ArticleNature2018
Somatic APP gene recombination in Alzheimer's disease and normal neurons.
Article in Nature, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 127 papers.
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Who cites it
127 citing papers in PubMed, 216 citations in OpenAlex.
- RNA-templated diversity generation via reverse transcription and homologous recombination: an evolutionary hypothesis.Theory in biosciences = Theorie in den Biowissenschaften · 2026Article
- RNA isoform diversity, splicing variants and switching in single cells of the Alzheimer's disease brain.Communications biology · 2026Article
- Alzheimer's disease: genetic background in the era of next-generation sequencing technologies.Brain communications · 2026Review
- Brain somatic mutations in Alzheimer's disease: linking genetic mosaicism to neurodegeneration.Molecular neurodegeneration · 2025Review
- RNA isoform diversity, splicing variants, and switching in single cells of the Alzheimer's disease brain.Research square · 2025Article
- Sequence Diversity and Encoded Enzymatic Differences of Monocistronic L1 ORF2 mRNA Variants in the Aged Normal and Alzheimer's Disease Brain.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes.Molecular neurodegeneration · 2025Article
- Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The genetic landscape of early-onset Alzheimer's disease in China.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Neuron-Astrocyte Interactions in Aging and Alzheimer's Disease: Dysregulation of Amyloid Precursor Protein.Ageing & longevity · 2025Article
- Somatic Mosaicism in Brain Disorders.Annual review of pathology · 2025Review
- Comprehending Alzheimer's Disease: Molecular Mechanisms and Treatment Strategies.Current Alzheimer research · 2025Review
- Structure-optimized sgRNA selection with PlatinumCRISPr for efficient Cas9 generation of knockouts.Genome research · 2024Article
- Cooperative nuclear action of RNA-binding proteins PSF and G3BP2 to sustain neuronal cell viability is decreased in aging and dementia.Aging cell · 2024Article
- Article
- Blockade of STING activation alleviates microglial dysfunction and a broad spectrum of Alzheimer's disease pathologies.Experimental & molecular medicine · 2024Article
- Article
- Alzheimer-Type Cerebral Amyloidosis in the Context of HIV Infection: Implications for a Proposed New Treatment Approach.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2024Article
- Mapping recurrent mosaic copy number variation in human neurons.Nature communications · 2024Article
- Human brain small extracellular vesicles contain selectively packaged, full-length mRNA.Cell reports · 2024Article
67 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Commented on byMosaic2019
- Commented on by
- Erratum issued
Authors and funding
11 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.