Environmental Exposure and DNA Damage

高龄母亲所生的孩子面临各种不良健康后果的风险增加，这表明高龄母亲与查尔兹DNA的表观遗传变化有关的假设。 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，并确定了一组与母亲年龄显著相关的KLHL 35基因附近的相邻CpG。 我们在一个由1062名挪威新生儿组成的独立小组和200名美国中年妇女中复制了这些发现;这表明这些变化可能在出生后持续40至60年。 虽然KLHL 35基因的功能在很大程度上仍然未知，但这一发现支持了一个假设，即母亲在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。 DNA甲基化的表观基因组范围研究通常使用高密度Illumina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，以消除背景噪声。 我们已经开发了一种新的背景校正方法，该方法使用指数和截断正态分布的混合物来模拟信号强度，以及截断正态分布来模拟背景噪声。 我们表明，这种方法是显着优于其他可用的方法，提高重现性和准确性，从而导致较小的P值估计的关联验证的CpG。 我们将这种方法，沿着一套额外的工具，用于分析表观遗传数据到一个名为ENmix的软件包，并使其在Bioconductor网站上免费提供。 现有的Illumina 450 K阵列及其继任者MethylationEPIC阵列都使用两种类型的探针来测量基因组中的DNA甲基化。 这两种探针类型具有不同的化学性质，并导致甲基化值的不同分布，如果未校正，则可能使下游分析产生偏差。 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，并将此工具RCP纳入Enmix软件。

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.