Somatic gene recombination in neurons

The basis of neuronal diversity is largely unknown. It has long been thought that it could arise from gene recombination—just as rearrangements of immunoglobulin genes has been shown to create antibody diversity. However, concerted efforts over the past 50 years have failed to demonstrate neuronal gene recombination. Jerold Chun and colleagues now report, for the first time, somatic gene recombination of the gene that encodes amyloid precursor protein (APP) in human neurons. Thousands of APP variant genomic complementary DNAs (gencDNAs) appear mosaically in the brains of patients with either normal or sporadic Alzheimer’s disease. In vivo, in a mouse model of Alzheimer’s disease, the formation of APP gencDNAs is shown to increase with age, exclusively within neurons. In a cohort of individuals with sporadic Alzheimer’s disease used for a proof-of-concept experiment, every sample showed increased abundance and/or diversity of APP gencDNAs, pointing to a possible new disease mechanism. These findings support the notion that somatic cells, and in particular brain cells, are subject to much higher rates of genomic variation than traditionally thought.