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Substitution rate variation at human CpG sites correlates with non-CpG divergence, methylation level and GC content
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
2011 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1465-6914, Vol. 12, no 6, R58- p.Article in journal (Refereed) Published
Abstract [en]

Background: A major goal in the study of molecular evolution is to unravel the mechanisms that induce variation in the germ line mutation rate and in the genome-wide mutation profile. The rate of germ line mutation is considerably higher for cytosines at CpG sites than for any other nucleotide in the human genome, an increase commonly attributed to cytosine methylation at CpG sites. The CpG mutation rate, however, is not uniform across the genome and, as methylation levels have recently been shown to vary throughout the genome, it has been hypothesized that methylation status may govern variation in the rate of CpG mutation.

Results: Here, we use genome-wide methylation data from human sperm cells to investigate the impact of DNA methylation on the CpG substitution rate in introns of human genes. We find that there is a significant correlation between the extent of methylation and the substitution rate at CpG sites. Further, we show that the CpG substitution rate is positively correlated with non-CpG divergence, suggesting susceptibility to factors responsible for the general mutation rate in the genome, and negatively correlated with GC content. We only observe a minor contribution of gene expression level, while recombination rate appears to have no significant effect.

Conclusions: Our study provides the first direct empirical support for the hypothesis that variation in the level of germ line methylation contributes to substitution rate variation at CpG sites. Moreover, we show that other genomic features also impact on CpG substitution rate variation.

Place, publisher, year, edition, pages
2011. Vol. 12, no 6, R58- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-162402DOI: 10.1186/gb-2011-12-6-r58ISI: 000296646600006OAI: oai:DiVA.org:uu-162402DiVA: diva2:460427
Available from: 2011-11-30 Created: 2011-11-30 Last updated: 2015-04-22Bibliographically approved
In thesis
1. Nucleotide Substitution Patterns in Vertebrate Genomes
Open this publication in new window or tab >>Nucleotide Substitution Patterns in Vertebrate Genomes
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The rates and patterns at which nucleotide substitutions occur vary significantly across the genome sequence of vertebrates. A prominent example is the difference in the rate of evolution of functional sequences versus nonfunctional (neutrally evolving) sequences, which is explained by the influence of natural selection on functional sequences. However, even within neutrally evolving sequences there is striking variation in the rates and patterns of nucleotide substitutions. Unraveling the underlying processes that induce this variation is necessary to understand the basic principles of variation in neutral substitution profiles, which in turn is crucial for the identification of regions in the genome where natural selection acts. This research question builds the main focus of the present thesis. I have studied the causes and consequences of variation in different patterns of nucleotide substitutions. In particular, I have investigated substitutional strand asymmetries in mammalian genes and could show that they result from the asymmetric nature of DNA replication and transcription. Comparative analysis of substitutional asymmetries then suggested that the organization of DNA replication and the level of transcription are conserved among mammals. Further, I have examined the variation in CpG mutation rate among human genes and could show that beside DNA methylation also GC content plays a decisive role in CpG mutability. In addition, I have studied the signatures of GC-biased gene conversion and its impact on the evolution of the GC isochore structure in chicken. By comparison of the results in chicken to previous results in human I found evidence that karyotype stability is critical for the evolution of GC isochores. Finally, beside the empirical studies, I have performed theoretical investigations of substitution rates in functional sequences. More precisely, I have explored the temporal dynamics of estimates of the ratio of non-synonymous to synonymous substitution rates dN/dS in a phylogentic-population genetic framework.


Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 50 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1048
nucleotide substitutions, mutation rate variation, strand asymmetries, CpG effect, GC-biased gene conversion, codon evolution
National Category
Evolutionary Biology Genetics
Research subject
Biology with specialization in Molecular Evolution
urn:nbn:se:uu:diva-198787 (URN)978-91-554-8681-5 (ISBN)
Public defence
2013-06-13, Lindahlsalen, EBC, Norbyvägen 18C, Uppsala, 13:00 (English)
Available from: 2013-05-23 Created: 2013-04-25 Last updated: 2015-04-22Bibliographically approved

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Mugal, Carina F.Ellegren, Hans
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