Detection of haplotype-dependent allele-specific DNA methylation in WGBS data.
Detection of haplotype-dependent allele-specific DNA methylation in WGBS data.
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DOI：
10.1038/s41467-020-19077-1
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发表时间：
2020-10-16
影响因子：
16.6
通讯作者：
Goutsias J
中科院分区：
文献类型：
--
作者：
Abante J;Fang Y;Feinberg AP;Goutsias J
在杂合基因组中，等位基因特异性测量可以揭示与遗传序列中的局部变化相关的同源等位基因之间的DNA甲基化的生物学显著差异。目前用于从全基因组亚硫酸氢盐测序（WGBS）数据检测此类事件的方法在单个胞嘧啶-磷酸-鸟嘌呤（CpG）位点处进行统计学独立的边际分析，从而忽略甲基化状态中的相关性，或者在四个CpG位点处进行甲基化模式的联合统计分析，产生不可靠的统计学证据。在这里，我们采用一维伊辛模型的统计物理学和开发的方法检测等位基因特异性甲基化（ASM）的DNA片段内的事件含有连锁单核苷酸多态性（SNP），称为单倍型集群。与现有的方法使用模拟和真实的WGBS数据的比较表明，我们的方法提供了一个改进的适合数据，特别是当考虑大的单倍型。重要的是，该方法采用稳健的假设检验来检测平均甲基化水平和甲基化熵的统计学显著失衡，以及鉴定遗传变异携带关于甲基化状态的显著信息的单倍型。因此，我们的ASM分析方法可能会导致生物学发现，对复杂人类疾病的遗传学具有重要意义。等位基因特异性测量可以揭示与遗传序列变化相关的同源等位基因之间的DNA甲基化差异。在这里，作者开发了一种检测连锁SNP单倍型内等位基因特异性甲基化事件的方法，将其与现有方法进行比较，并表明它可以识别遗传变异携带有关起源等位基因甲基化状态的重要信息的单倍型。
In heterozygous genomes, allele-specific measurements can reveal biologically significant differences in DNA methylation between homologous alleles associated with local changes in genetic sequence. Current approaches for detecting such events from whole-genome bisulfite sequencing (WGBS) data perform statistically independent marginal analysis at individual cytosine-phosphate-guanine (CpG) sites, thus ignoring correlations in the methylation state, or carry-out a joint statistical analysis of methylation patterns at four CpG sites producing unreliable statistical evidence. Here, we employ the one-dimensional Ising model of statistical physics and develop a method for detecting allele-specific methylation (ASM) events within segments of DNA containing clusters of linked single-nucleotide polymorphisms (SNPs), called haplotypes. Comparisons with existing approaches using simulated and real WGBS data show that our method provides an improved fit to data, especially when considering large haplotypes. Importantly, the method employs robust hypothesis testing for detecting statistically significant imbalances in mean methylation level and methylation entropy, as well as for identifying haplotypes for which the genetic variant carries significant information about the methylation state. As such, our ASM analysis approach can potentially lead to biological discoveries with important implications for the genetics of complex human diseases. Allele-specific measurements can reveal differences in DNA methylation between homologous alleles associated with changes in genetic sequence. Here, the authors develop a method for detecting allele specific methylation events within haplotypes of linked SNPs, compare it with existing methods, and show it identifies haplotypes for which the genetic variant carries significant information about the methylation state of the allele of origin.
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影响因子：
9.8
作者：
Schalkwyk, Leonard C.;Meaburn, Emma L.;Mill, Jonathan
通讯作者：
Mill, Jonathan
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Cheung WA;Shao X;Morin A;Siroux V;Kwan T;Ge B;Aïssi D;Chen L;Vasquez L;Allum F;Guénard F;Bouzigon E;Simon MM;Boulier E;Redensek A;Watt S;Datta A;Clarke L;Flicek P;Mead D;Paul DS;Beck S;Bourque G;Lathrop M;Tchernof A;Vohl MC;Demenais F;Pin I;Downes K;Stunnenberg HG;Soranzo N;Pastinen T;Grundberg E
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