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Methylome


DNA methylation is a process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging and carcinogenesis.

Two of DNA's four bases, cytosine and adenine, can be methylated. Cytosine methylation is widespread in both eukaryotes and prokaryotes, even though the rate of cytosine DNA methylation can differ greatly between species: 14% of cytosines are methylated in Arabidopsis thaliana, 8% in Physarum, 4% in Mus musculus, 2.3% in Escherichia coli, 0.03% in Drosophila, 0.006% in Dictyostelium and virtually none (< 0.0002%) in Caenorhabditis or yeast species such as S. cerevisiae and S. pombe (but not N. crassa). Adenine methylation has been observed in bacterial, plant and recently in mammalian DNA, but have received considerably less attention.

Methylation of cytosine to form 5-methylcytosine occurs at the same 5 position on the pyrimidine ring where the DNA base thymine's methyl group is located, distinguishing thymine from the analogous RNA base uracil which has no methyl group. Spontaneous deamination of 5-methylcytosine converts it to thymine. This results in a T:G mismatch. Repair mechanisms may then correct it back to the original C:G pair; alternatively, they may substitute G for A, turning the original C:G pair into an A:T pair, effectively changing a base and introducing a mutation. This misincorporated base will not be corrected during DNA replication as thymine is a DNA base. If the mismatch is not repaired and the cell enters the cell cycle the strand carrying the T will be complemented by an A in one of the daughter cells, such that the mutation becomes permanent. The near-universal replacement of uracil by thymine in DNA, but not RNA, may have evolved as an error-control mechanism, to facilitate removal of uracils generated by the spontaneous deamination of cytosine. DNA methylation as well as many of its contemporary DNA methyltransferases has been thought to evolve from early world primitive RNA methylation activity and is supported by several lines of evidences.


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