Medical Genomics, UCL Cancer Institute, University College London, London, UK.
Epigenetics. 2012 Oct;7(10):1188-99. doi: 10.4161/epi.22127. Epub 2012 Sep 11.
Regulatory change has long been hypothesized to drive the delineation of the human phenotype from other closely related primates. Here we provide evidence that CpG dinucleotides play a special role in this process. CpGs enable epigenome variability via DNA methylation, and this epigenetic mark functions as a regulatory mechanism. Therefore, species-specific CpGs may influence species-specific regulation. We report non-polymorphic species-specific CpG dinucleotides (termed "CpG beacons") as a distinct genomic feature associated with CpG island (CGI) evolution, human traits and disease. Using an inter-primate comparison, we identified 21 extreme CpG beacon clusters (≥ 20/kb peaks, empirical p < 1.0 × 10(-3)) in humans, which include associations with four monogenic developmental and neurological disease related genes (Benjamini-Hochberg corrected p = 6.03 × 10(-3)). We also demonstrate that beacon-mediated CpG density gain in CGIs correlates with reduced methylation in these species in orthologous CGIs over time, via human, chimpanzee and macaque MeDIP-seq. Therefore mapping into both the genomic and epigenomic space the identified CpG beacon clusters define points of intersection where a substantial two-way interaction between genetic sequence and epigenetic state has occurred. Taken together, our data support a model for CpG beacons to contribute to CGI evolution from genesis to tissue-specific to constitutively active CGIs.
调控变化长期以来一直被假设为驱动人类表型与其他密切相关的灵长类动物区分开来的原因。在这里，我们提供了证据表明，CpG 二核苷酸在这个过程中起着特殊的作用。CpG 能够通过 DNA 甲基化来实现表观基因组的变异性，这种表观遗传标记作为一种调控机制。因此，物种特异性的 CpG 可能会影响物种特异性的调控。我们报告了非多态性的物种特异性 CpG 二核苷酸（称为“CpG 信标”），这是与 CpG 岛（CGI）进化、人类特征和疾病相关的独特基因组特征。通过灵长类动物间的比较，我们在人类中鉴定出了 21 个极端 CpG 信标簇（≥ 20/kb 峰，经验 p < 1.0 × 10(-3))，其中包括与四个单基因发育和神经疾病相关基因的关联（Benjamini-Hochberg 校正后的 p = 6.03 × 10(-3)）。我们还证明了信标介导的 CGIs 中的 CpG 密度增加与在同源 CGIs 中，随着时间的推移，这些物种中的甲基化减少有关，这是通过人类、黑猩猩和猕猴的 MeDIP-seq 实验证实的。因此，通过对鉴定出的 CpG 信标簇进行基因组和表观基因组空间的映射，定义了遗传序列和表观遗传状态之间发生大量双向相互作用的交点。总之，我们的数据支持了 CpG 信标有助于从发生到组织特异性再到组成性激活 CGIs 的 CGI 进化的模型。
