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 will utilize high-throughput sequencing and rigorous statistical methods to empirically measure the whole-genome somatic mutation rate in cells of the hematopoietic lineage from genetically identical mice collected at birth, sexual maturity, and old age. Our analyses of these data will determine the extent to which somatic mutations are associated with age, cellular turnover, proliferation, and functional decline. Further, we will explore the potential mechanisms of lifespan extension conferred by treatment with rapamycin by measuring the whole-genome somatic mutation rate in treatment animals and controls. 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.

Public Health Relevance

The accumulation of damage to DNA is central to the development of cancer and to the aging process, but the extent and dynamics of mutation accumulation in mammals are poorly understood. The proposed research will characterize the dynamics of mutations accumulated during hematopolesis, which are potentially relevant for a range of blood cancers, hemophilia, and other serious conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM104318-02
Application #
8728963
Study Section
Special Emphasis Panel (ZGM1-TWD-B)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$418,075
Indirect Cost
Name
Mount Desert Island Biological Lab
Department
Type
DUNS #
077470003
City
Salsbury Cove
State
ME
Country
United States
Zip Code
04672
Davis, Allan Peter; Grondin, Cynthia J; Lennon-Hopkins, Kelley et al. (2015) The Comparative Toxicogenomics Database's 10th year anniversary: update 2015. Nucleic Acids Res 43:D914-20
Fidler, Aaron L; Vanacore, Roberto M; Chetyrkin, Sergei V et al. (2014) A unique covalent bond in basement membrane is a primordial innovation for tissue evolution. Proc Natl Acad Sci U S A 111:331-6
Wyffels, Jennifer; King, Benjamin L; Vincent, James et al. (2014) SkateBase, an elasmobranch genome project and collection of molecular resources for chondrichthyan fishes. F1000Res 3:191
Updike, Dustin L; Knutson, Andrew Kek?pa'a; Egelhofer, Thea A et al. (2014) Germ-granule components prevent somatic development in the C. elegans germline. Curr Biol 24:970-5
Shaw, Joseph R; Hampton, Thomas H; King, Benjamin L et al. (2014) Natural selection canalizes expression variation of environmentally induced plasticity-enabling genes. Mol Biol Evol 31:3002-15
Field, Daniel J; Gauthier, Jacques A; King, Benjamin L et al. (2014) Toward consilience in reptile phylogeny: miRNAs support an archosaur, not lepidosaur, affinity for turtles. Evol Dev 16:189-96