Detection of allele-specific methylation through a generalized heterogeneous epigenome model

Abstract

Motivations: High-throughput sequencing has made it possible to sequence DNA methylation of a whole genome at the single-base resolution. A sample, however, may contain a number of distinct methylation patterns. For instance, cells of different types and in different developmental stages may have different methylation patterns. Alleles may be differentially methylated, which may partially explain that the large portions of epigenomes from single cell types are partially methylated, and may have major effects on transcriptional output. Approaches relying on DNA sequence polymorphism to identify individual patterns from a mixture of heterogeneous epigenomes are insufficient as methylcytosines occur at a much higher density than SNPs.

Results: We have developed a mixture model-based approach for resolving distinct epigenomes from a heterogeneous sample. In particular, the model is applied to the detection of allele-specific methylation (ASM). The methods are tested on a synthetic methylome and applied to an Arabidopsis single root cell methylome.

Fig. 1.

Experimental (a and b) versus predicted (c and d) methylation levels of the synthetic methylome. Experimental methylation levels from Wer+ are shown in circles, Scr+ in stars. Two symbols in the bottom figures (c and d) indicate two predicted individual methylomes for the synthetic methylome. The left (a and c) is of an allele-specific region: chromosome 1: [7313026, 7313482] on forward strand. The region contains 50 methylcytosines (mC); 160 reads are aligned to this region. The right (b and d) is of a non-specific region: chromosome 3: [12698733, 12699133] on forward strand. The region contains 42 mC; 367 reads are aligned to the region

Fig. 2.

Read assignments (a and b) and methylation levels (c and d) of the predicted ASM regions of Arabidopsis Wer+ cell. Circle and star symbols in c and d represent two alleles. Lines in top (a and b) figures are restricted reads (solid and dotted lines represent two alleles); small diamonds on lines are methylations. Left (a and c) : a region of Table 4(1): chrom 4: [13269127, 13269376] − strand. Right (b and d) : a region of Table 4(2): chrom 5: [17406449, 17406557] + strand

Fig. 3.

An example from Table 4 group (3): region: chrom 1: [77393, 77508] − strand, 20 mC. (a) reads assignments. (b) predicted methylation levels