Tissue-specific somatic mutations during development and aging

项目总结(见说明)： 随着时间的推移，体细胞(不可遗传)DNA突变的积累是衰老的一个标志和潜在的机制。目前的理论假设，未修复的随机DNA损伤会导致随机的DNA突变，随着时间的推移，这些突变会在单个细胞内积累，并随着这些细胞的复制而传递。这些突变被认为会损害细胞功能，或导致细胞死亡或衰老，导致器官功能受损和衰老。或者，罕见的突变可能会导致细胞转化和癌症。这些理论依赖于随着年龄增长在组织中积累的突变程度，但我们无法准确测量哺乳动物的体细胞突变率。 在这项研究中，我们将利用高通量测序和严格的统计方法，从出生、性成熟和老年收集的遗传相同的小鼠中，经验性地测量造血系细胞的全基因组体细胞突变率。我们对这些数据的分析将确定体细胞突变与年龄、细胞周转、增殖和功能衰退相关的程度。此外，我们将通过测量治疗动物和对照的全基因组体细胞突变率来探索雷帕霉素治疗延长寿命的潜在机制。这项对体细胞突变的多因素研究将提供迄今为止对哺乳动物体细胞突变率的最准确测量，将开始定义控制突变随年龄积累的参数，并将开始经验性地测试癌症和衰老的常见理论。

PROJECT SUMMARY (See instructions): 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.