Evolutionary conservation of DNA methylation in CpG sites within ultraconserved noncoding elements

Ultraconserved noncoding elements (UCNEs) constitute less than 1 Mb of vertebrate genomes and are impervious to accumulating mutations. About 4000 UCNEs exist in vertebrate genomes, each at least 200 nucleotides in length, sharing greater than 95% sequence identity between human and chicken. Despite extreme sequence conservation over 400 million years of vertebrate evolution, we show both ordered interspecies and within-species interindividual variation in DNA methylation in these regions. Here, we surveyed UCNEs with high CpG density in 56 species finding half to be intermediately methylated and the remaining near 0% or 100%. Intermediately methylated UCNEs displayed a greater range of methylation between mouse tissues. In a human population, most UCNEs showed greater variation than the LINE1 transposon, a frequently used epigenetic biomarker. Global methylation was found to be inversely correlated to hydroxymethylation across 60 vertebrates. Within UCNEs, DNA methylation is flexible, conserved between related species, and relaxed from the underlying sequence selection pressure, while remaining heritable through speciation.

超保守非编码元件（Ultraconserved noncoding elements，UCNEs）仅占脊椎动物基因组不到1 Mb的序列，且完全耐受突变积累。脊椎动物基因组中约存在4000个UCNEs，每个元件长度至少为200个核苷酸，人类与鸡的同源序列一致性超过95%。尽管在4亿多年的脊椎动物演化历程中序列保持高度保守，本研究仍发现这些区域的DNA甲基化同时存在有序的种间变异与种内个体间变异。本研究对56个物种中高CpG密度的UCNEs进行了筛查，发现其中一半呈中度甲基化，其余则接近0%或100%的甲基化水平。中度甲基化的UCNEs在小鼠不同组织间展现出更大的甲基化水平差异范围。在人类群体中，大多数UCNEs的甲基化变异程度高于LINE1转座子（LINE1 transposon）——后者是一类广泛使用的表观遗传生物标志物。在60种脊椎动物中，整体基因组甲基化水平与羟甲基化水平呈负相关。在UCNEs内部，DNA甲基化具有可塑性，在近缘物种间保持保守，且不受其自身序列的选择压力约束，但仍可通过物种形成过程稳定遗传。