SNP-based prediction of the human germ cell methylation landscape

Base substitution occurs at a high rate at CpG dinucleotides due to the frequent methylation of CpG and the deamination of methylated cytosine to thymine. If these substitutions occur in germ cells, they constitute a heritable mutation that may eventually rise to polymorphic frequencies, hence resulting in a SNP that is methylation associated. In this study, we sought to identify clusters of methylation associated SNPs as a basis for prediction of methylation landscapes of germ cell genomes. Genomic regions enriched with methylation associated SNPs, namely "methylation associated SNP clusters", were identified with an agglomerative hierarchical clustering algorithm. Repetitive elements, segmental duplications, and syntenic tandem DNA repeats were enriched in methylation associated SNP clusters. The frequency of methylation associated SNPs in Alu Y/S elements exhibited a gradient pattern suggestive of linear spreading, being higher in proximity to methylation associated SNP clusters and lower closer to CpG islands. Interestingly, methylation associated SNP clusters were over-represented near the transcriptional initiation sites of immune response genes. We propose a de novo DNA methylation model during germ cell development whereby a pattern is established by long-range chromatic interactions through syntenic repeats combined with regional methylation spreading from methylation associated SNP clusters.