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首页> 外文期刊>Epigenetics & Chromatin >Genetic and epigenetic variation among inbred mouse littermates: identification of inter-individual differentially methylated regions
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Genetic and epigenetic variation among inbred mouse littermates: identification of inter-individual differentially methylated regions

机译：近交小鼠同窝仔的遗传和表观遗传变异：个体间差异甲基化区域的鉴定

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Phenotypic variability among inbred littermates reared in controlled environments remains poorly understood. Metastable epialleles refer to loci that intrinsically behave in this way and a few examples have been described. They display differential methylation in association with differential expression. For example, inbred mice carrying the agouti viable yellow (A vy ) allele show a range of coat colours associated with different DNA methylation states at the locus. The availability of next-generation sequencing, in particular whole genome sequencing of bisulphite converted DNA, allows us, for the first time, to search for metastable epialleles at base pair resolution. Using whole genome bisulphite sequencing of DNA from the livers of five mice from the A vy colony, we searched for sites at which DNA methylation differed among the mice. A small number of loci, 356, were detected and we call these inter-individual Differentially Methylated Regions, iiDMRs, 55 of which overlap with endogenous retroviral elements (ERVs). Whole genome resequencing of two mice from the colony identified very few differences and these did not occur at or near the iiDMRs. Further work suggested that the majority of ERV iiDMRs are metastable epialleles; the level of methylation was maintained in tissue from other germ layers and the level of mRNA from the neighbouring gene inversely correlated with methylation state. Most iiDMRs that were not overlapping ERV insertions occurred at tissue-specific DMRs and it cannot be ruled out that these are driven by changes in the ratio of cell types in the tissues analysed. Using the most thorough genome-wide profiling technologies for differentially methylated regions, we find very few intrinsically epigenetically variable regions that we term iiDMRs. The most robust of these are at retroviral elements and appear to be metastable epialleles. The non-ERV iiDMRs cannot be described as metastable epialleles at this stage but provide a novel class of variably methylated elements for further study.
机译：在受控环境中饲养的近交同窝仔的表型变异性仍然知之甚少。亚稳态的等位基因是指以这种方式固有地表现的基因座，并且已经描述了一些例子。它们显示差异甲基化与差异表达。例如，携带刺豚鼠可行的黄色（A vy）等位基因的近交小鼠在该基因座处显示出一系列与不同DNA甲基化状态有关的被毛颜色。下一代测序的可用性，尤其是亚硫酸氢盐转化的DNA的全基因组测序，使我们第一次能够以碱基对的分辨率寻找亚稳态的等位基因。使用来自A vy殖民地的五只小鼠肝脏的全基因组亚硫酸氢盐DNA测序，我们搜索了小鼠之间DNA甲基化差异的位点。检测到少量基因座356，我们称这些个体差异甲基化区域为iiDMR，其中55个与内源性逆转录病毒元件（ERV）重叠。来自该菌落的两只小鼠的全基因组重测序发现很少的差异，并且这些差异在iiDMR处或iiDMR附近没有发生。进一步的研究表明，大多数ERV iiDMR是亚稳态的等位基因。组织中其他细菌层的甲基化水平得以维持，而邻近基因的mRNA水平则与甲基化状态呈负相关。大多数不与ERV插入重叠的iiDMR发生在组织特异性DMR处，不能排除这些是由分析组织中细胞类型比例的变化驱动的。使用针对差异甲基化区域的最全面的全基因组分布分析技术，我们发现很少被称为iiDMR的内在表观遗传可变区。其中最强大的是逆转录病毒元件，似乎是亚稳定的等位基因。在这个阶段，非ERV iiDMRs不能被描述为亚稳态的等位基因，但它提供了一类新的可变甲基化元素，需要进一步研究。

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