Mutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variation
Publication Date
February 29, 2008
Journal
PLOS Computational Biology
Authors
Navin Elango, Seong Ho Kim, Nisc Comparative Sequencing Program, Eric Vigoda, et al
Volume
4
Issue
2
Pages
e1000015
DOI
http://doi.org/10.1371/journal.pcbi.1000015
Publisher URL
http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1000015
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/18463707
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265638
Europe PMC
http://europepmc.org/abstract/MED/18463707
Web of Science
000269692800015
Scopus
40149097494
Mendeley
http://www.mendeley.com/research/mutations-different-molecular-origins-exhibit-contrasting-patterns-regional-substitution-rate-variat
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Mendeley | Further Information

{"title"=>"Mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation", "type"=>"journal", "authors"=>[{"first_name"=>"Navin", "last_name"=>"Elango", "scopus_author_id"=>"12141680400"}, {"first_name"=>"Seong Ho", "last_name"=>"Kim", "scopus_author_id"=>"57007267800"}, {"first_name"=>"Eric", "last_name"=>"Vigoda", "scopus_author_id"=>"7004060546"}, {"first_name"=>"Soojin V.", "last_name"=>"Yi", "scopus_author_id"=>"8343641700"}], "year"=>2008, "source"=>"PLoS Computational Biology", "identifiers"=>{"pmid"=>"18463707", "pui"=>"351328498", "issn"=>"1553734X", "doi"=>"10.1371/journal.pcbi.1000015", "isbn"=>"10.1371/journal.pcbi.1000015", "scopus"=>"2-s2.0-40149097494", "sgr"=>"40149097494"}, "id"=>"3a76e9ed-b64f-3a91-ae07-51d2f3ab2fdc", "abstract"=>"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.", "link"=>"http://www.mendeley.com/research/mutations-different-molecular-origins-exhibit-contrasting-patterns-regional-substitution-rate-variat", "reader_count"=>28, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>4, "Researcher"=>10, "Student > Ph. D. Student"=>7, "Student > Master"=>2, "Professor"=>5}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>4, "Researcher"=>10, "Student > Ph. D. Student"=>7, "Student > Master"=>2, "Professor"=>5}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>24}, "reader_count_by_subdiscipline"=>{"Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>24}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}}, "reader_count_by_country"=>{"Netherlands"=>1, "Brazil"=>1, "United Kingdom"=>1, "France"=>1}, "group_count"=>1}

