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

Somatic gene recombination of amyloid precursor protein (APP) in human neurons has been identified, encompassing thousands of genomic variants occurring mosaically in normal and sporadic Alzheimer’s disease (AD) brains. Multiple sequencing strategies and junction-specific genomic in situ hybridization revealed APP recombination, lacking introns and having precise exonic junctions, termed genomic cDNAs (gencDNAs), often with multiple recombined junctions contained within a single nucleus. Most variants showed structural changes, particularly deletion of central exons with partial exons fused together, forming intra-exonic junctions, containing single nucleotide variations. APP is a causal gene mutated in forms of AD, and our studies identified variants enriched in sporadic AD neurons, including 10 mutations identical to those in published familial AD, yet arising somatically. Additional studies linked APP neuronal RNA transcription to the appearance of gencDNAs that could be preferentially transcribed to generate myriad gene variants contributing to diversity and function in the normal and diseased brain.