CpG island

In genetics, CpG islands or CG islands are genomic regions that contain a high frequency of CpG sites but to date objective definitions for CpG islands are limited. In mammalian genomes, CpG islands are typically 300-3,000 base pairs in length. They are in and near approximately 40% of promoters of mammalian genes. About 70% of human promoters have a high CpG content. Given the GC frequency however, the number of CpG dinucleotides is much lower than expected. The "p" in CpG refers to the phosphodiester bond between the cytosine and the guanine, which indicates that the C and the G are next to each other in sequence regardless of being single- or double- stranded. More explicitly, both C and G would be on the same strand of DNA/RNA covalently bonded (chemically connected) by a phosphodiester bond (a strong bond). This differs from the easily confused base-pairing of C and G which share three hydrogen bonds (weaker bond) across two separate strands of DNA (also known as complementary base pairing).

The usual formal definition of a CpG island is a region with at least 200 bp and with a GC percentage that is greater than 50% and with an observed/expected CpG ratio that is greater than 60%, where the value of expected CpG is calculated by formula (GC content/2)2. Another recent study revised the rules of CpG island prediction in order to exclude other GC-rich genomic sequences such as Alu repeats. Based on an extensive search on the complete sequences of human chromosomes 21 and 22, DNA regions greater than 500 bp with a GC content greater than 55% and observed CpG/expected CpG of 0.65 were more likely to be the true CpG islands associated with the 5' regions of genes.

CpG islands are characterized by CpG dinucleotide content of at least 60% of that which would be statistically expected (~4–6%), whereas the rest of the genome has much lower CpG frequency (~1%), a phenomenon called CG suppression. Unlike CpG sites in the coding region of a gene, in most instances, the CpG sites in the CpG islands of promoters are unmethylated if genes are expressed. This observation led to the speculation that methylation of CpG sites in the promoter of a gene may inhibit the expression of a gene. Methylation is central to imprinting alongside histone modifications.

CpG islands typically occur at or near the transcription start site of genes, particularly housekeeping genes, in vertebrates. Normally a C (cytosine) base followed immediately by a G (guanine) base (a CpG) is rare in vertebrate DNA because the cytosines in such an arrangement tend to be methylated. This methylation helps distinguish the newly synthesized DNA strand from the parent strand, which aids in the final stages of DNA proofreading after duplication. However, over evolutionary time methylated cytosines tend to turn into thymines because of spontaneous deamination. While there is a special enzyme in human (Thymine-DNA glycosylase, or TDG) that specifically replaces T's from T/G mismatches, it is not sufficiently effective to prevent the relatively rapid mutation of the dinucleotides. The result is that CpGs are relatively rare unless there is selective pressure to keep them or a region is not methylated for some reason, perhaps having to do with the regulation of gene expression.