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Genome sequencing of normal cells reveals developmental lineages and mutational processes

2014; Nature Portfolio; Volume: 513; Issue: 7518 Linguagem: Inglês

10.1038/nature13448

1476-4687

Sam Behjati, Meritxell Huch, Ruben van Boxtel, Wouter R. Karthaus, David C. Wedge, Asif U. Tamuri, Iñigo Martincorena, Mia Petljak, Ludmil B. Alexandrov, Gunes Gundem, Patrick Tarpey, Sophie Roerink, Joyce Blokker, Mark Maddison, Laura Mudie, Ben Robinson, Serena Nik‐Zainal, Peter J. Campbell, Nick Goldman, Marc van de Wetering, Edwin Cuppen, Hans Clevers, Michael R. Stratton,

Evolution and Genetic Dynamics

On the basis of whole-genome sequences of clonal lines derived from normal mouse tissues, variation in mutational patterns and load across different tissues are described and early embryonic cell divisions are reconstructed. By whole-genome sequencing of clonal lines derived from multiple tissues of healthy mice, Michael Stratton and colleagues have reconstructed the early cell divisions of each animal, demonstrating the contributions of embryonic cells to adult tissues. They find that tissues differ by the numbers and types of mutations accumulated by each cell, probably as a result of the differences in the number of cell divisions they have undergone and varying contributions of different mutational processes. Thus, the number of somatic mutations can be used as a 'cell division clock', and if mutation rates are similar in mice and humans, this approach should also be applied to human cells. The somatic mutations present in the genome of a cell accumulate over the lifetime of a multicellular organism. These mutations can provide insights into the developmental lineage tree1, the number of divisions that each cell has undergone and the mutational processes that have been operative2. Here we describe whole genomes of clonal lines3 derived from multiple tissues of healthy mice. Using somatic base substitutions, we reconstructed the early cell divisions of each animal, demonstrating the contributions of embryonic cells to adult tissues. Differences were observed between tissues in the numbers and types of mutations accumulated by each cell, which likely reflect differences in the number of cell divisions they have undergone and varying contributions of different mutational processes. If somatic mutation rates are similar to those in mice, the results indicate that precise insights into development and mutagenesis of normal human cells will be possible.