Somatic Mutations and Aging
Abstract
Since the 1950s, somatic mutations have been hypothesized to contribute to human aging. In spite of the emergence of a wealth of genomic technologies, almost all were designed to detect mutations present throughout the tissue, leaving them unable to detect somatic mutations, which are generally present in only one or a few cells.;I examined age-related patterns of somatic mutation accumulation in humans by analyzing data from The Cancer Genome Atlas; since tumors are clonal expansions of single cells, the mutations in a tumor reflect those present in the original cell prior to tumorigenesis. I found that, after controlling for tumor type, the somatic mutation frequency in tumors increased exponentially with the age of the patient at diagnosis.;The accelerated aging and reduced life expectancy in organisms with mutations in DNA repair genes suggest that longevity is inversely correlated with the somatic mutation rate, but a demonstration of this correlation in normal aging has not yet been achieved. I used sequencing of clones and amplified single cells to directly observe somatic mutations in human and mouse dermal fibroblasts and compared them with de novo germline mutations observed by sequencing parents and children. I found that, after correcting for number of cell divisions, the somatic mutation rate in both species was over an order of magnitude higher than the germline mutation rate, providing strong evidence for the disposable nature of somatic cells. I also found that both germline and somatic mutation rates in mice were several times higher than their human counterparts, suggesting that superior genome maintenance is at least partially responsible for humans' longer lifespan. Finally, I found that germline and somatic mutations from each species had distinct spectra, suggesting both tissue- and species-specific differences in DNA repair.;My results constitute the most definitive evidence yet for several longstanding hypotheses regarding aging. Together, these findings and the techniques used to arrive at them open up a new line of inquiry into somatic mutations as a cause of aging.
Permanent Link(s)
https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:10302004https://hdl.handle.net/20.500.12202/400
Citation
Source: Dissertation Abstracts International, Volume: 78-05(E), Section: B.;Advisors: Jan Vijg; Yousin Suh.