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bioRxiv · 10.1101/221960

Aging and neurodegeneration are associated with increased mutations in single human neurons

Lodato, M. A.·Rodin, R. E.·Bohrson, C. L.·Coulter, M. E.·Barton, A. R.·Kwon, M.·Sherman, M. A.·Vitzhum, C. M.·Luquette, L. J.·Yandava, C.·Yang, P.·Chittenden, T. W.·Hatem, N. E.·Ryu, S. C.·Woodworth, M. B.·Park, P. J.·Walsh, C. A.
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Abstract

It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of fifteen normal individuals (aged 4 months to 82 years) as well as nine individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and Xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age--which we term genosenium--shows age-related, region-related, and disease-related molecular signatures, and may be important in other human age-associated conditions.\n\nOne-Sentence SummarySomatic single-nucleotide variants accumulate in human neurons in aging with regional specificity and in progeroid diseases.

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Lodato, M. A., Rodin, R. E., Bohrson, C. L., Coulter, M. E., Barton, A. R., Kwon, M., Sherman, M. A., Vitzhum, C. M., Luquette, L. J., Yandava, C., Yang, P., Chittenden, T. W., Hatem, N. E., Ryu, S. C., Woodworth, M. B., Park, P. J., Walsh, C. A.. 2017-11-21. Aging and neurodegeneration are associated with increased mutations in single human neurons. https://doi.org/10.1101/221960

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