We have characterized the landscape of DNA methylation (DNAm) across the first two decades of human neocortical development in NeuN+ neurons using wholegenome bisulfite sequencing and compared them to nonneurons (primarily glia) and prenatal homogenate cortex. We show that DNAm changes more dramatically during the first five years of postnatal life than during the entire remaining period. We further refined global patterns of increasingly divergent neuronal CpG and CpH methylation (mCpG and mCpH) into six developmental trajectories and found that in contrast to genomewide patterns, neighboring mCpG and mCpH levels within these regions were highly correlated. We then integrated paired RNAseq data and identified direct regulation of hundreds of transcripts and their splicing events exclusively by mCpH levels, independently from mCpG levels, across this period. We finally explored the relationship between DNAm patterns and development of brainrelated phenotypes and found enriched heritability for many phenotypes within DNAm features we identify.

No abstract