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Resolving rates of mutation in the brain using single-neuron genomics

  1. Gilad D Evrony
  2. Eunjung Lee
  3. Peter J Park
  4. Christopher A Walsh  Is a corresponding author
  1. Boston Children's Hospital, United States
  2. Harvard Medical School, United States
Research Article
  • Cited 97
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Cite this article as: eLife 2016;5:e12966 doi: 10.7554/eLife.12966

Abstract

Whether somatic mutations contribute functional diversity to brain cells is a long-standing question. Single-neuron genomics enables direct measurement of somatic mutation rates in human brain and promises to answer this question. A recent study (Upton et al., 2015) reported high rates of somatic LINE-1 element (L1) retrotransposition in the hippocampus and cerebral cortex that would have major implications for normal brain function, and further claimed these mutation events preferentially impact genes important for neuronal function. We identify errors in single-cell sequencing approach, bioinformatic analysis, and validation methods that led to thousands of false-positive artifacts being mistakenly interpreted as somatic mutation events. Our reanalysis of the data supports a corrected mutation frequency (0.2 per cell) more than fifty-fold lower than reported, inconsistent with the authors' conclusion of 'ubiquitous' L1 mosaicism, but consistent with L1 elements mobilizing occasionally. Through consideration of the challenges and pitfalls identified, we provide a foundation and framework for designing single-cell genomics studies.

Article and author information

Author details

  1. Gilad D Evrony

    Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Eunjung Lee

    Department of Biomedical Informatics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Peter J Park

    Department of Biomedical Informatics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Christopher A Walsh

    Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children's Hospital, Boston, United States
    For correspondence
    Christopher.Walsh@childrens.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Sean R Eddy, Howard Hughes Medical Institute and Harvard University, United States

Publication history

  1. Received: November 11, 2015
  2. Accepted: February 1, 2016
  3. Accepted Manuscript published: February 22, 2016 (version 1)
  4. Accepted Manuscript updated: February 25, 2016 (version 2)
  5. Version of Record published: March 16, 2016 (version 3)

Copyright

© 2016, Evrony et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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