DNA methylation is a highly studied epigenetic signature that is associated with regulation of gene expression, whereby genes with high levels of promoter methylation are generally repressed. Genomic imprinting occurs when one of the parental alleles is methylated, i.e., when there is inherited allele-specific methylation (ASM). A special case of imprinting occurs during X chromosome inactivation in females, where one of the two X chromosomes is silenced, to achieve dosage compensation between the sexes. Another more widespread form of ASM is sequence dependent (SD-ASM), where ASM is linked to a nearby heterozygous single nucleotide polymorphism (SNP). We developed a method to screen for genomic regions that exhibit loss or gain of ASM in samples from two conditions (treatments, diseases, etc.). The method relies on the availability of bisulfite sequencing data from multiple samples of the two conditions. We leverage other established computational methods to screen for these regions within a new R package called DAMEfinder. It calculates an ASM score for all CpG sites or pairs in the genome of each sample, and then quantifies the change in ASM between conditions. It then clusters nearby CpG sites with consistent change into regions. In the absence of SNP information, our method relies only on reads to quantify ASM. This novel ASM score compares favorably to current methods that also screen for ASM. Not only does it easily discern between imprinted and non-imprinted regions, but also females from males based on X chromosome inactivation. We also applied DAMEfinder to a colorectal cancer dataset and observed that colorectal cancer subtypes are distinguishable according to their ASM signature. We also re-discover known cases of loss of imprinting. We have designed DAMEfinder to detect regions of differential ASM (DAMEs), which is a more refined definition of differential methylation, and can therefore help in breaking down the complexity of DNA methylation and its influence in development and disease.

中文翻译：

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DAMEfinder：一种检测差异等位基因特异性甲基化的方法。

DNA甲基化是经过高度研究的表观遗传学特征，与基因表达的调节相关，因此通常会抑制具有高水平启动子甲基化的基因。当亲本等位基因之一被甲基化时，即当遗传了等位基因特异性甲基化（ASM）时，就会发生基因组印迹。在女性的X染色体失活期间，会出现一个特殊的烙印情况，其中两个X染色体之一被沉默，以实现两性之间的剂量补偿。ASM的另一种更普遍的形式是序列依赖性（SD-ASM），其中ASM与附近的杂合单核苷酸多态性（SNP）连接。我们开发了一种方法，可从两种情况（治疗，疾病等）中筛选出样本中出现ASM丢失或增加的基因组区域。该方法依赖于来自两个条件的多个样品的亚硫酸氢盐测序数据的可用性。我们利用其他已建立的计算方法，在名为DAMEfinder的新R包中筛选这些区域。它计算每个样品基因组中所有CpG位点或对的ASM得分，然后量化条件之间ASM的变化。然后，它会将附近的CpG站点聚集在一起，并在区域中进行一致的更改。在没有SNP信息的情况下，我们的方法仅依靠读取来量化ASM。这个新颖的ASM评分与目前也筛选ASM的方法相比具有优势。它不仅可以轻松区分印迹区域和非印迹区域，还可以基于X染色体失活来区分雌性和雄性。我们还将DAMEfinder应用于结直肠癌数据集，并观察到结直肠癌亚型根据其ASM签名是可区分的。我们还会重新发现已知的印记丢失案例。我们设计了DAMEfinder来检测差异ASM（DAME）区域，这是差异甲基化的更精确定义，因此可以帮助打破DNA甲基化的复杂性及其对发育和疾病的影响。