Abstract
BackgroundWhole-genome bisulfite sequencing currently provides the highest-precision view of the epigenome, with quantitative information about populations of cells down to single nucleotide resolution. Several studies have demonstrated the value of this precision: meaningful features that correlate strongly with biological functions can be found associated with only a few CpG sites. Understanding the role of DNA methylation, and more broadly the role of DNA accessibility, requires that methylation differences between populations of cells are identified with extreme precision and in complex experimental designs.ResultsIn this work we investigated the use of beta-binomial regression as a general approach for modeling whole-genome bisulfite data to identify differentially methylated sites and genomic intervals.ConclusionsThe regression-based analysis can handle medium- and large-scale experiments where it becomes critical to accurately model variation in methylation levels between replicates and account for influence of various experimental factors like cell types or batch effects.
Highlights
Whole-genome bisulfite sequencing currently provides the highest-precision view of the epigenome, with quantitative information about populations of cells down to single nucleotide resolution
The distributions of the probability of success parameter of the binomials were taken from the work of Rakyan and others [7]: The non-differentially methylated CpGs in all samples had intermediate methylation levels taken from Beta(2, 2), while differentially methylated CpGs in control and case samples had low methylation levels from Beta(1.5, 6) and high methylation levels from Beta(6, 1.5) respectively
In this work, we discussed the utility of the beta-binomial regression for comparing the distribution of read proportions corresponding to a single site across a set of Whole-genome bisulfite sequencing (WGBS) samples under a given experimental design and statistically combining the results of individual comparisons to estimate the differentially methylated (DM) status of individual sites and genomic regions
Summary
Whole-genome bisulfite sequencing currently provides the highest-precision view of the epigenome, with quantitative information about populations of cells down to single nucleotide resolution. Several studies have demonstrated the value of this precision: meaningful features that correlate strongly with biological functions can be found associated with only a few CpG sites. Whole-genome bisulfite sequencing (WGBS) is currently the state-of-the-art technology for obtaining a comprehensive, nucleotide-resolution view of the epigenome. During sequencing, unmethylated cytosines are read out as thymines In this way, the presence of mismatches in the aligned reads can determine the methylation states of the cytosines in the DNA molecules that gave rise to the reads. Typical WGBS experiments involve DNA molecules originating from many distinct cells and, the methylation state of a particular cytosine may differ from one molecule to another. Methylation levels can be estimated from the proportions of reads indicating methylation at each site
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