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

作者：Lodato, Michael A.; Rodin, Rachel E.; Bohrson, Craig L.; Coulter, Michael E.; Barton, Alison R.; Kwon, Minseok; Sherman, Maxwell A.; Vitzthum, Carl M.; Luquette, Lovelace J.; Yandava, Chandri N.; Yang, Pengwei; Chittenden, Thomas W.; Hatem, Nicole E.; Ryu, Steven C.; Woodworth, Mollie B.; Park, Peter J.; Walsh, Christopher A.

来源：Science, 2018, 359(6375): 555-558.

DOI：10.1126/science.aao4426

• NUCLEOTIDE EXCISION-REPAIR
• SOMATIC MUTATIONS
• HUMAN BRAIN
• DNA-DAMAGE
• DEFICIENT
• CANCER
• MICE

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 15 normal individuals (aged 4 months to 82 years), as well as 9 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.

• 出版日期2018-2-2