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Whole organism lineage tracing by combinatorial and cumulative genome editing

View ORCID ProfileAaron McKenna, Gregory M. Findlay, View ORCID ProfileJames A. Gagnon, Marshall S. Horwitz, View ORCID ProfileAlexander F. Schier, View ORCID ProfileJay Shendure
doi: https://doi.org/10.1101/052712
Aaron McKenna
1Department of Genome Sciences, University of Washington, Seattle WA, USA
†These authors contributed equally to this work
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Gregory M. Findlay
1Department of Genome Sciences, University of Washington, Seattle WA, USA
†These authors contributed equally to this work
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James A. Gagnon
2Department of Molecular and Cellular Biology, Harvard University, Cambridge MA, USA
†These authors contributed equally to this work
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Marshall S. Horwitz
1Department of Genome Sciences, University of Washington, Seattle WA, USA
3Department of Pathology, University of Washington, Seattle WA, USA
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Alexander F. Schier
2Department of Molecular and Cellular Biology, Harvard University, Cambridge MA, USA
4Center for Brain Science, Harvard University, Cambridge MA, USA
5The Broad Institute of Harvard and MIT, Cambridge MA, USA
6FAS Center for Systems Biology, Harvard University, Cambridge MA, USA
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  • For correspondence: shendure@uw.edu schier@fas.harvard.edu
Jay Shendure
1Department of Genome Sciences, University of Washington, Seattle WA, USA
7Howard Hughes Medical Institute, Seattle WA, USA
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  • For correspondence: shendure@uw.edu schier@fas.harvard.edu
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Abstract

Multicellular systems develop from single cells through a lineage, but current lineage tracing approaches scale poorly to whole organisms. Here we use genome editing to progressively introduce and accumulate diverse mutations in a DNA barcode over multiple rounds of cell division. The barcode, an array of CRISPR/Cas9 target sites, records lineage relationships in the patterns of mutations shared between cells. In cell culture and zebrafish, we show that rates and patterns of editing are tunable, and that thousands of lineage-informative barcode alleles can be generated. We find that most cells in adult zebrafish organs derive from relatively few embryonic progenitors. Genome editing of synthetic target arrays for lineage tracing (GESTALT) will help generate large-scale maps of cell lineage in multicellular systems.

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Posted May 11, 2016.
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Whole organism lineage tracing by combinatorial and cumulative genome editing
Aaron McKenna, Gregory M. Findlay, James A. Gagnon, Marshall S. Horwitz, Alexander F. Schier, Jay Shendure
bioRxiv 052712; doi: https://doi.org/10.1101/052712
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Whole organism lineage tracing by combinatorial and cumulative genome editing
Aaron McKenna, Gregory M. Findlay, James A. Gagnon, Marshall S. Horwitz, Alexander F. Schier, Jay Shendure
bioRxiv 052712; doi: https://doi.org/10.1101/052712

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