CrossRef

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/936061"], "description"=>"<p>The same experiment as in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000015#pcbi-1000015-g003\" target=\"_blank\">Figure 3</a> with the G+C content of each window normalized with respect to GC<i><sub>global</sub></i> (removing global effect). (A) The distance-decaying effect of G+C content on the rate of CpG substitution persists even after removing the global effect. In case of GpC substitutions, there was no distance-decaying effect. (B) Results of the chi-square test for the independence of the rate of CpG substitution and the G+C content of the windows. The blue line indicates log<sub>10</sub> (<i>P</i>-value) = −1.30. The distance-decaying effect subsided after ∼1,500 bps. (C) Results of the same experiment as in (B), but for GpC sites. There is no distance-decaying effect, as expected.</p>", "links"=>[], "tags"=>["cpg", "substitution", "normalized"], "article_id"=>606505, "categories"=>["Medicine", "Genetics", "Evolutionary Biology"], "users"=>["Navin Elango", "Seong-Ho Kim", "Eric Vigoda", "Soojin V. Yi"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000015.g004", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sliding_window_analysis_of_the_relationship_between_CpG_substitution_rate_and_normalized_G_C_content_/606505", "title"=>"Sliding window analysis of the relationship between CpG substitution rate and normalized G+C content.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-02-29 01:48:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/936002"], "description"=>"<p>(A) At each distance (along the X-axis), CpG sites were divided into four bins based on G+C content at that distance from the site (as measured from the G+C content of the 200 bps window centered at that distance; G+C<38: red curve, 38< = G+C<45%: green curve, 45< = G+C<52%: blue curve, G+C>52%: black curve). The proportion of CpG sites mutated in each of these bins is plotted as a function of distance from the site. At distances closer to the CpG site, the rate of substitution in high local-GC bins (black curve) is clearly lower compared to that of low local-GC bins (red curve). This relationship progressively declines as we move farther away from the site, suggesting a distance-decaying relationship between G+C content and CpG substitution rate. In case of GpC sites, we do not observe a distance-decaying effect (see inset). (B) Results of the chi-square test for the independence of the rate of CpG substitution and the G+C content of the windows at each distance, in log scale. The blue line indicates the <i>P</i>-value cutoff of 0.05 [or log<sub>10</sub> (<i>P</i>-value) = −1.30]. The <i>P</i>-values are very low at distances close to the CpG site, and progressively become larger as the distance from the CpG site increases (distance-decaying effect). The rate of CpG substitution becomes independent of the G+C content [log<sub>10</sub> (<i>P</i>-value)>−1.30] after ∼2,000 bps from the CpG. (C): Results of the chi-square test for the independence of the rate of GpC substitution and the G+C content of the windows at each distance, in log scale. Again, the blue line indicates the <i>P</i>-value cutoff of 0.05 (or log<sub>10</sub> (<i>P</i>-value) = −1.30). The rate of GpC substitution becomes independent of the G+C content [log<sub>10</sub> (<i>P</i>-value)>−1.30] at a distance very close to the GpC site, and no distance-decaying effect was observed.</p>", "links"=>[], "tags"=>["cpg", "substitution"], "article_id"=>606447, "categories"=>["Medicine", "Genetics", "Evolutionary Biology"], "users"=>["Navin Elango", "Seong-Ho Kim", "Eric Vigoda", "Soojin V. Yi"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000015.g003", "stats"=>{"downloads"=>4, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sliding_window_analysis_of_the_relationship_between_CpG_substitution_rate_and_G_C_content_of_windows_/606447", "title"=>"Sliding window analysis of the relationship between CpG substitution rate and G+C content of windows.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-02-29 01:47:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/935951"], "description"=>"<p>(A) Non-coding regions (intergenic and introns) were partitioned into six equal-sized bins based on their G+C contents. The rates of CG->TA substitutions in CpG sites of these bins are negatively correlated with their G+C contents. The negative relationship holds when introns were analyzed separately. In case of intergenic regions the relationship was not significant. Nevertheless, we found a negative trend. (B) GpC substitution rates in non-coding regions exhibited a negative relationship with G+C contents. When divided into intergenic regions and introns, however, the relationships were not significant, although there was a clear negative trend. Refer text for r<i><sup>2</sup></i> values and <i>P</i>- values.</p>", "links"=>[], "tags"=>["substitution", "non-coding"], "article_id"=>606397, "categories"=>["Medicine", "Genetics", "Evolutionary Biology"], "users"=>["Navin Elango", "Seong-Ho Kim", "Eric Vigoda", "Soojin V. Yi"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000015.g002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Negative_correlation_between_the_rate_of_CG_gt_TA_substitution_and_G_C_content_of_non_coding_regions_/606397", "title"=>"Negative correlation between the rate of CG->TA substitution and G+C content of non-coding regions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-02-29 01:46:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/935902"], "description"=>"<p>The rate of CG->TA transitions in CpG sites (A), and GpC sites (B) in 50 kb segments of non-coding regions having at least 10,000 aligned sites. Variation of CpG substitution rate among non-coding regions is significantly greater than that expected under a uniform substitution rate model. A similar result was obtained for GpC sites (see text).</p>", "links"=>[], "tags"=>["substitutions", "non-coding"], "article_id"=>606345, "categories"=>["Medicine", "Genetics", "Evolutionary Biology"], "users"=>["Navin Elango", "Seong-Ho Kim", "Eric Vigoda", "Soojin V. Yi"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000015.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Histogram_of_the_rate_of_CG_gt_TA_substitutions_in_non_coding_regions_/606345", "title"=>"Histogram of the rate of CG->TA substitutions in non-coding regions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-02-29 01:45:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/461543", "https://ndownloader.figshare.com/files/461601", "https://ndownloader.figshare.com/files/461624", "https://ndownloader.figshare.com/files/461650", "https://ndownloader.figshare.com/files/461692", "https://ndownloader.figshare.com/files/461730"], "description"=>"<div><p>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.</p><p>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.</p><p>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.</p></div>", "links"=>[], "tags"=>["mutations", "molecular", "origins", "contrasting", "patterns", "substitution"], "article_id"=>150954, "categories"=>["Medicine", "Genetics", "Evolutionary Biology"], "users"=>["Navin Elango", "Seong-Ho Kim", "Eric Vigoda", "Soojin V. Yi"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1000015.s001", "https://dx.doi.org/10.1371/journal.pcbi.1000015.s002", "https://dx.doi.org/10.1371/journal.pcbi.1000015.s003", "https://dx.doi.org/10.1371/journal.pcbi.1000015.s004", "https://dx.doi.org/10.1371/journal.pcbi.1000015.s005", "https://dx.doi.org/10.1371/journal.pcbi.1000015.s006"], "stats"=>{"downloads"=>17, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Mutations_of_Different_Molecular_Origins_Exhibit_Contrasting_Patterns_of_Regional_Substitution_Rate_Variation/150954", "title"=>"Mutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variation", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2008-02-29 00:15:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/936118"], "description"=>"<p>The number of CpG and GpC sites identified in our dataset and the number of CG->TA transition substitution in these sites.</p>*<p>CG->TA transition substitutions only. The substitutions in humans and chimpanzees were pooled.</p><p>See <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000015#s5\" target=\"_blank\">Methods</a> section for definition of sites. There were 8,971,241 and 5,767,731 aligned sites in intergenic regions and introns, respectively.</p>", "links"=>[], "tags"=>["computational biology/comparative sequence analysis", "evolutionary biology/evolutionary and comparative genetics", "evolutionary biology/genomics", "genetics and genomics/bioinformatics", "genetics and genomics/comparative genomics", "genetics and genomics/genomics"], "article_id"=>606559, "categories"=>["Medicine", "Genetics", "Evolutionary Biology"], "users"=>["Navin Elango", "Seong-Ho Kim", "Eric Vigoda", "Soojin V. Yi"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000015.t001", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Description_of_the_Dataset_/606559", "title"=>"Description of the Dataset.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-02-29 01:49:19"}

PMC Usage Stats | Further Information

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Relative Metric

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