Mammalian Somatic Mutations and Aging
2011 new Scholar Award in aging
The accumulation of somatic (non-heritable) DNA mutations over time is a hallmark and potential mechanism of aging. Current theory postulates that un-repaired, stochastic DNA damage results in random DNA mutations that accumulate over time within individual cells, and are passed on as these cells replicate. These mutations are thought to impair cellular function, or to induce cell death or senescence, leading to impaired organ function and aging. Alternately, rare mutations may lead to cellular transformation and cancer. These theories depend upon the extent of mutations accumulated in tissues with age, but we do not have an accurate measurement of the mammalian somatic mutation rate.
In the this study, we are using high-throughput sequencing and rigorous statistical methods to empirically measure the whole-genome somatic mutation rate in mice at multiple stages of adulthood and old age. We are assaying mutations in four diverse tissues, and in three genetically diverse mouse strains with varying lifespans. Our analyses of these data will determine the extent to which somatic mutations are associated with age, tissue, and genetic background. This multi-factorial study of somatic mutations will provide the most accurate measurement of the mammalian somatic mutation rate to date, will begin to define the parameters that control the accumulation of mutations with age, and will begin to empirically test common theories of cancer and aging.