Estimation of CpG coverage in whole methylome next-generation sequencing studies.
Estimation of CpG coverage in whole methylome next-generation sequencing studies.
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DOI：
10.1186/1471-2105-14-50
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发表时间：
2013-02-12
影响因子：
3
通讯作者：
Aberg KA
中科院分区：
文献类型：
--
作者：
van den Oord EJ;Bukszar J;Rudolf G;Nerella S;McClay JL;Xie LY;Aberg KA
甲基化研究是对DNA序列遗传学研究的一个有希望的补充。然而，由于缺乏详细的生物学知识，因此全甲基化关联研究（MWAS）对于检测疾病相关位点至关重要。一种具有成本效益的方法涉及从富含甲基化DNA片段的样品中创建的单端文库的下一代测序（NGS）。单端文库的局限性在于未观察到片段大小分布。这妨碍了数据分析的几个方面，例如基于覆盖CpG的片段数量的富集测量的计算。我们开发了一种非参数方法，该方法使用孤立的CpG来估计来自经验测序数据的样品特异性片段大小分布。通过仿真，我们表明我们的方法是高度准确的。虽然传统的（扩展的）读段计数方法导致严重偏倚的覆盖率估计，并引入人为的个体间差异，但通过使用估计的片段大小分布，我们几乎可以完全消除这些偏倚。此外，我们发现使用我们的方法估计的片段大小分布获得的覆盖率估计值与在双端测序数据中“观察到”的片段大小分布之间的相关性为0.999。我们提出了一种非参数的方法来估计片段大小分布，这是高度精确的，可以提高分析的成本效益的MWAS研究，序列单端库创建的样品，富集甲基化的DNA片段。
Methylation studies are a promising complement to genetic studies of DNA sequence. However, detailed prior biological knowledge is typically lacking, so methylome-wide association studies (MWAS) will be critical to detect disease relevant sites. A cost-effective approach involves the next-generation sequencing (NGS) of single-end libraries created from samples that are enriched for methylated DNA fragments. A limitation of single-end libraries is that the fragment size distribution is not observed. This hampers several aspects of the data analysis such as the calculation of enrichment measures that are based on the number of fragments covering the CpGs. We developed a non-parametric method that uses isolated CpGs to estimate sample-specific fragment size distributions from the empirical sequencing data. Through simulations we show that our method is highly accurate. While the traditional (extended) read count methods resulted in severely biased coverage estimates and introduces artificial inter-individual differences, through the use of the estimated fragment size distributions we could remove these biases almost entirely. Furthermore, we found correlations of 0.999 between coverage estimates obtained using fragment size distributions that were estimated with our method versus those that were “observed” in paired-end sequencing data. We propose a non-parametric method for estimating fragment size distributions that is highly precise and can improve the analysis of cost-effective MWAS studies that sequence single-end libraries created from samples that are enriched for methylated DNA fragments.
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DOI：
10.1093/bioinformatics/btq669
发表时间：
2011-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Lan X;Bonneville R;Apostolos J;Wu W;Jin VX
通讯作者：
Jin VX
影响因子：
48
作者：
Pepke, Shirley;Wold, Barbara;Mortazavi, Ali
通讯作者：
Mortazavi, Ali
MBD分离的基因组测序提供了对人基因组中DNA甲基化的高通量和全面调查。
影响因子：
14.9
作者：
Serre D;Lee BH;Ting AH
通讯作者：
Ting AH
DOI：
10.1038/nrg3000
发表时间：
2011-07-12
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
46.9
作者：
Rozowsky, Joel;Euskirchen, Ghia;Auerbach, Raymond K.;Zhang, Zhengdong D.;Gibson, Theodore;Bjornson, Robert;Carriero, Nicholas;Snyder, Michael;Gerstein, Mark B.
通讯作者：
Gerstein, Mark B.