McLain Adam T, Faulk Christopher
Department of Biology and Chemistry, College of Arts and Sciences, SUNY Polytechnic Institute, Utica, NY 13502, USA.
Department of Animal Sciences, University of Minnesota, College of Food, Agricultural, and Natural Resource Sciences, Saint Paul, MN 55108, USA.
Aging (Albany NY). 2018 Apr 14;10(4):561-572. doi: 10.18632/aging.101413.
Gene promoters are evolutionarily conserved across holozoans and enriched in CpG sites, the target for DNA methylation. As animals age, the epigenetic pattern of DNA methylation degrades, with highly methylated CpG sites gradually becoming demethylated while CpG islands increase in methylation. Across vertebrates, aging is a trait that varies among species. We used this variation to determine whether promoter CpG density correlates with species' maximum lifespan. Human promoter sequences were used to identify conserved regions in 131 mammals and a subset of 28 primate genomes. We identified approximately 1000 gene promoters (5% of the total), that significantly correlated CpG density with lifespan. The correlations were performed via the phylogenetic least squares method to account for trait similarity by common descent using phylogenetic branch lengths. Gene set enrichment analysis revealed no significantly enriched pathways or processes, consistent with the hypothesis that aging is not under positive selection. However, within both mammals and primates, 95% of the promoters showed a positive correlation between increasing CpG density and species lifespan, and two thirds were shared between the primate subset and mammalian datasets. Thus, these genes may require greater buffering capacity against age-related dysregulation of DNA methylation in longer-lived species.
基因启动子在全动物界中具有进化保守性，且富含CpG位点，而CpG位点是DNA甲基化的作用靶点。随着动物衰老，DNA甲基化的表观遗传模式会发生降解，高度甲基化的CpG位点会逐渐去甲基化，同时CpG岛的甲基化程度增加。在整个脊椎动物中，衰老这一特征在不同物种间存在差异。我们利用这种差异来确定启动子CpG密度是否与物种的最大寿命相关。我们使用人类启动子序列来识别131种哺乳动物以及28种灵长类基因组子集的保守区域。我们鉴定出大约1000个基因启动子（占总数的5%），其CpG密度与寿命显著相关。通过系统发育最小二乘法进行相关性分析，以利用系统发育分支长度来考虑共同祖先导致的性状相似性。基因集富集分析未发现显著富集的通路或过程，这与衰老不受正向选择的假设一致。然而，在哺乳动物和灵长类动物中，95%的启动子在CpG密度增加与物种寿命之间呈现正相关，并且在灵长类子集和哺乳动物数据集中有三分之二是共享的。因此，在寿命较长的物种中，这些基因可能需要更大的缓冲能力来抵抗与年龄相关的DNA甲基化失调。
