title: Sequence context at human single nucleotide polymorphisms: overrepresentation of CpG dinucleotide at polymorphic sites and suppression of variation in CpG islands.
abstract: Human polymorphisms originate as mutations, and the influence of context on mutagenesis should be reflected in the distribution of sequences surrounding single nucleotide polymorphisms (SNPs). We have performed a computational survey of nearly two million human SNPs to determine if sequence-dependent hotspots for polymorphism exist in the human genome. Here we show that sequences containing CpG dinucleotides, which occur at low frequencies in the human genome, are 6.7-fold more abundant at polymorphic sites than expected. In contrast, polymorphisms in CpG sequences located within CpG islands, important regulatory regions that modulate gene expression, are 6.8-fold less prevalent than expected. The distribution of polymorphic alleles at CpGs in CpG islands is also significantly different from that in non-island regions. These data strongly support a role for 5-methylcytosine deamination in the generation of human variation, and suggest that variation at CpGs in islands is suppressed.
authors.affiliation: Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, C3-03 P.O. Box 12233, Research Triangle Park, NC 27709, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tomso
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bell
mesh_terms: D044503:5-Methylcytosine; D000483:Alleles; D002875:Chromosomes / Q000235:genetics; D018899:CpG Islands / Q000235:genetics*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D016208:Databases, Factual; D003641:Deamination; D018900:Dinucleotide Repeats / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D017931:DNA Primers; D044503:5-Methylcytosine; D003596:Cytosine