Somatic APP gene recombination in Alzheimer's disease and normal neurons
Authors: Christine S Liu
Chris Park
Jerold Chun
Richard Rivera
Ming-Hsiang Lee
Grace Kennedy
Gwendolyn E Kaeser
Benjamin Siddoway
Igor Segota
William J Romanow
Tao Long
Journal: Nature (2018)
Discipline: Multidisciplinary
Keywords: human brain; gene recombination; Alzheimer's disease; APP gene; genomic cDNAs
Affiliations: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Biomedical Sciences Program, School of Medicine, University of California, San Diego, La Jolla, CA, USA., Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. .

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. 

Retracted: No

PubPeer comments:
 In July of 2019, Junho Kim and colleagues deposited at bioRxiv a preprint calling into question the data of this article . This was first adressed by another preprint by Lee et al., 2019 (August) https: www.biorxiv.org content 10.1101 730291v1 Finally, in October of 2019, Junho Kim and colleagues deposited a new preprint with new data, calling again into question the conclusions of the original paper of Lee et al. From the preprint abstract:  We reanalyzed the data from the Lee study, revealing evidence that APP gencDNA originates mainly from contamination by exogenous APP recombinant vectors, rather from true somatic retrotransposition of endogenous APP. Our reanalysis of two recent whole exome sequencing (WES) datasetsu2014one by the authors of the Lee study3 and the other by Park et al.4u2014revealed that reads claimed to support APP gencDNA in AD samples resulted from contamination by PCR products and mRNA, respectively. **Lastly, we present our own single-cell whole genome sequencing (scWGS) data that show no evidence for somatic APP retrotransposition in AD neurons or in neurons from normal individuals of various ages** , 
 A Matters Arising to this article was published in Nature on 19 August 2020 entitled  APP gene copy number changes reflect exogenous contamination https: www.nature.com articles s41586-020-2522-3 Authors reply: https: www.nature.com articles s41586-020-2523-2 ,