The Mutational Burden of 5-Methylcytosine

Abstract

The importance of the epigenetic modification of cytosine (C) to 5-methylcytosine (m⁵C) is discussed in other chapters of this volume. In this chapter, we address the heavy mutational burden induced by the methylation of C at CpG dinucleotides, which is the price that must be paid for having a m⁵C epigenetic system. The mutability of m⁵C to thymine (T) has presumably led to a depletion of the CpG dinucleotide in the mammalian genome over the course of evolution. Furthermore, m⁵C residues, which comprise only about 1% of the human genome, account for about 30% of the base substitution mutations found in genetic disease (Cooper and Yousouffian 1988) and 25% of the mutations found in tumor suppressor genes (Jones et al. 1991; Greenblatt et al. 1994).

The mutability of m⁵C was first demonstrated in Escherichia coli. Cytosine bases that were methylated in the E. coli lacI gene were found to be hot spots for spontaneous base substitution mutations, and the hot spots disappeared when the same sites were unmethylated (Coulondre et al. 1978). It was speculated that the reason for this increase was that whereas C deaminates to uracil (U), m⁵C deaminates to T, which is a normal DNA base and therefore inherently more difficult to repair (Duncan and Miller 1980; Shenoy et al. 1987). This mechanism of DNA mutation is unique in that it is not induced by exogenous chemicals and it occurs in nonreplicating DNA. The deamination of m⁵C is a first-order chemical process, which is consistent with the...