Somatic mutation and epimutation rate and species-specific longevity

摘要：DNA损伤长期以来一直被认为是衰老的驱动因素。DNA损伤非常常见， 估计哺乳动物中每个细胞每天约有100，000个损伤。这种病变可以直接影响转录， 引起细胞反应，如凋亡和细胞衰老，或由于在细胞周期中的错误而导致突变。 修复或复制受损的DNA模板。项目3的重点是体细胞DNA突变， 可以从碱基替换到大的染色体畸变而变化。这通常被称为“基因组 不稳定”，现在被认为是衰老过程的标志。因为DNA突变无法修复（除了 通过细胞或有机体死亡），它们在衰老过程中积累在细胞和组织中，这是经验性的。 在多个物种中得到证实，包括人类和小鼠。准确检测和定量分析 细胞和组织中的DNA突变是一个挑战，因为正常组织中的新生突变丰度非常低， 体细胞我们开发的方法，允许准确的定量检测从头体细胞 正常细胞和组织中的突变。在之前仍在进行的项目期间，我们使用了其中一种方法 比较DNA损伤后来自不同啮齿动物物种的细胞中的突变频率和谱（参见 进度报告）。基因组维持能力长期以来一直与物种特异性的进化有关。 最大寿命因此，项目3正在测试一个假设，即来自短寿命物种的细胞，如小鼠， 在DNA损伤后，比长寿物种的相同细胞类型显示出更多的突变。在这次更新中， 在项目期间，我们将专门测试基因组结构变异（Aim 1）和DNA 甲基化的变化（目标2）引起的γ辐射与物种特异性寿命的啮齿动物。在 目标3然后，我们将测试我们的合作者在项目1和项目2中开发的干预措施， 在长寿啮齿动物中发现的长寿机制，促进基因组和/或表观基因组的完整性， 应用于小鼠。

SUMMARY: DNA damage has long been implicated as a driver of aging. DNA damage is very frequent, with estimates of about 100,000 lesions per cell per day in mammals. Such lesions can impact transcription directly, elicit cellular responses, such as apoptosis and cellular senescence, or result in mutations due to errors during repair or replication of a damaged DNA template. Project 3 has been focused on somatic DNA mutations, which can vary from base substitutions to large chromosomal aberrations. This is commonly termed "genomic instability", now considered a hallmark of the aging process. Because DNA mutations cannot be repaired (except through cell or organismal death) they accumulate in cells and tissues during aging, which has been empirically confirmed in multiple species, including humans and mouse. Accurate detection and quantitative analysis of DNA mutations in cells and tissues is a challenge due to the very low abundance of de novo mutations in normal somatic cells. We developed methods that allow for the accurate quantitative detection of de novo somatic mutations in normal cells and tissues. In the previous, still ongoing project period, we used one of these methods to compare mutation frequency and spectra in cells from different rodent species after DNA damage (see Progress Report). Genome maintenance capacity has long been implicated in the evolution of species-specific maximum life span. Hence, Project 3 is testing the hypothesis that cells from short-lived species, such as mice, would show more mutations after DNA damage than the same cell type from long-lived species. In this renewal project period, we will specifically test the hypothesis that genome structural variation (Aim 1) and DNA methylation changes (Aim 2) induced by gamma radiation correlate with species-specific life span in rodents. In Aim 3 we will then test if interventions developed by our collaborators in Project 1 and Project 2, based on the longevity mechanisms discovered in long-lived rodents, promote genome and/or epigenome integrity when applied to mice.