Universität des Saarlandes, Saarbrücken, Germany.
BMC Genomics. 2010 Nov 22;11:649. doi: 10.1186/1471-2164-11-649.
Genomic imprinting is an evolutionary conserved mechanism of epigenetic gene regulation in placental mammals that results in silencing of one of the parental alleles. In order to decipher interactions between allele-specific DNA methylation of imprinted genes and evolutionary conservation, we performed a genome-wide comparative investigation of genomic sequences and highly conserved elements of imprinted genes in human and mouse.
Evolutionarily conserved elements in imprinted regions differ from those associated with autosomal genes in various ways. Whereas for maternally expressed genes strong divergence of protein-encoding sequences is most prominent, paternally expressed genes exhibit substantial conservation of coding and noncoding sequences. Conserved elements in imprinted regions are marked by enrichment of CpG dinucleotides and low (TpG+CpA)/(2·CpG) ratios indicate reduced CpG deamination. Interestingly, paternally and maternally expressed genes can be distinguished by differences in G+C and CpG contents that might be associated with unusual epigenetic features. Especially noncoding conserved elements of paternally expressed genes are exceptionally G+C and CpG rich. In addition, we confirmed a frequent occurrence of intronic CpG islands and observed a decelerated degeneration of ancient LINE-1 repeats. We also found a moderate enrichment of YY1 and CTCF binding sites in imprinted regions and identified several short sequence motifs in highly conserved elements that might act as additional regulatory elements.
We discovered several novel conserved DNA features that might be related to allele-specific DNA methylation. Our results hint at reduced CpG deamination rates in imprinted regions, which affects mostly noncoding conserved elements of paternally expressed genes. Pronounced differences between maternally and paternally expressed genes imply specific modes of evolution as a result of differences in epigenetic features and a special response to selective pressure. In addition, our data support the potential role of intronic CpG islands as epigenetic key regulatory elements and suggest that evolutionary conserved LINE-1 elements fulfill regulatory functions in imprinted regions.
基因组印记是一种在胎盘哺乳动物中进化保守的表观遗传基因调控机制，导致一个亲本等位基因的沉默。为了解读印记基因的等位基因特异性 DNA 甲基化与进化保守性之间的相互作用，我们对人类和小鼠的印记基因的基因组序列和高度保守元件进行了全基因组比较研究。
印记区域中的进化保守元件与常染色体基因的那些元件在各种方面都不同。虽然对于母源表达的基因，蛋白质编码序列的强烈分歧最为显著，但父源表达的基因在编码和非编码序列中表现出相当大的保守性。印记区域中的保守元件以富含 CpG 二核苷酸和低（TpG+CpA）/（2·CpG）比值为特征，表明 CpG 脱氨酶的减少。有趣的是，父源和母源表达的基因可以通过 G+C 和 CpG 含量的差异来区分，这些差异可能与不寻常的表观遗传特征有关。特别是父源表达基因的非编码保守元件异常富含 G+C 和 CpG。此外，我们证实了内含子 CpG 岛的频繁发生，并观察到古老的 LINE-1 重复的退化速度减慢。我们还发现印记区域中 YY1 和 CTCF 结合位点的适度富集，并在高度保守元件中鉴定出几个短序列基序，它们可能作为额外的调节元件发挥作用。
我们发现了一些新的与等位基因特异性 DNA 甲基化相关的保守 DNA 特征。我们的结果表明，印记区域中的 CpG 脱氨酶率降低，这主要影响父源表达基因的非编码保守元件。母源和父源表达基因之间的显著差异暗示了由于表观遗传特征的差异和对选择压力的特殊反应，存在特定的进化模式。此外，我们的数据支持内含子 CpG 岛作为表观遗传关键调节元件的潜在作用，并表明进化保守的 LINE-1 元件在印记区域中发挥调节功能。
