Somatic mutation and epimutation rate and species-specific longevity

摘要：长期以来，DNA损伤一直被认为是衰老的驱动因素。DNA损伤非常频繁， 据估计，哺乳动物每天每个细胞大约有100,000个病变。这种损伤会直接影响转录， 引发细胞反应，如细胞凋亡和细胞衰老，或因错误而导致突变 修复或复制损坏的DNA模板。项目3一直专注于体细胞DNA突变， 可以从碱基替换到大的染色体异常。这通常被称为“基因组”。 现在被认为是衰老过程的标志。因为DNA突变是无法修复的(除了 通过细胞或生物体死亡)，它们在衰老过程中在细胞和组织中积累，这是经验性的 在包括人类和小鼠在内的多个物种中得到证实。准确的检测和定量分析 细胞和组织中的dna突变是一项挑战，因为正常人中从头突变的丰度很低。 体细胞。我们开发了能够准确定量检测新生体细胞的方法。 正常细胞和组织中的突变。在上一个仍在进行的项目期间，我们使用了以下方法之一 比较不同物种啮齿动物细胞在DNA损伤后的突变频率和频谱(请参阅 进度报告)。长期以来，基因组维持能力一直与物种特有的进化有关 最大寿命。因此，项目3正在测试一种假设，即来自短寿命物种的细胞，如小鼠， 在DNA损伤后，会显示出比长寿物种中相同类型的细胞更多的突变。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(目标1)和DNA 伽马辐射引起的甲基化改变(目标2)与啮齿动物特定物种的寿命相关。在……里面 目标3然后我们将测试我们的合作者在项目1和项目2中开发的干预措施是否基于 长寿啮齿动物中发现的长寿机制，在以下情况下促进基因组和/或表观基因组的完整性 适用于小鼠。

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.