Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia.

Journal: Nature neuroscience
PMID: 33432196

Abstract

Retrotransposons can cause somatic genome variation in the human nervous system, which is hypothesized to have relevance to brain development and neuropsychiatric disease. However, the detection of individual somatic mobile element insertions presents a difficult signal-to-noise problem. Using a machine-learning method (RetroSom) and deep whole-genome sequencing, we analyzed L1 and Alu retrotransposition in sorted neurons and glia from human brains. We characterized two brain-specific L1 insertions in neurons and glia from a donor with schizophrenia. There was anatomical distribution of the L1 insertions in neurons and glia across both hemispheres, indicating retrotransposition occurred during early embryogenesis. Both insertions were within the introns of genes (CNNM2 and FRMD4A) inside genomic loci associated with neuropsychiatric disorders. Proof-of-principle experiments revealed these L1 insertions significantly reduced gene expression. These results demonstrate that RetroSom has broad applications for studies of brain development and may provide insight into the possible pathological effects of somatic retrotransposition.

Authors

  • Xiaowei Zhu
    Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.
  • Bo Zhou
    Department of Neurology, The Third People's Hospital of Yibin, Yibin, China.
  • Reenal Pattni
    Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.
  • Kelly Gleason
    Division of Translational Research in Schizophrenia, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Chunfeng Tan
    Division of Translational Research in Schizophrenia, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Agnieszka Kalinowski
    Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.
  • Steven Sloan
    Department of Human Genetics, Emory University, Atlanta, GA, USA.
  • Anna-Sophie Fiston-Lavier
    Institut des Sciences de l'Evolution de Montpellier (UMR 5554, CNRS-UM-IRD-EPHE), Université de Montpellier, Montpellier, France.
  • Jessica Mariani
    Child Study Center, Yale University, New Haven, CT, USA.
  • Dmitri Petrov
    Department of Biology, Stanford University, Palo Alto, CA, USA.
  • Ben A Barres
    Department of Neurobiology, Stanford University, Palo Alto, CA, USA.
  • Laramie Duncan
    Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.
  • Alexej Abyzov
    Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • Hannes Vogel
    Department of Pathology, Stanford University, Palo Alto, CA, USA.
  • John V Moran
    Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Flora M Vaccarino
    Child Study Center, Yale University, New Haven, CT, USA.
  • Carol A Tamminga
    Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Douglas F Levinson
    Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.
  • Alexander E Urban
    Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA. aeurban@stanford.edu.

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