Somatic APP gene recombination in Alzheimer’s disease and normal neurons

Ming-Hsiang Lee, Benjamin Siddoway, Gwendolyn E. Kaeser, Igor Segota, Richard Rivera, William J. Romanow, Christine S. Liu, Chris Park, Grace Kennedy, Tao Long and Jerold Chun ()
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Ming-Hsiang Lee: Sanford Burnham Prebys Medical Discovery Institute
Benjamin Siddoway: Sanford Burnham Prebys Medical Discovery Institute
Gwendolyn E. Kaeser: Sanford Burnham Prebys Medical Discovery Institute
Igor Segota: Sanford Burnham Prebys Medical Discovery Institute
Richard Rivera: Sanford Burnham Prebys Medical Discovery Institute
William J. Romanow: Sanford Burnham Prebys Medical Discovery Institute
Christine S. Liu: Sanford Burnham Prebys Medical Discovery Institute
Chris Park: Sanford Burnham Prebys Medical Discovery Institute
Grace Kennedy: Sanford Burnham Prebys Medical Discovery Institute
Tao Long: Sanford Burnham Prebys Medical Discovery Institute
Jerold Chun: Sanford Burnham Prebys Medical Discovery Institute

Nature, 2018, vol. 563, issue 7733, 639-645

Abstract: Abstract The diversity and complexity of the human brain are widely assumed to be encoded within a constant genome. Somatic gene recombination, which changes germline DNA sequences to increase molecular diversity, could theoretically alter this code but has not been documented in the brain, to our knowledge. Here we describe recombination of the Alzheimer’s disease-related gene APP, which encodes amyloid precursor protein, in human neurons, occurring mosaically as thousands of variant ‘genomic cDNAs’ (gencDNAs). gencDNAs lacked introns and ranged from full-length cDNA copies of expressed, brain-specific RNA splice variants to myriad smaller forms that contained intra-exonic junctions, insertions, deletions, and/or single nucleotide variations. DNA in situ hybridization identified gencDNAs within single neurons that were distinct from wild-type loci and absent from non-neuronal cells. Mechanistic studies supported neuronal ‘retro-insertion’ of RNA to produce gencDNAs; this process involved transcription, DNA breaks, reverse transcriptase activity, and age. Neurons from individuals with sporadic Alzheimer’s disease showed increased gencDNA diversity, including eleven mutations known to be associated with familial Alzheimer’s disease that were absent from healthy neurons. Neuronal gene recombination may allow ‘recording’ of neural activity for selective ‘playback’ of preferred gene variants whose expression bypasses splicing; this has implications for cellular diversity, learning and memory, plasticity, and diseases of the human brain.

Date: 2018
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DOI: 10.1038/s41586-018-0718-6

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