Germline methylation patterns inferred from local nucleotide frequency of repetitive sequences in the human genome

Given the genomic abundance and susceptibility to DNA methylation, interspersed repetitive sequences in the human genome can be exploited as valuable resources in genome-wide methylation studies. To learn about the relationships between DNA methylation and repeat sequences, we performed a global measurement of CpG dinucleotide frequencies for interspersed repetitive sequences and inferred germline methylation patterns in the human genome. Although extensive CpG depletion was observed for most repeat sequences, those in the proximity to CpG islands have been relatively removed from germline methylation being the potential source of germline activation. We also investigated the CpG depletion patterns of Alu pairs to see whether they might play an active role in germline methylation. Two kinds of Alu pairs, direct or inverted pairs classified according to the orientation, showed contrast CpG depletion patterns with respect to separating distance of Alus, i.e., as two Alu elements are more closely spaced in a pair, a higher extent of CpG depletion was observed in inverted orientation and vice versa for directly repetitive Alu pairs. This suggests that specific organization of repetitive sequences, such as inverted Alu pairs, might play a role in triggering DNA methylation consistent with a homology-dependent methylation hypothesis.