Somatic APP gene recombination in Alzheimer’s disease and normal neurons
Open accessAbstract
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.
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Sporadic AD was recently associated with the insertion of processed pseudogenes of APP, some possibly expressing disease-associated variants, into adult neuron genomes in a process that required reverse transcriptase activity.
“Sporadic AD was recently associated with the insertion of processed pseudogenes of APP (amyloid precursor protein), some possibly expressing disease-associated variants, into adult neuron genomes140 in a process that required reverse transcriptase activity.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [140]
The Abstract and ‘Proof-of-concept linkage between gencDNAs and AD in neurons’ report APP genomic cDNAs in neurons, including variants enriched in sporadic AD with mutations matching familial AD mutations. The Discussion explicitly distinguishes these gencDNAs from processed pseudogenes and presents reverse transcriptase activity as a possible mechanism, not an established requirement. It also treats expression of the variants as a possibility rather than a demonstrated outcome. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPrevious studies have shown increased neuronal genomic mosaicism (including SNVs, copy number variations, and cDNA insertions) in neurodegeneration.
“Previous studies have shown increased neuronal genomic mosaicism (including SNVs, copy number variations, and cDNA insertions in neurodegeneration)124–128.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [126]
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Palmer, C. R., Liu, C. S., Romanow, W. J., Lee, M.-H., & Chun, J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2114326118 · Cited by 89 · see citing works
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Lodato, M. A., & Walsh, C. A. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz191 · Cited by 56 · see citing works
Chen, Y., Sun, Y., Luo, Z., Chen, X., Wang, Y., Qi, B., Lin, J., Lin, W.-W., Sun, C., Zhou, Y., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.881488 · Cited by 40 · see citing works
- Authors
- Lee, M.-H., Siddoway, B., Kaeser, G. E., Segota, I., Rivera, R., Romanow, W. J., Liu, C. S., Park, C., Kennedy, G., Long, T., & Chun, J.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Chun, Jerold
- ORCID
- Venue
- Nature
- Published
- 2018-11-21
- Volume
- 563
- Issue
- 7733
- Pages
- 639-645
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6391999
- OpenAlex
- W2901502534
- Cited by
- 210
- References
- 66
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 24 · 2023: 12 · 2022: 28 · 2021: 27 · 2020: 42 · 2019: 56 · 2018: 4 · 2017: 2
- FWCI
- 22.30
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-01-22)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (P50AG005131, T32AG000216)
- National Institute of General Medical Sciences (T32GM007752)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- Alzheimer's disease, amyloid precursor protein gene, APP, reverse transcriptase, familial Alzheimer's disease mutations, neuronal heterogeneity, DNA strand breaks, in situ hybridization
- MeSH terms
- Alzheimer Disease, Animals, DNA-Directed DNA Polymerase, Exons, Female, Humans, Introns, Male, Mice, Transgenic, Neurons, Organ Specificity, Recombination, Genetic, RNA, Messenger, Genetic Variation, Amyloid beta-Protein Precursor, Point Mutation, Sequence Deletion, Alternative Splicing, Sequence Analysis, DNA, DNA, Complementary, Mice
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