Editing CpG site (section)

=== Under-representation caused by high mutation rate ===
CpG dinucleotides have long been observed to occur with a much lower frequency in the sequence of vertebrate genomes than would be expected due to random chance. For example, in the human genome, which has a 42% [[GC content]],<ref name="Lander2001">{{Cite journal|last1=Lander|first1=Eric S.|author-link1 =Eric Lander|last2=Linton|first2=Lauren M. |last3=Birren|first3=Bruce |last4=Nusbaum|first4=Chad |last5=Zody|first5=Michael C.|last6=Baldwin |first6=Jennifer|last7=Devon |first7=Keri|last8=Dewar |first8=Ken |last9=Doyle|first9=Michael|date=15 February 2001|title=Initial sequencing and analysis of the human genome|journal=Nature|language=En|volume=409|issue=6822|pages=860–921|doi=10.1038/35057062|pmid=11237011|issn=1476-4687|bibcode=2001Natur.409..860L|doi-access=free|hdl=2027.42/62798|hdl-access=free}}</ref> a pair of [[nucleotide]]s consisting of cytosine followed by guanine would be expected to occur <math>0.21 \times 0.21 = 4.41 \%</math> of the time. The frequency of CpG dinucleotides in human genomes is less than one-fifth of the expected frequency.<ref>{{Cite journal|last=International Human Genome Sequencing Consortium|date=2001-02-15|title=Initial sequencing and analysis of the human genome|journal=Nature|language=en|volume=409|issue=6822|pages=860–921|doi=10.1038/35057062|pmid=11237011|bibcode=2001Natur.409..860L |issn=0028-0836|doi-access=free|hdl=2027.42/62798|hdl-access=free}}</ref> 

This underrepresentation is a consequence of the high [[mutation rate]] of methylated CpG sites: the spontaneously occurring [[deamination]] of a methylated cytosine results in a [[thymine]], and the resulting G:T mismatched bases are often improperly resolved to A:T; whereas the deamination of unmethylated cytosine results in a [[uracil]], which as a foreign base is quickly replaced by a cytosine by the [[base excision repair]] mechanism. The C to T [[transition (genetics)|transition]] rate at methylated CpG sites is ~10 fold higher than at unmethylated sites.<ref>{{cite journal|vauthors=Hwang DG, [[Philip Palmer Green|Green P]]|title=Bayesian Markov chain Monte Carlo sequence analysis reveals varying neutral substitution patterns in mammalian evolution. |journal=Proc Natl Acad Sci U S A |volume=101 | issue=39 |pages=13994–4001 |year=2004 |pmid= 15292512 |doi=10.1073/pnas.0404142101 |pmc=521089|bibcode=2004PNAS..10113994H |doi-access=free }}</ref><ref>{{cite book|vauthors=Walsh CP, Xu GL |chapter=Cytosine Methylation and DNA Repair |title=DNA Methylation: Basic Mechanisms |volume=301 |pages=283–315 |year=2006 |pmid=16570853 |doi=10.1007/3-540-31390-7_11|series=Current Topics in Microbiology and Immunology |isbn=3-540-29114-8 }}</ref><ref>{{cite journal|vauthors=[[Norman Arnheim|Arnheim N]], Calabrese P |title=Understanding what determines the frequency and pattern of human germline mutations. |journal=Nat Rev Genet |volume=10 | issue=7 |pages=478–488 |year=2009 |pmid= 19488047 |doi=10.1038/nrg2529 |pmc=2744436}}</ref><ref>{{cite journal|vauthors=Ségurel L, Wyman MJ, Przeworski M |title=Determinants of Mutation Rate Variation in the Human Germline |journal=Annu Rev Genom Hum Genet |volume=15 |pages=47–70 |year=2014 |pmid= 25000986 |doi=10.1146/annurev-genom-031714-125740|doi-access=free }}</ref>