Journal Article

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

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

2018

Overview

Most neurons that make up the human brain are postmitotic, living and functioning for a very long time without renewal (see the Perspective by Lee). Bae et al. examined the genomes of single neurons from the prenatal developing human brain. Both the type of mutation and the rates of accumulation changed between gastrulation and neurogenesis. These early mutations could be generating useful neuronal diversity or could predispose individuals to later dysfunction. Lodato et al. also found that neurons take on somatic mutations as they age by sequencing single neurons from subjects aged 4 months to 82 years. Somatic mutations accumulated with increasing age and accumulated faster in individuals affected by inborn errors in DNA repair. Postmitotic mutations might only affect one neuron, but the accumulated divergence of genomes across the brain could affect function. Science , this issue p. 550 , p. 555 ; see also p. 521 Brain mutations accumulate with age. 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 159 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.

• Publisher: The American Association for the Advancement of Science
• Subject: Accumulation / Adolescent / Adult / Age / Age Factors / Aged / Aged, 80 and over / Aging / Aging - genetics / Brain / Child / Child, Preschool / Cockayne syndrome / Cockayne Syndrome - genetics / Deoxyribonucleic acid / Divergence / DNA / DNA Mutational Analysis / DNA repair / DNA Repair - genetics / DNA sequencing / Female / Gastrulation / Genetic disorders / Genomes / Hippocampus / Hippocampus - cytology / Hippocampus - embryology / Humans / Infant / Male / Middle Aged / Mutation / Mutation Rate / Neurodegeneration / Neurodegenerative Diseases - genetics / Neurogenesis / Neurogenesis - genetics / Neurons / Prefrontal cortex / Prefrontal Cortex - cytology / Prefrontal Cortex - embryology / Repair / Single-Cell Analysis / Whole Genome Sequencing / Xeroderma pigmentosum / Xeroderma Pigmentosum - genetics / Young Adult