Wang Y and Leung FC (2008), Comparative genomic study reveals a transition ...

ECB-ART-41084

Genomics Proteomics Bioinformatics 2008 Dec 01;63-4:144-54. doi: 10.1016/S1672-0229(09)60002-4.

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Comparative genomic study reveals a transition from TA richness in invertebrates to GC richness in vertebrates at CpG flanking sites: an indication for context-dependent mutagenicity of methylated CpG sites.

Wang Y , Leung FC .

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Vertebrate genomes are characterized with CpG deficiency, particularly for GC-poor regions. The GC content-related CpG deficiency is probably caused by context-dependent deamination of methylated CpG sites. This hypothesis was examined in this study by comparing nucleotide frequencies at CpG flanking positions among invertebrate and vertebrate genomes. The finding is a transition of nucleotide preference of 5'' T to 5'' A at the invertebrate-vertebrate boundary, indicating that a large number of CpG sites with 5'' Ts were depleted because of global DNA methylation developed in vertebrates. At genome level, we investigated CpG observed/expected (obs/exp) values in 500 bp fragments, and found that higher CpG obs/exp value is shown in GC-poor regions of invertebrate genomes (except sea urchin) but in GC-rich sequences of vertebrate genomes. We next compared GC content at CpG flanking positions with genomic average, showing that the GC content is lower than the average in invertebrate genomes, but higher than that in vertebrate genomes. These results indicate that although 5'' T and 5'' A are different in inducing deamination of methylated CpG sites, GC content is even more important in affecting the deamination rate. In all the tests, the results of sea urchin are similar to vertebrates perhaps due to its fractional DNA methylation. CpG deficiency is therefore suggested to be mainly a result of high mutation rates of methylated CpG sites in GC-poor regions.

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Genes referenced: ebf2 LOC100887844 LOC100893907 LOC115925415

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	Fig. 1. Nucleotide frequency at CpG flanking positions. Nucleotide frequencies at CpG flanking positions were obtained from repeat-masked genomic sequences. Six 5′ flanking positions are labeled as −1 to −6; six 3′ flanking positions are labeled as 1 to 6.
	Fig. 2. Percentage of genomic fragments in different CpG obs/exp (o/e) ranges. CpG obs/exp values of all the genomic fragments in 500 bp unit were calculated. The fragments have been classified into three groups according to GC content. The axis x represents CpG obs/exp ranges in which the proportion of the fragments was shown. The three lines represent the proportions of the genomic segments for three GC groups: G+C=20%–35% (solid black line), 35%–50% (dashed line) and >50% (gray solid line).
	Fig. 3. Cumulative percent of genomic fragments in CpG obs/exp (o/e) ranges. All of the genomic fragments of 500 bp from 8 organisms were classified according to their GC level (G+C=20%–35%, 35%–50% and >50%) and CpG obs/exp values were then measured. In each GC level group, the percentage of the fragments belonging to individual CpG obs/exp ranges (interval is 0.05) was measured as shown in Figure 2, and then cumulative percentage was calculated for each of the CpG obs/exp ranges. The numbers on axis x represent the starting value of the CpG obs/exp ranges; the axis y denotes cumulative percentage of the genomic fragments.
	Fig. 4. G+C percent difference between real and Markov artificial sequences. The positions of −6 to +6 are the 12 flanking positions of CpG sites. The GC contents in percent were measured in real and Markov artificial sequences, and the GC content differences (GCreal−GCartificial) were as shown of individual positions. The artificial sequences were Markov first-order sequences created using repeat-masked real genomic sequences.

References [+] :

Aïssani, CpG islands, genes and isochores in the genomes of vertebrates. 1991, Pubmed