title: The Complete Genome Sequences, Unique Mutational Spectra, and Developmental Potency of Adult Neurons Revealed by Cloning.
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.
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla CA 92037, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hazen
authors.affiliation: Department of Biochemistry and Molecular Genetics, 1340 Jefferson Park Ave, University of Virginia School of Medicine, Charlottesville, VA 22901, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Faust
authors.affiliation: Mouse Genetics Core Facility, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Alberto R
authors.initials: AR
authors.lastname: Rodriguez
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla CA 92037, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Ferguson
authors.affiliation: Department of Biochemistry and Molecular Genetics, 1340 Jefferson Park Ave, University of Virginia School of Medicine, Charlottesville, VA 22901, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Shumilina
authors.affiliation: Department of Biochemistry and Molecular Genetics, 1340 Jefferson Park Ave, University of Virginia School of Medicine, Charlottesville, VA 22901, USA.
authors.forename: Royden A
authors.initials: RA
authors.lastname: Clark
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla CA 92037, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boland
authors.affiliation: Mouse Genetics Core Facility, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Martin
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla CA 92037, USA.|Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Chubukov
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla CA 92037, USA.|Neuroscience Graduate Program, 9500 Gilman Drive, University of California San Diego, La Jolla, California, USA.
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Tsunemoto
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Torkamani
authors.affiliation: Mouse Genetics Core Facility, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kupriyanov
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave, St. Louis, MO 63108, USA.|Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, USA.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Hall
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla CA 92037, USA.|Neuroscience Graduate Program, 9500 Gilman Drive, University of California San Diego, La Jolla, California, USA.
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Baldwin
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D003001:Cloning, Molecular; D004251:DNA Transposable Elements / Q000235:genetics; D004622:Embryo, Mammalian; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D053652:Nuclear Transfer Techniques; D009830:Olfactory Bulb / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D009865:Oocytes / Q000502:physiology; D017422:Sequence Analysis, DNA
chemical_list: C442481:CDHR1 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D004251:DNA Transposable Elements; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins