CpG Mutation Rates in the Human Genome Are Highly Dependent on Local GC Content

Fryxell, Karl J.; Moon, Wonjong

doi:10.1093/molbev/msi043

Cited by 190 publications

(170 citation statements)

References 58 publications

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“…We further explored three potential factors that have been found to affect SNM mutation rate in non-MA experiments. First, local GC content is known to be associated with gene density, codon use, substitution rate, and mutation rate at CG sites (43,(46)(47)(48). We found no genome-wide correlation in mutation rate with local GC content in yeast, suggesting that GC contentrelated effects on substitution rate are largely due to postmutation selection or selection-like processes such as biased gene conversion.…”

Section: Discussionmentioning

confidence: 65%

“…However, a recent study using air chromatography found ∼0.364% methylation at cytosines in S. cerevisiae (42). If methylated cytosines in yeast have similar 10×-50× elevations in mutation rate as in humans (43)(44)(45), 1/5-1/25 of all CCG and TCG sites would have to be methylated for the observed ∼2× overall increase in mutation rate at these sites. Taking 0.364% to be the methylation rate in S. cerevisiae and assuming all methylation takes place within CCG and TCG contexts where we found elevated mutation rates, which correspond to ∼3% of the analyzed sequences, this value leads to an estimate of ∼1/22 of CCG and TCG sites being methylated.…”

Section: Discussionmentioning

confidence: 96%

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Precise estimates of mutation rate and spectrum in yeast

Zhu

Siegal

Hall

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

394

444

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Mutation is the ultimate source of genetic variation. The most direct and unbiased method of studying spontaneous mutations is via mutation accumulation (MA) lines. Until recently, MA experiments were limited by the cost of sequencing and thus provided us with small numbers of mutational events and therefore imprecise estimates of rates and patterns of mutation. We used whole-genome sequencing to identify nearly 1,000 spontaneous mutation events accumulated over ∼311,000 generations in 145 diploid MA lines of the budding yeast Saccharomyces cerevisiae. MA experiments are usually assumed to have negligible levels of selection, but even mild selection will remove strongly deleterious events. We take advantage of such patterns of selection and show that mutation classes such as indels and aneuploidies (especially monosomies) are proportionately much more likely to contribute mutations of large effect. We also provide conservative estimates of indel, aneuploidy, environment-dependent dominant lethal, and recessive lethal mutation rates. To our knowledge, for the first time in yeast MA data, we identified a sufficiently large number of single-nucleotide mutations to measure context-dependent mutation rates and were able to (i) confirm strong AT bias of mutation in yeast driven by high rate of mutations from C/G to T/A and (ii) detect a higher rate of mutation at C/G nucleotides in two specific contexts consistent with cytosine methylation in S. cerevisiae.neighbor-dependent mutation rate | strongly deleterious mutation S pontaneous mutations are the source of all genetic variation in nature. The rate of emergence of new mutations and the relative proportions of advantageous, neutral, and deleterious mutations are key determinants in how species evolve and adapt to new selective challenges. Unfortunately, our knowledge of the properties of spontaneous mutations remains incomplete primarily due to the difficulty of observing large enough numbers of mutational events in an unbiased way.Analyzing patterns of divergence in nonfunctional sequences is a statistically powerful method used to study relative rates of different mutation classes. This method is applicable to most organisms and now can generally be carried out on a genomewide scale. However, this approach relies crucially on the assumption that mutations in certain regions, such as pseudogenes or fourfold degenerate codon positions, are not affected by selection and are thus reliable approximations of true mutation rate. It is now becoming apparent that selection or selectionlike processes, such as biased gene conversion, are acting even at these sequences and can substantially bias the observed patterns (1-5).Studies focusing on mutations in reporter genes use a more restrictive method that can be applied only in model organisms. In some cases, such reporter genes can be placed genome-wide and thus provide estimates of genomic variation in mutation rates. However, this approach is limited by the inability to detect mutations without a visible phenotype and thus ...

