Mutation Rate of Non‐CpG DNA

Abstract

Base substitutions (mutations) change the informational content of deoxyribonucleic acid (DNA). Therefore, understanding the determinants of the base mutation rate is a fundamental problem in biology. Biochemically, mutations are a function of the fidelity of DNA replication, damage and repair. Each can be affected by nucleotide composition and context. However, various downstream factors determine the ultimate survival of these mutations in a population, including natural selection and chance (genetic drift). The result in mammals is two dramatically different mutation rates. The C of most CpG dinucleotides mutates approximately 10‐ to 50‐fold faster than Cs in other contexts or any other nucleotide (i.e. in non‐CpG sites). But, the non‐CpG mutation rate also varies between different genomic regions. Here we address the difference between CpG and non‐CpG mutation rates and the factors that are correlated with the variance in non‐CpG rates. A predominant one is CpG content.

Key concepts:

  • Evolutionary processes determine the extent to which the base substitutions (mutations), which result from biochemical errors inherent in the processes that replicate and maintain the integrity of the genome, contribute to the mutation rate experienced by a population.

  • These biochemical mutations are a function of the fidelity of DNA replication, the efficiency with which replication errors and DNA damage are repaired and whether DNA repair processes themselves produce errors in undamaged DNA.

Keywords: mutation; CpG; DNA‐repair; evolution; methylation

Figure 1.

Using copies of extinct L1 retrotransposon families to measure the divergence between chimpanzee and humans. (a) The left side shows the phylogenetic relationship between rhesus monkey (Macaca mulatta, M), chimpanzee (Pan troglodytes, P) and human (Homo sapiens, H). The right side lists the five primate‐specific L1 families (L1 Pa3–L1 Pa5), and the grey bars indicate the estimated time during which they were active, in the common ancestor of these species. The double‐headed arrows (T3–T7) indicate the time between the peak activity of these families and the approximate time of the chimpanzee – human divergence. The double‐headed arrow (Tp−h), indicates the time between this divergence and the present. (b) The y‐axis indicates the percentage of CpG and TpG(CpA) at corresponding positions relative to the amounts in the full‐length reconstructed ancestral sequences of each family. Reproduced and modified with permission form Cold Spring Harbor Laboratory Press © 2009 (Walser et al., ).

Figure 2.

The divergence of orthologous L1 inserts in chimpanzee and humans (A) Left y‐axis – divergence of autosomal orthologues of different L1 families in chimpanzee and humans. Right y‐axes – the % recombination of the orthologue‐containing regions and the % C+G content of either the L1 orthologue or their flanking DNA. (B) The % mutations at non‐CpG site in orthologues of various families as a function of the mutations at CpG sites. Reproduced and modified with permission form Cold Spring Harbor Laboratory Press © 2009 (Walser et al., ).

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Further Reading

Furano AV (2000) The biological properties and evolutionary dynamics of mammalian LINE‐1 retrotransposons. Progress in Nucleic Acids Research & Molecular Biology 64: 255–294.

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Walsh CP and Xu GL (2006) Cytosine methylation and DNA repair. Current Topics in Microbiology and Immunology 301: 283–315.

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Furano, Anthony V, and Walser, Jean‐Claude(Dec 2009) Mutation Rate of Non‐CpG DNA. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021740]