Environmental Exposure and DNA Damage

环境暴露和 DNA 损伤

• 批准号: 9352105
• 负责人: JACK A TAYLOR
• 金额: $ 47.19万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9352105
• 关键词: Adult; Area; Bioconductor; Birth; Cancer Etiology; Characteristics; Chemistry; Child; Clinical Research; Computer software; DNA; DNA Damage; DNA Methylation; DNA Modification Process; Data; Detection; Disease; Early Diagnosis; Environmental Exposure; Environmental Risk Factor; Epidemiologic Studies; Epigenetic Process; Gene Targeting; Genes; Genome; Health; Lead; Maternal Age; Measures; Methods; Methylation; MicroRNAs; Modeling; Modification; Molecular; Mothers; Newborn Infant; Noise; Normal Statistical Distribution; Outcome; Pattern; Prevention; Process; Reproducibility; Research; Research Design; Risk; Signal Transduction; Site; Testing; Woman; advanced maternal age; density; environmental agent; epigenome; improved; middle age; novel; offspring; outcome forecast; tool; web site

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.

高龄母亲所生的孩子出现各种不良健康结果的风险增加，这表明高龄母亲与孩子 DNA 的表观遗传变化有关的假设。 我们利用 890 名挪威新生儿基因组中 450,000 个 CpG 位点的 DNA 甲基化测量结果探索了这一假设，并确定了 KLHL35 基因附近的一组相邻 CpG，这些 CpG 与母亲年龄显着相关。 我们在一个由 1062 名挪威新生儿组成的独立小组和一组由 200 名美国中年妇女组成的独立小组中复制了这些发现；表明这些变化可能会在出生后持续 40 至 60 年。 虽然 KLHL35 基因的功能在很大程度上仍然未知，但这一发现支持了这样的假设：母亲怀孕时的年龄可能会导致其后代发生持续的表观遗传变化，并持续到成年。 DNA 甲基化的全表观基因组研究通常使用高密度 Illumina 甲基化芯片。 为了检测与暴露或疾病相关的微小变化，需要处理这些原始数据以消除背景噪音。 我们开发了一种新颖的背景校正方法，该方法使用指数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，该方法在提高重现性和准确性方面明显优于其他可用方法，从而导致验证的 CpG 关联的 P 值估计更小。 我们将此方法与一组用于分析表观遗传数据的附加工具合并到一个名为 ENmix 的软件包中，并在 Bioconductor 网站上免费提供。 现有的 Illumina 450K 阵列及其后续产品 MmethylationEPIC 阵列均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，如果不加以校正，可能会导致下游分析出现偏差。 我们开发了一种新方法，利用相邻探针之间的相关性来调整这些分布，使它们更加相似，并将该工具 RCP 合并到 Enmix 软件中。