Koch Zane, Li Adam, Evans Daniel S, Cummings Steven, Ideker Trey
Program in Bioinformatics and Systems Biology, University of California, San Diego, La Jolla, CA, USA.
California Pacific Medical Center Research Institute, San Francisco, CA, USA.
Nat Aging. 2025 Apr;5(4):709-719. doi: 10.1038/s43587-024-00794-x. Epub 2025 Jan 13.
DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping allows mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging more rapidly or slowly than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.
DNA甲基化标记最近被用于构建称为表观遗传时钟的模型，该模型可预测日历年龄。由于胞嘧啶甲基化会促进C到T的突变，我们推测随着年龄增长观察到的甲基化变化应反映体细胞突变的累积，并且两者应产生类似的衰老估计值。在对9331名人类个体的多模态数据进行分析时，我们发现CpG突变确实与甲基化变化相吻合，不仅在突变位点，而且在甲基化组±10千碱基范围内都存在广泛的重塑。这种一对多的映射使得基于突变的年龄预测与表观遗传时钟一致，包括哪些个体比预期衰老得更快或更慢。此外，随着年龄增长而积累突变的基因组位点也往往具有特别能预测年龄的甲基化模式。这些结果表明，散发性体细胞突变的积累与生命过程中观察到的广泛甲基化变化之间存在紧密联系。
