Analysis of DNA methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation.
Analysis of DNA methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation.
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DOI：
10.1371/journal.pgen.1002228
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发表时间：
2011-08
期刊：
影响因子：
4.5
通讯作者：
Myers RM
中科院分区：
文献类型：
--
作者：
Gertz J;Varley KE;Reddy TE;Bowling KM;Pauli F;Parker SL;Kucera KS;Willard HF;Myers RM
CpG二核苷酸中胞嘧啶甲基化对细胞分化和许多癌症的进展至关重要，并且在配子印迹中起重要作用。为了同时评估人类全基因组DNA甲基化模式的变异和遗传，我们对一个三代家庭的六个成员的体细胞DNA进行了还原亚硫酸氢盐测序（RRBS）。我们观察到8.1%的杂合SNP与顺式甲基化差异相关，这为孟德尔遗传和相关性提供了一个强大的特征。同源染色体之间的绝大多数差异甲基化（>92%）发生在特定的单倍型上，而不是与起源亲本的性别相关，表明基因型影响的DNA甲基化远多于配子印迹。我们发现，家族中75%的基因型依赖性差异甲基化事件也见于无关个体，总体基因型可以解释80%的DNA甲基化变异。这些事件在CpG岛中代表性不足，在基因间区域富集，并且位于低进化保守性区域。尽管它们通常不在功能受限区域，但22%（是偶然预期的两倍）的携带基因型依赖性DNA甲基化的基因表现出等位基因特异性基因表达，如通过淋巴母细胞系的RNA-seq所测量的，这表明这些事件中的一些与基因表达差异相关。总的来说，我们的研究结果表明，基因型对DNA甲基化模式的影响在基因组中广泛存在，并且大大超过了印迹对全基因组甲基化模式的影响。DNA甲基化是一种动态的表观遗传标记，对哺乳动物的发育至关重要。DNA甲基化水平可以受到环境、染色体的亲本来源和基因组序列的影响。在这项研究中，我们通过分析三代家庭以及无关个体的甲基化水平来评估DNA序列对DNA甲基化的影响。通过沿着家族DNA甲基化模式以及附近的SNP，我们发现染色体之间的等位基因差异在决定DNA甲基化方面比染色体的亲本起源起更大的作用，这表明DNA序列对DNA甲基化的影响比配子印记更大。我们还发现，在家族中发现的DNA甲基化的等位基因差异也可以在无关个体中观察到。事实上，DNA甲基化的大部分变异可以用基因型来解释。我们的研究结果强调了基因组序列在设定DNA甲基化模式中的重要性，并表明在疾病背景下评估DNA甲基化时需要考虑基因型。
The methylation of cytosines in CpG dinucleotides is essential for cellular differentiation and the progression of many cancers, and it plays an important role in gametic imprinting. To assess variation and inheritance of genome-wide patterns of DNA methylation simultaneously in humans, we applied reduced representation bisulfite sequencing (RRBS) to somatic DNA from six members of a three-generation family. We observed that 8.1% of heterozygous SNPs are associated with differential methylation in cis, which provides a robust signature for Mendelian transmission and relatedness. The vast majority of differential methylation between homologous chromosomes (>92%) occurs on a particular haplotype as opposed to being associated with the gender of the parent of origin, indicating that genotype affects DNA methylation of far more loci than does gametic imprinting. We found that 75% of genotype-dependent differential methylation events in the family are also seen in unrelated individuals and that overall genotype can explain 80% of the variation in DNA methylation. These events are under-represented in CpG islands, enriched in intergenic regions, and located in regions of low evolutionary conservation. Even though they are generally not in functionally constrained regions, 22% (twice as many as expected by chance) of genes harboring genotype-dependent DNA methylation exhibited allele-specific gene expression as measured by RNA-seq of a lymphoblastoid cell line, indicating that some of these events are associated with gene expression differences. Overall, our results demonstrate that the influence of genotype on patterns of DNA methylation is widespread in the genome and greatly exceeds the influence of imprinting on genome-wide methylation patterns. DNA methylation is a dynamic epigenetic mark that is essential for mammalian organismal development. DNA methylation levels can be influenced by environment, a chromosome's parental origin, and genome sequence. In this study, we evaluated the impact that DNA sequence has on DNA methylation by analyzing methylation levels in a three-generation family as well as unrelated individuals. By following DNA methylation patterns through the family along with nearby SNPs, we found that allelic differences between chromosomes play a much larger role in determining DNA methylation than the parental origin of the chromosome, indicating that DNA sequence has a larger impact on DNA methylation than gametic imprinting. We also found that allelic differences in DNA methylation found in the family can also be observed in unrelated individuals. In fact, the majority of variation in DNA methylation can be explained by genotype. Our results emphasize the importance of genome sequence in setting patterns of DNA methylation and indicate that genotype will need to be taken into account when assessing DNA methylation in the context of disease.
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影响因子：
30.8
作者：
Kerkel, Kristi;Spadola, Alexandra;Tycko, Benjamin
通讯作者：
Tycko, Benjamin
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0906183107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Feinberg, Andrew P.;Irizarry, Rafael A.
通讯作者：
Irizarry, Rafael A.
DOI：
10.1126/science.1184655
发表时间：
2010-04-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
McDaniell R;Lee BK;Song L;Liu Z;Boyle AP;Erdos MR;Scott LJ;Morken MA;Kucera KS;Battenhouse A;Keefe D;Collins FS;Willard HF;Lieb JD;Furey TS;Crawford GE;Iyer VR;Birney E
通讯作者：
Birney E
影响因子：
12.3
作者：
Langmead B;Trapnell C;Pop M;Salzberg SL
通讯作者：
Salzberg SL