Linking evolution to aging through DNA methylation and CpG density by examining twelve mammalian species

项目摘要 随着生物年龄的增长，随着表观基因组的变化，基因调控变得越来越不稳定。 在基因组内，一个主要的表观遗传标记，dna甲基化，通常发生在cpG二核苷酸。 导致基因抑制。因此，CpG位点依赖于它们的甲基化起到了基因控制开关的作用 状态。随着年龄的增长，CpG位点在基因启动子上获得甲基化，而甲基化水平的漂移导致 细胞和个体之间的差异。甲基化的CpG位点也是高度突变的，所以过度进化 在哺乳动物中，CpG二核苷酸已经耗尽。这些事实加在一起提出了一个 根本问题。衰老过程是否通过选择CpG位点与物种的进化联系在一起 特定的基因？在131种哺乳动物中，它们中的许多被数千万 经过多年的进化历史，我们发现在大约1000个基因中，启动子中的CpG密度是正的 与物种的寿命相关。这些基因表现出CpG密度的增加伴随着 它们表明了一种潜在的生物信号，值得进一步探索，以便 阐明对衰老的遗传基础的见解。我们的主要假设是，增加的CpG密度缓冲 衰老过程中甲基化增加的影响。这项提议旨在解决两个基本问题 在生物学方面：1)这些基因是否成为进化的目标，在长寿物种中CpG密度增加 在衰老过程中保持表观遗传完整性和保持基因表达？2)表观基因组漂移较少 在这些基因中，导致长寿物种随着时间的推移更稳定的基因表达？要解决这些问题 问题，我们将检查来自12个不同哺乳动物物种的个体的表观基因组(8 灵长类动物，4只啮齿动物)，分三个年龄组(青少年、性成熟成年人、老年人)。利用基因组- 广泛降低代表性的亚硫酸氢盐测序，我们将比较基因启动子DNA甲基化随时间的变化 以及跨物种的。目标1将探索自然选择如何在长寿中以不同的方式影响DNA甲基化 与短命物种的对比。目标2将研究基因如何随着时间的推移变得不稳定，以及自然选择如何 针对这种不稳定做出选择。通过这些研究，我们希望揭示表观遗传标记在特定的 基因是衰老的重要驱动因素，因此提供了干预靶点和 进化创新，延年益寿。目前，这一想法得到了计算比较的支持 基因组学，目前还没有一个明确的分子解释。衰老之间的联系的实验室验证 表观基因组和CpG密度随寿命的演变可能会对我们理解 我们是如何变老的。

Project Summary As organisms age, gene regulation becomes increasingly unstable along with changes in the epigenome. Within the genome, a principle epigenetic mark, DNA methylation, occurs at CpG dinucleotides generally causing gene repression. Thus, CpG sites act as genetic control switches depending on their methylation status. As we age, CpG sites gain methylation at gene promoters and drifting methylation levels cause variation between cells and individuals. Methylated CpG sites are also highly mutagenic, so over evolutionary time there has been a depletion of CpG dinucleotides in mammalian species. Together these facts raise a fundamental question. Is the aging process linked to the evolution of a species by the selection of CpG sites at specific genes? Across one hundred thirty-one mammal species, many of them separated by tens of millions of years of evolutionary history, we revealed that in about 1000 genes, CpG density in promoters was positively correlated with species’ lifespans. These genes showed increased CpG density concomitant with increased lifespan and are indicative of an underlying biological signal, one that merits further exploration in order to elucidate insights into the genetic basis of aging. Our main hypothesis is that increased CpG density buffers the impacts of increased methylation during aging. This proposal aims to address two fundamental questions in biology: 1) Have these genes become targets for evolution, increasing in CpG density in long-lived species to maintain epigenetic integrity and preserve gene expression during aging? 2) Does the epigenome drift less in these genes, resulting in more stable gene expression over time in long-lived species? To address these questions, we will examine the epigenomes of individuals from twelve different mammalian species (8 primates, 4 rodents) in three age cohorts (juveniles, sexually mature adults, elder individuals). Using genome- wide reduced-representation bisulfite sequencing, we will compare gene promoter DNA methylation over time and across species. Aim 1 will explore how natural selection impacts DNA methylation differently in long-lived vs. short lived species. Aim 2 will examine how genes become unstable over time and how natural selection selects against that instability. Through these studies we hope to uncover whether epigenetic marks at specific genes are important drivers of aging, therefore providing interventional targets and a molecular mechanism of evolutionary innovation for long lifespan. Currently, this idea is supported by computational comparative genomics, yet does not have a clear molecular explanation. Laboratory validation of the link between the aging epigenome and the evolution of CpG density with lifespan could have broad impact on our understanding of how we age.