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 96%

Precise estimates of mutation rate and spectrum in yeast

Zhu

Siegal

Hall

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

394

444

View full text Add to dashboard Cite

show abstract

“…GpC dinucleotides have the same C and G composition as CpG dinucleotides but are not targeted by DNA methylation (6,28). For this reason, GpC O/E often is used as an indicator of nucleotide composition bias while controlling for the influence of DNA methylation (22,29).…”

Section: Resultsmentioning

confidence: 99%

DNA methylation is widespread and associated with differential gene expression in castes of the honeybee, Apis mellifera

Elango

Hunt

Goodisman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

313

391

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The recent, unexpected discovery of a functional DNA methylation system in the genome of the social bee Apis mellifera underscores the potential importance of DNA methylation in invertebrates. The extent of genomic DNA methylation and its role in A. mellifera remain unknown, however. Here we show that genes in A. mellifera can be divided into 2 distinct classes, one with low-CpG dinucleotide content and the other with high-CpG dinucleotide content. This dichotomy is explained by the gradual depletion of CpG dinucleotides, a well-known consequence of DNA methylation. The loss of CpG dinucleotides associated with DNA methylation also may explain the unusual mutational patterns seen in A. mellifera that lead to AT-rich regions of the genome. A detailed investigation of this dichotomy implicates DNA methylation in A. mellifera development. High-CpG genes, which are predicted to be hypomethylated in germlines, are enriched with functions associated with developmental processes, whereas low-CpG genes, predicted to be hypermethylated in germlines, are enriched with functions associated with basic biological processes. Furthermore, genes more highly expressed in one caste than another are overrepresented among high-CpG genes. Our results highlight the potential significance of epigenetic modifications, such as DNA methylation, in developmental processes in social insects. In particular, the pervasiveness of DNA methylation in the genome of A. mellifera provides fertile ground for future studies of phenotypic plasticity and genomic imprinting.comparative genomics ͉ phenotypic plasticity

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“…CpG dinucleotides are rare in the genome except in specific regions (CpG islands (19) ) and frequently undergo methylation. Two kinds of base transitions (C→T and G→A) underlie the two mutations that alone account for virtually all clinically observed mutations (R201C, R201H) of the GNAS gene in cases of FD/MAS.…”

Section: Both R201c and R201h Mutations Arise From Cytosine Methylationmentioning

confidence: 99%

Fibrous Dysplasia as a Stem Cell Disease

Riminucci

Saggio

Robey

et al. 2006

Journal of Bone and Mineral Research

108

100

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ABSTRACT:At a time when significant attention is devoted worldwide to stem cells as a potential tool for curing incurable diseases, fibrous dysplasia of bone (FD) provides a paradigm for stem cell diseases. Consideration of the time and mechanism of the causative mutations and of nature of the pluripotent cells that mutate in early embryonic development indicates that, as a disease of the entire organism, FD can be seen as a disease of pluripotent embryonic cells. As a disease of bone as an organ, in turn, FD can be seen as a disease of postnatal skeletal stem cells, which give rise to dysfunctional osteoblasts. Recognizing FD as a stem cell disease provides a novel conceptual angle and a way to generate appropriate models of the disease, which will continue to provide further insight into its natural history and pathogenesis. In addition, skeletal stem cells may represent a tool for innovative treatments. These can be conceived as directed to alter the in vivo behavior of mutated stem cells, to replace mutated cells through local transplantation, or to correct the genetic defect in the stem cells themselves. In vitro and in vivo models are currently being generated that will permit exploration of these avenues in depth.

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CpG Mutation Rates in the Human Genome Are Highly Dependent on Local GC Content

Cited by 190 publications

References 58 publications

Precise estimates of mutation rate and spectrum in yeast

Precise estimates of mutation rate and spectrum in yeast

DNA methylation is widespread and associated with differential gene expression in castes of the honeybee, Apis mellifera

Fibrous Dysplasia as a Stem Cell Disease

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