MAY 09, 2019 10:30 AM PDT

Somatic Gene Recombination in the Brain

Speaker

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.


Show Resources
You May Also Like
MAY 17, 2022 9:00 AM PDT
MAY 17, 2022 9:00 AM PDT
Date: May 17, 2022 Time: 9:00am (PDT), 12:00pm (EDT), 8:00pm (CEST) Gene therapeutics have great potential to treat many severe diseases in an unprecedented, targeted manner. The biopharmace...
MAR 23, 2022 11:00 AM PDT
MAR 23, 2022 11:00 AM PDT
Date: March 23, 2021 Time: 11:00am (PDT), 2:00pm (EDT), 8:00pm (CEDT) In this presentation, Dr. Middleton will review the development and deployment of large-scale saliva-based COVID-19 test...
APR 28, 2022 8:00 AM PDT
APR 28, 2022 8:00 AM PDT
Date: April 28, 2022 Time: 8:00am (PDT), 11:00am (EDT), 5:00pm (CEST) Human pluripotent stem cells (PSCs) and their derivatives hold great potentials in...
MAR 30, 2022 6:00 AM PDT
MAR 30, 2022 6:00 AM PDT
Targeted NGS has been instrumental in helping the healthcare community deliver on the promise of precision medicine. The Ion Torrent Genexus Integrated Sequencer has enabled targeted genomic...
MAR 02, 2022 9:00 AM PST
C.E. CREDITS
MAR 02, 2022 9:00 AM PST
Date: March 02, 2022 Time: 9:00am (PST), 12:00pm (EST) Single cell RNA-seq is known to only capture a small fraction of the transcriptome of each cell. Often, this is due to inherent limitat...
DEC 09, 2021 11:00 AM PST
C.E. CREDITS
DEC 09, 2021 11:00 AM PST
Date: December 09, 2021 Time: 11:00am (PDT), 2:00pm (EDT) The burden of antimicrobial resistance (AMR) has been acknowledged worldwide by leading health institutes. Besides the need for new...
MAY 09, 2019 10:30 AM PDT

Somatic Gene Recombination in the Brain



Show Resources
Loading Comments...
Show Resources