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dc.contributor.authorElango, Navinen_US
dc.contributor.authorKim, Seong-Hoen_US
dc.contributor.authorVigoda, Ericen_US
dc.contributor.authorYi, Soojin V.en_US
dc.date.accessioned2009-12-11T19:12:26Z
dc.date.available2009-12-11T19:12:26Z
dc.date.issued2008-02-29
dc.identifier.citationElango N, Kim S-H, NISC Comparative Sequencing Program, Vigoda E, Yi SV (2008) Mutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variation. PLoS Comput Biol 4(2): e1000015. doi:10.1371/journal.pcbi.1000015en
dc.identifier.issn1553-734X
dc.identifier.urihttp://hdl.handle.net/1853/31373
dc.descriptionCopyright: 2008 Elango et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.descriptionDOI: 10.1371/journal.pcbi.1000015
dc.description.abstractTransitions at CpG dinucleotides, referred to as “CpG substitutions”, are a major mutational input into vertebrate genomes and a leading cause of human genetic disease. The prevalence of CpG substitutions is due to their mutational origin, which is dependent on DNA methylation. In comparison, other single nucleotide substitutions (for example those occurring at GpC dinucleotides) mainly arise from errors during DNA replication. Here we analyzed high quality BAC-based data from human, chimpanzee, and baboon to investigate regional variation of CpG substitution rates. We show that CpG substitutions occur approximately 15 times more frequently than other single nucleotide substitutions in primate genomes, and that they exhibit substantial regional variation. Patterns of CpG rate variation are consistent with differences in methylation level and susceptibility to subsequent deamination. In particular, we propose a “distance-decaying” hypothesis, positing that due to the molecular mechanism of a CpG substitution, rates are correlated with the stability of double-stranded DNA surrounding each CpG dinucleotide, and the effect of local DNA stability may decrease with distance from the CpG dinucleotide. Consistent with our “distance-decaying” hypothesis, rates of CpG substitution are strongly (negatively) correlated with regional G+C content. The influence of G+C content decays as the distance from the target CpG site increases. We estimate that the influence of local G+C content extends up to 1,500~2,000 bps centered on each CpG site. We also show that the distance-decaying relationship persisted when we controlled for the effect of long-range homogeneity of nucleotide composition. GpC sites, in contrast, do not exhibit such “distance-decaying” relationship. Our results highlight an example of the distinctive properties of methylation-dependent substitutions versus substitutions mostly arising from errors during DNA replication. Furthermore, the negative relationship between G+C content and CpG rates may provide an explanation for the observation that GC-rich SINEs show lower CpG rates than other repetitive elements.en
dc.language.isoen_USen
dc.publisherGeorgia Institute of Technologyen
dc.subjectCpG substitutionsen
dc.subjectGenetic diseasesen
dc.subjectDNA methylationen
dc.subjectDistance-decaying hypothesisen
dc.titleMutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variationen
dc.typeArticleen
dc.contributor.corporatenameGeorgia Institute of Technology. School of Biologyen_US
dc.contributor.corporatenameNISC Comparative Sequencing Programen_US
dc.contributor.corporatenameNational Institutes of Health (U.S.). Genome Technology Branchen_US
dc.contributor.corporatenameGeorgia Institute of Technology. College of Computingen_US
dc.publisher.originalPublic Library of Science
dc.identifier.doi10.1371/journal.pcbi.1000015


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