Large-scale structure of genomic methylation patterns

TLDR

Mammalian genomes rely on cytosine methylation for normal function, yet how methylation patterns relate to DNA sequence remains unclear. The study mapped human brain methylation by analyzing CpG depletion patterns and sequencing 3,073 unmethylated and 2,565 methylated domains. The genome consists of short unmethylated domains enriched for regulatory elements surrounded by long methylated domains, indicating that cytosine methylation limits effective genome size, buffers regulatory networks, and may explain the C value paradox, with methylation being universal in large genomes but absent in many small‑genome eukaryotes.

Abstract

The mammalian genome depends on patterns of methylated cytosines for normal function, but the relationship between genomic methylation patterns and the underlying sequence is unclear. We have characterized the methylation landscape of the human genome by global analysis of patterns of CpG depletion and by direct sequencing of 3073 unmethylated domains and 2565 methylated domains from human brain DNA. The genome was found to consist of short (<4 kb) unmethylated domains embedded in a matrix of long methylated domains. Unmethylated domains were enriched in promoters, CpG islands, and first exons, while methylated domains comprised interspersed and tandem-repeated sequences, exons other than first exons, and non-annotated single-copy sequences that are depleted in the CpG dinucleotide. The enrichment of regulatory sequences in the relatively small unmethylated compartment suggests that cytosine methylation constrains the effective size of the genome through the selective exposure of regulatory sequences. This buffers regulatory networks against changes in total genome size and provides an explanation for the C value paradox, which concerns the wide variations in genome size that scale independently of gene number. This suggestion is compatible with the finding that cytosine methylation is universal among large-genome eukaryotes, while many eukaryotes with genome sizes <5 × 10 8 bp do not methylate their DNA.