MAY 09, 2019 10:30 AM PDT

Somatic Gene Recombination in the Brain

Speakers
  • Professor and Senior Vice President, Sanford Burnham Prebys Medical Discovery Institute
    Biography
      Jerold Chun, MD, PhD, is Professor and Senior Vice President of Neuroscience Drug Discovery at Sanford Burnham Prebys Medical Discovery Institute (SBP). He received his MD and PhD (Neuroscience) degrees through the Medical Scientist Training Program at Stanford University School of Medicine. He moved east as a Helen Hay Whitney Postdoctoral Fellow at the Whitehead Institute for Biomedical Research, MIT. Dr. Chun then joined the faculty at the UCSD School of Medicine, where he became Professor of Pharmacology and Neurosciences and directed the Neurosciences Graduate Program. He subsequently became Department Head of Molecular Neuroscience at Merck Research Laboratories before returning to academia as Professor at The Scripps Research Institute and adjunct Professor at UCSD, leading to his current position. He has made important contributions to our understanding of the brain and its diseases, including the discovery of genomic mosaicism and somatic gene recombination in the brain and its involvement in the most common forms of Alzheimer's disease with relevance to other brain diseases. In separate work, he identified the first lysophospholipid receptor, which is part of a growing class of lipid receptors that underlie new neuroscience medicines (e.g., fingolimod and siponimod for Multiple Sclerosis) and understanding of other diseases, including hydrocephalus, schizophrenia, neuropathic pain, and fibrosis. Dr. Chun has authored more than 300 scientific publications, has been recognized in Thomson Reuters' World's Most Influential Scientific Minds citation list, and is a member of numerous advisory, review, and editorial boards in both academia and industry.

    Abstract:

    Speculations that some form DNA alteration might be utilized by the brain date to the 1960s [1] wherein hypotheses for genomic alterations of germline DNA were proposed for immunoglobulins and, by analogy, nervous system development.  In the mid 1970s, the first evidence for what is now known as V(D)J recombination of immunoglobulins was reported [2]. However, brain recombination processes were not reported.  Circumstantial evidence for possible recombination processes emerged in the 1990s with brain expression of immune recombination genes like RAG1 [3], however no genomic locus was found.  However, related work identified the first evidence for pervasive genomic alterations – “Genomic Mosaicism” - in the form of aneuploidies of neural progenitor cells [4] and a growing range of genomic elements are known to be altered in single cells of the vertebrate brain:  chromosomes, smaller copy number variations (CNVs), Line1 elements, and single nucleotide variations (SNVs), all reported globally as DNA content variation (DCV) (reviewed in [5]).  Gene recombination, however, remained speculative.  The realization that the brain is a complex genomic mosaic led to identification of APP as a gene possibly affected by SGR [6, 7], which was recently demonstrated [8].  Unlike V(D)J recombination, SGR is (thus far) most evident in post-mitotic neurons and involves reverse transcription of APP spliced RNA that produces a “genomic complementary DNA” or “gencDNA” in neurons, ranging from 0-to-multiple copies, with integration in places distinct from germline alleles.  It appears to be dysregulated in Alzheimer’s disease with more copies of different variant forms including species with SNVs that are identical to mutations reported in familial AD yet occurring mosaically and somatically.  The involvement of reverse transcription implicates reverse transcriptase inhibition as a possible therapeutic:  literature and epidemiological assessments of patient databases for aged persons taking these medicines supports their use as near-term therapeutics for treating AD.  SGR likely affects other genes and diseases.

    Learning Objectives: 

    1. The brain is composed of cells, particularly neurons, having distinct if not unique genomic DNA sequences.  This is referred to as “Genomic Mosaicism.”
    2. Somatic gene recombination (SGR) occurs in human brain neurons (and likely other cells), and is dysregulated in sporadic Alzheimer’s disease.  It involves reverse transcription, implicating reverse transcriptase inhibitors used now to treat HIV and hepatitis B, in the near-term treatment of AD.


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