Using DNA Methylation Data to Understand the Evolutionary Basis of Human Aging

 描述（由申请人提供）：人类生物衰老的进化基础尚未得到很好的理解。基本理论表明，衰老应该受到自然选择的反对，因为它会导致生育率下降和死亡风险增加，并与达尔文适应性的重大下降有关。那么，为什么衰老是人类的普遍特征呢？为什么所有的人都会变老？有几种理论对人类衰老的存在提出了解释。主要理论包括：1）突变积累理论; 2）拮抗多效性理论，其中可抛弃索马理论是其特例。这些理论并不是相互排斥的，很可能这三种理论都解释了衰老过程的一部分。然而，每个理论的贡献大小仍然是未知的。这些信息将有助于阐明不同类型的基因在衰老过程中所起的作用。为了填补这一知识空白，我们将使用DNA甲基化数据作为衰老的创新措施来测试衰老进化理论的预测。全基因组DNA甲基化模式已被证明是高度动态的年龄，并假设是反映老化过程。纵向和家族DNA甲基化数据将使我们能够测试以前未探索的理论预测与衰老作为一个终身的过程。该研究的具体目的是：1）检验DNA甲基化的遗传力和衰老速率是否与一次性索马或突变累积模型一致，以及2）检验DNA甲基化数据是否支持一次性索马模型所暗示的随机衰老过程。我们提出的方法，以达到我们的具体目标代表了新的扩展现有的分析方法和数学模型的原始配方。为了达到我们的第一个目标，我们将使用一个既定的定量遗传学方法的组合来测试特定的假设，DNA甲基化模式的变化和衰老的速度的遗传性。为了达到我们的第二个目标，我们将开发一个原始的和可测试的随机模型的DNA甲基化变化在整个生命。

 DESCRIPTION (provided by applicant): The evolutionary basis of human biological aging is not well understood. Basic theory suggests that aging should be opposed by natural selection as it causes decreased fertility and an increased risk of death, and is associated with major decreases in Darwinian fitness. Why then is aging a universal human trait? Why is it that all humans age? Several theories have proposed explanations for the existence of human aging. Major theories include: 1) the theory of mutation accumulation, and 2) the theory of antagonistic pleiotropy, with the theory of disposable soma as a special case. These theories are not mutually exclusive, and it is likely that all three explain some portion of the aging process. The size of the contribution each theory makes, however, is still unknown. Such information will help to clarify the roles that different types of genes play in the aging process. To help fill this gapin knowledge we will test predictions of evolutionary theories of aging using DNA methylation data as an innovative measure of aging. Genome-wide DNA methylations patterns have been shown to be highly dynamic with age, and are hypothesized to be reflective of the aging process. Longitudinal and familial DNA methylation data will allow us to test previously unexplored theory predictions related to aging as a lifelong process. The specific aims of the proposed research are to: 1) test whether the heritability of DNA methylation and rate of aging are consistent with disposable soma or mutation accumulation models, and 2) test whether DNA methylation data support a stochastic aging process implied by the disposable soma model. The approaches we propose to reach our specific aims represent novel extensions of existing methods of analysis and original formulations of mathematical models. To reach our first aim we will use a combination of established quantitative genetic methods to test specific hypotheses about the heritability of DNA methylation pattern changes and the rate of aging. To reach our second aim we will develop an original and testable stochastic model of DNA methylation changes throughout life.