Environmental Exposure and DNA Damage

年龄较大的母亲所生的孩子出现各种不良健康后果的风险增加，这表明了一种假设，即母亲年龄较高与孩子DNA的表观遗传学变化有关。我们在一组890名挪威新生儿的基因组中使用450,000个CpG位点的DNA甲基化测量来探索这一假设，并确定了KLHL35基因附近一组邻近的CPG，它们与母亲的年龄显著相关。我们在一组独立的1062名挪威新生儿和200名美国中年女性身上重复了这些发现；这表明这些变化可能会在出生后40到60年内持续存在。虽然KLHL35基因的功能在很大程度上仍不清楚，但这一发现支持了一种假设，即母亲怀孕时的年龄可能会导致其后代持续的表观遗传变化，并持续到成年。 表观基因组DNA甲基化的研究通常使用高密度的灯盏花甲基化阵列。为了检测与暴露或疾病相关的微小变化，需要对这些原始数据进行处理，以去除背景噪声。我们开发了一种新的背景校正方法，该方法使用指数正态分布和截断正态分布的混合来模拟信号强度，并使用截断正态分布来模拟背景噪声。我们表明，这种方法在提高重复性和准确性方面明显优于其他可用的方法，从而为验证的CPGS产生了较小的关联P值估计。我们将这种方法，以及一套用于分析表观遗传学数据的额外工具整合到一个名为ENMix的软件包中，并在BioConductor网站上免费提供。 现有的Illumina 450K阵列及其继任者甲基化EPIC阵列都使用两种类型的探针来测量整个基因组的DNA甲基化。这两种类型的探针具有不同的化学成分，并导致不同的甲基化值分布，如果不进行校正，可能会影响下游分析。我们开发了一种新的方法，使用相邻探针之间的相关性来调整这些分布，使它们更相似，并将该工具RCP整合到EnMix软件中。

Children born to older mothers are at increased risk of a variety of adverse health outcomes, suggesting the hypothesis that advanced maternal age is associated with epigenetic changes in the childs DNA. We explored this hypothesis using DNA methylation measures at 450,000 CpG sites across the genome in a set of 890 Norwegian newborns and identified a set of adjacent CpGs near the KLHL35 gene that were significantly associated with maternal age. We replicated these finding in an independent group of 1062 Norwegian newborns, and in a set of 200 US middle-aged women; suggesting that these changes may persist 40 to 60 years after birth. While the function of the KLHL35 gene remains largely unknown, this finding supports the hypothesis that a mothers age at pregnancy may lead to persistent epigenetic changes in her offspring that persist into adulthood. Epigenome-wide studies of DNA methylation often make use of high density Illumina methylation arrays. In order to detect small changes associated with exposure or disease, this raw data needs to be processed to remove background noise. We have developed a novel background correction method that uses a mixture of exponential and truncated normal distributions to model signal intensity, and a truncated normal distribution to model background noise. We show that this method is significantly better than other available methods in improving reproducibility and accuracy, resulting in smaller P-value estimates of association for validated CpGs. We incorporate this method, along with a set of additional tools for the analysis of epigenetic data into a software package called ENmix, and make it freely available on the Bioconductor website. Both the existing Illumina 450K array and its successor the MethylationEPIC array use two types of probes to measure DNA methylation across the genome. These two probe types have different chemistries and result in different distributions of methylation values which, if uncorrected, may bias downstream analyses. We developed a novel method using the correlation between adjacent probes to adjust these distributions so that they are more alike, and have incorporated this tool, RCP, into Enmix software.