TY - JOUR
T1 - The Complete Genome Sequences, Unique Mutational Spectra, and Developmental Potency of Adult Neurons Revealed by Cloning
AU - Hazen, Jennifer L.
AU - Faust, Gregory G.
AU - Rodriguez, Alberto R.
AU - Ferguson, William C.
AU - Shumilina, Svetlana
AU - Clark, Royden A.
AU - Boland, Michael J.
AU - Martin, Greg
AU - Chubukov, Pavel
AU - Tsunemoto, Rachel K.
AU - Torkamani, Ali
AU - Kupriyanov, Sergey
AU - Hall, Ira M.
AU - Baldwin, Kristin K.
N1 - Funding Information:
We would like to thank Kevin Eggan and Chad Cowan for early help with somatic cell nuclear transfer, Michael Duran for assistance in validating mutations, Valentina Lo Sardo for help with cell culture and for feedback on the manuscript, Sohyon Lee for help with the manuscript, and Susan Carlson for help with animal husbandry. This work was supported by funding from the National Institute on Deafness and Other Communication Disorders (DC012592 to K.K.B.); the National Institute of Mental Health (MH102698 to K.K.B. and I.M.H.); the California Institute for Regenerative Medicine (RB3-02186 to K.K.B.); the Baxter Family, Norris, and Del Webb Foundations (K.K.B.), and by Las Patronas and the Dorris Neuroscience Center (K.K.B.), the NIH Director’s New Innovator Award (DP2OD006493-01 to I.M.H.), and a predoctoral fellowship from the California Institute of Regenerative Medicine (J.L.H. and R.K.T.).
Funding Information:
We would like to thank Kevin Eggan and Chad Cowan for early help with somatic cell nuclear transfer, Michael Duran for assistance in validating mutations, Valentina Lo Sardo for help with cell culture and for feedback on the manuscript, Sohyon Lee for help with the manuscript, and Susan Carlson for help with animal husbandry. This work was supported by funding from the National Institute on Deafness and Other Communication Disorders (DC012592 to K.K.B.); the National Institute of Mental Health (MH102698 to K.K.B. and I.M.H.); the California Institute for Regenerative Medicine (RB3-02186 to K.K.B.); the Baxter Family, Norris, and Del Webb Foundations (K.K.B.), and by Las Patronas and the Dorris Neuroscience Center (K.K.B.), the NIH Director’s New Innovator Award (DP2OD006493-01 to I.M.H.), and a predoctoral fellowship from the California Institute of Regenerative Medicine (J.L.H. and R.K.T.).
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/3/16
Y1 - 2016/3/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84960805198&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2016.02.004
DO - 10.1016/j.neuron.2016.02.004
M3 - Article
C2 - 26948891
AN - SCOPUS:84960805198
SN - 0896-6273
VL - 89
SP - 1223
EP - 1236
JO - Neuron
JF - Neuron
IS - 6
ER -