Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation.

Transitions 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 comparis...

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Autores principales:	Navin Elango, Seong-Ho Kim, Eric Vigoda, Soojin V Yi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/833e7632d73b4400a36329e85caafe11
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spelling	oai:doaj.org-article:833e7632d73b4400a36329e85caafe112021-11-25T05:41:23ZMutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation.1553-734X1553-735810.1371/journal.pcbi.1000015https://doaj.org/article/833e7632d73b4400a36329e85caafe112008-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18463707/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Transitions 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 approximately 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.Navin ElangoSeong-Ho KimEric VigodaSoojin V YiPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 4, Iss 2, p e1000015 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Navin Elango Seong-Ho Kim Eric Vigoda Soojin V Yi Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation.
description	Transitions 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 approximately 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.
format	article
author	Navin Elango Seong-Ho Kim Eric Vigoda Soojin V Yi
author_facet	Navin Elango Seong-Ho Kim Eric Vigoda Soojin V Yi
author_sort	Navin Elango
title	Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation.
title_short	Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation.
title_full	Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation.
title_fullStr	Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation.
title_full_unstemmed	Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation.
title_sort	mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/833e7632d73b4400a36329e85caafe11
work_keys_str_mv	AT navinelango mutationsofdifferentmolecularoriginsexhibitcontrastingpatternsofregionalsubstitutionratevariation AT seonghokim mutationsofdifferentmolecularoriginsexhibitcontrastingpatternsofregionalsubstitutionratevariation AT ericvigoda mutationsofdifferentmolecularoriginsexhibitcontrastingpatternsofregionalsubstitutionratevariation AT soojinvyi mutationsofdifferentmolecularoriginsexhibitcontrastingpatternsofregionalsubstitutionratevariation
_version_	1718414526968233984

Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation.

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