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Neuron. 2016 Mar 16;89(6):1223-1236. doi: 10.1016/j.neuron.2016.02.004. Epub 2016 Mar 3.

The Complete Genome Sequences, Unique Mutational Spectra, and Developmental Potency of Adult Neurons Revealed by Cloning.

Author information

1
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla CA 92037, USA.
2
Department of Biochemistry and Molecular Genetics, 1340 Jefferson Park Ave, University of Virginia School of Medicine, Charlottesville, VA 22901, USA.
3
Mouse Genetics Core Facility, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
4
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
5
Neuroscience Graduate Program, 9500 Gilman Drive, University of California San Diego, La Jolla, California, USA.
6
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave, St. Louis, MO 63108, USA.
7
Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, USA.
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Contributed equally

Abstract

Somatic mutation in neurons is linked to neurologic disease and implicated in cell-type diversification. However, the origin, extent, and patterns of genomic mutation in neurons remain unknown. We established a nuclear transfer method to clonally amplify the genomes of neurons from adult mice for whole-genome sequencing. Comprehensive mutation detection and independent validation revealed that individual neurons harbor ∼100 unique mutations from all classes but lack recurrent rearrangements. Most neurons contain at least one gene-disrupting mutation and rare (0-2) mobile element insertions. The frequency and gene bias of neuronal mutations differ from other lineages, potentially due to novel mechanisms governing postmitotic mutation. Fertile mice were cloned from several neurons, establishing the compatibility of mutated adult neuronal genomes with reprogramming to pluripotency and development.

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PMID:
26948891
PMCID:
PMC4795965
DOI:
10.1016/j.neuron.2016.02.004
[Indexed for MEDLINE]
Free PMC Article

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