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EXCESSIVE SOMATIC MUTATIONS WITH DISTINCTIVE PATTERNS IN ALZHEIMER’S DISEASE NEURONS REVEALED BY NOVEL SINGLE-CELL WHOLE GENOME SEQUENCING METHOD
Abstract
Aims
Alzheimer’s disease (AD) is characterized pathologically by deposition of misfolded amyloid-β and tau proteins. However, protein-directed therapeutic strategies have shown limited clinical benefit, pointing to the need to examine pathogenesis from a broader lens.
Neurons each harbor somatic single nucleotide variants (sSNV) in their genomes, which increase with age, at a rate of ~15-20 sSNV per year. In AD, DNA damage is increased, with potentially significant effects on the genome of each cell.
Methods
We performed single-cell whole genome sequencing on neurons from AD and age-matched controls, using two independent genome amplification methods, and analyzed the burden of somatic mutations and associated nucleotide change signatures for mutational patterns.
Results
We found significantly increased sSNV in AD, with hundreds of additional somatic mutations per neuron, and a distinct mutation pattern. AD neurons show an increase in Signature C, which contains distinct nucleotide changes including C>A variants. We find elevated 8-Oxoguanine DNA lesions, evidence that these mutations may result from oxidative DNA damage. Mutations also show influences of transcription in sSNV generation. Somatic mutations are predicted to produce deleterious effects on the neuron, including gene inactivation and neoantigen-stimulated immune attack.
Conclusions
AD neurons show increased somatic mutations, with mutagenic causes that illuminate upstream components of disease pathogenesis, including DNA oxidation and transcription-coupled DNA repair. Somatic mutations further predispose neurons for dysfunction and death. The identification of somatic mutation accumulation as a novel element of neurodegeneration will enable further dissection of the cascade of events in disease pathogenesis.