Analysis of somatic mutations in the aging human brain using single-cell whole genome sequencing

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 DESCRIPTION (provided by applicant): While a large part of human variation in both normal traits and disease susceptibility is controlled by inherited genetic variation, including variants inherited in a Mendelian fashion and de novo mutations which occur in parental gametogenesis, somatic mutation is increasingly being appreciated as a powerful force which determines human phenotypes. However, we lack a global understanding of somatic mutation because until now technological limitations have prevented examination of low mosaicism genomic variants. Our lab has developed novel techniques which allow us to examine somatic mosaicism at unprecedented resolution by performing whole genome sequencing on single human postmortem neuronal nuclei. I have used this technology to perform extensive characterization of somatic mutations in postmortem human neurons from a normal 17 year old individual. In this application, I propose to extend this analysis to test the hypothesis that somatic mutations accumulate with age in the human brain. Question- Does the burden of somatic mutations increase with age, indicating that it may be a mechanism of aging? Aging is a biological process characterized by the gradual deterioration at the cell, and tissue and organ level, and age-related cognitive decline is a major health concern for the elderly. Neurons are long-lived and post-mitotic, and thus as an individual ages neurons have an extended period of time to be exposed to genotoxic insults, such as oxidative or radiological damage, and as a result acquire mutations. Thus, as age increases so might the number of somatic mutations in post-mitotic neurons. Therefore, I will determine whether a correlation exists between age and somatic mosaicism. Since specific mutational process induce characteristic signature alterations, by identifying which types of mutations accumulate with age, I will define a candidate list of process which may causal in aging in the brain.