Preservation of methylated CpG dinucleotides in human CpG islands

CpG dinucleotides are extensively underrepresented in mammalian genomes. It is widely accepted that genome-wide CpG depletion is predominantly caused by an elevated CpG > TpG mutation rate due to frequent cytosine methylation in the CpG context. Meanwhile the CpG content in genomic regions called CpG islands (CGIs) is noticeably higher. This observation is usually explained by lower CpG > TpG substitution rates within CGIs due to reduced cytosine methylation levels.

By combining genome-wide data on substitutions and methylation levels in several human cell types we have shown that cytosine methylation in human sperm cells was strongly and consistently associated with increased CpG > TpG substitution rates. In contrast, this correlation was not observed for embryonic stem cells or fibroblasts. Surprisingly, the decreased sperm CpG methylation level was insufficient to explain the reduced CpG > TpG substitution rates in CGIs.

While cytosine methylation in human sperm cells is strongly associated with increased CpG > TpG substitution rates, substitution rates are significantly reduced within CGIs even after sperm CpG methylation levels and local GC content are controlled for. Our findings are consistent with strong negative selection preserving methylated CpGs within CGIs including intergenic ones.