprogramming works, how the cellular context constrains reprogramming routes, and what synergistic effects arise with various reprogramming factors. Better-defined criteria are needed to classify neurons obtained by reprogramming and to determine how they differ from their endogenous counterparts. Functional analyses are also necessary to clarify when a new neuron achieves the needed function, even if its other features do not match endogenous neurons. The challenge requires collaborative expertise in stem cell biology, embryology, and fundamental neuroscience. Future ability to reprogram postmitotic neurons in the adult brain will be important for the growth of this field and likely influence the way we think about neuronal stability, regeneration, and function. </jats:p>

<jats:title>A Matter of Timing</jats:title> <jats:p> Plants flower only when their developmental programs give the go-ahead; otherwise floral genes remain repressed. <jats:bold> Sun <jats:italic>et al.</jats:italic> </jats:bold> ( <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" related-article-type="in-this-issue" xlink:href="10.1126/science.1248559">10.1126/science.1248559</jats:related-article> ; see the Perspective by <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6170" page="498" related-article-type="in-this-issue" vol="343" xlink:href="10.1126/science.1249343"> <jats:bold>Zhang</jats:bold> </jats:related-article> ) analyzed the regulatory program that controls expression of the transcription factor KNUCKLES (KNU), which is required in the control of floral genes. KNU expression was silenced by the presence of Polycomb group (PcG) proteins. The floral homeotic protein AGAMOUS competed for control of KNU and activated its expression, but with a 2-day lag time. Thus, eviction of PcG by activating DNA binding proteins can insert a lag time before a switch in gene expression takes place. </jats:p>