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

项目摘要 随着生物体年龄的增长，基因调控随着表观基因组的变化而沿着变得越来越不稳定。 在基因组内，主要的表观遗传标记DNA甲基化通常发生在CpG二核苷酸处， 导致基因抑制。因此，CpG位点作为遗传控制开关取决于它们的甲基化 status.随着年龄的增长，CpG位点在基因启动子处获得甲基化，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位点也是高度致突变的，因此过度进化 在哺乳动物物种中，CpG二核苷酸已经耗尽。这些事实共同提出了一个 根本问题。衰老过程是否与物种的进化有关，是通过选择 特定基因？在131种哺乳动物中，许多物种被数千万个 通过对近1000个基因的进化研究，发现启动子区的CpG密度与基因的进化过程呈正相关， 与物种的寿命相关这些基因显示增加的CpG密度伴随增加的 寿命，并指示潜在的生物信号，值得进一步探索， 阐明衰老的遗传基础。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。这项建议旨在解决两个基本问题 生物学：1）这些基因是否成为进化的目标，在长寿物种中增加CpG密度 在衰老过程中保持表观遗传的完整性和基因表达？2)表观基因组的漂移是否更少 在这些基因中，随着时间的推移，在长寿物种中导致更稳定的基因表达？解决这些 问题，我们将研究12种不同哺乳动物的表观基因组（8 灵长类动物，4啮齿类动物）在三个年龄组（青少年，性成熟的成年人，老年人）。利用基因组- 广泛的减少代表性亚硫酸氢盐测序，我们将比较基因启动子DNA甲基化随着时间的推移 而且是跨物种的。目的1将探讨自然选择如何影响DNA甲基化不同的长寿 vs.短命物种目标2将研究基因是如何随着时间的推移变得不稳定的，以及自然选择是如何 来对抗这种不稳定性。通过这些研究，我们希望揭示表观遗传标记是否在特定的 基因是衰老的重要驱动因素，因此提供了干预靶点和衰老的分子机制。 进化创新，延长使用寿命。目前，这一想法得到了计算比较的支持。 基因组学，但没有一个明确的分子解释。实验室验证老化之间的联系 表观基因组和CpG密度随寿命的演变可能对我们理解 我们如何变老

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.