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Genome Res. 16:567-575, 2006 ©2006 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/06 $5.00 A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome1 Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, 2 Department of Neuropsychiatry, Graduate School of Medical Sciences 3 Radioisotope Center, Kyushu University, Fukuoka 812-8582, Japan
8-Oxoguanine (8-oxoG), a major spontaneous form of oxidative DNA damage, is considered to be a natural cause of genomic diversity in organisms because of its mutagenic potential. The steady-state level of 8-oxoG in the nuclear genome of a human cell has been estimated to be several residues per 106 guanines. In the present study, to clarify the genome-wide distribution of 8-oxoG in the steady state, we performed fluorescence in situ detection of 8-oxoG on human metaphase chromosomes using a monoclonal antibody. Multiple dot-like signals were observed on each metaphase chromosome. We then mapped the position of the signal at megabase resolution referring to the cytogenetically identified chromosomal band, and demonstrated that 8-oxoG is unevenly distributed in the normal human genome and that the distribution pattern is conserved among different individuals. Moreover, we found that regions with a high frequency of recombination and single nucleotide polymorphisms (SNPs) are preferentially located within chromosomal regions with a high density of 8-oxoG. Our findings suggest that 8-oxoG is one of the main causes of frequent recombinations and SNPs in the human genome, which largely contribute to the genomic diversity in human beings.
Mutations are sequence variations in the genome caused by base substitutions, insertions/deletions, duplications, and recombinations, which largely contribute to genomic diversity in living organisms (Aquadro et al. 2001  ; Nevo 2001). Mutagenesis is known to be a biological outcome of processing damaged DNA during genome replication, transcription, repair, and recombination, and enzymes that act upon DNA in the transactions have been well documented (Hanawalt 1998; Maki 2002). Analyses of spontaneous mutagenesis in various organisms revealed that these mutations do not occur randomly in the genome sequence and that their distribution and mutation spectrum exhibit strong bias in the genome (Drake 1991; Maki 2002). Recent progress in human genome projects demonstrated that human genome sequence variation, such as single nucleotide polymorphisms (SNPs), differs greatly in extent across the genome (Sachidanandam et al. 2001; Lercher and Hurst 2002; Malcom et al. 2003). This may be a result of the nonrandom distribution of premutagenic lesions; however, how and where DNA is damaged in the genome remains to be elucidated.
Amongst the various forms of DNA damage, oxidative DNA lesions caused by reactive oxygen species (ROS) that are generated both as a byproduct of oxidative metabolism and as a consequence of exposure to ionizing radiation and other environmental factors are considered to be a major threat to the genome (Hanawalt 1998
It has been reported that there are constitutively several thousand residues of 8-oxoG in the nuclear genome of normal human tissues or cultured cells (Gedik and Collins 2005
In situ detection of 8-oxoG in human chromosomes Using HPLC-MS/MS, we determined the contents of 2'-deoxy-8-oxoguanosine (8-oxo-dG) in human nuclear DNA prepared from freshly isolated peripheral lymphocytes or from those cultured after PHA stimulation. The former contained 2.66 (SEM = 0.05) residues of 8-oxo-dG per 106 residues of deoxyguanosine (dG), and the latter, 3.07 (SEM = 0.17) residues of 8-oxo-dG per 106 residues of dG. These numbers correspond to  10,000 8-oxoG residues per single nucleus of a human cell (2n: 6.4 x 109 bp = 12.8 x 109 bases, which contain 3.2 x 109 guanine residues), and this represents the steady-state level of 8-oxoG in the human genome. Next, we performed immunofluorescence microscopy using anti-8-oxo-dG monoclonal antibody (N45.1) for in situ detection of 8-oxoG in a human metaphase spread prepared from PHA-stimulated peripheral lymphocytes. The preparation was pretreated with RNase A to eliminate fluorescent signals derived from 8-oxoG in RNA and with HCl to denature the double-stranded DNA. In addition to diffused fine signals with a weak fluorescence intensity, multiple dot-like signals with a strong fluorescence intensity were observed in all interphase nuclei (data not shown) or metaphase chromosomes (Fig. 1A). Since each dot-like signal exhibited a different fluorescence intensity, each single fluorescent dot was likely derived from multiple 8-oxoG residues in the same region. Thus, a chromosomal region with a strong fluorescent signal was considered to have a high density of 8-oxoG, in contrast to a chromosomal region without such a signal. Twin dots of fluorescent signals were often found at the same region in sister chromatids (Fig. 1A, arrowhead).
When a specimen was sequentially treated with RNase A and DNase I prior to the first antibody reaction, no fluorescent signal was observed, while pretreatment with RNase A and RNase H, instead of with DNase I, altered neither its intensity nor pattern (data not shown). Pretreatment of a specimen with a bacterial enzyme, MutM, which excises 8-oxoG opposite cytosine, completely abolished the fluorescent signal (Fig. 1B). Furthermore, pre-adsorption of the anti-8-oxo-dG with free 8-oxo-dG also diminished the immunoreactivity to the level obtained without the primary antibody (data not shown). We thus established a method for in situ detection of 8-oxoG in human chromosomes.
We next performed a MutM-dependent in situ end-labeling assay to detect MutM-sensitive sites, and multiple dot-like signals were again detected on each chromosome (Fig. 1C). Without the pretreatment with MutM, no signal was detected (Fig. 1D). By comparing the distribution of fluorescent signals on chromosome 7 obtained with the two approaches (Fig. 1E,F), we found that five of six regions found to be MutM sensitive coincided with 8-oxoG-containing regions detected by immunofluorescence microscopy. From these results, we concluded that the fluorescent signals obtained with the two approaches represent 8-oxoG present in the human genome, thus indicating that the fluorescent dots represent chromosomal regions with a high density of steady-state 8-oxoG. Minor differences between the sites identified by the anti-8-oxoG antibody and those found to be MutM sensitive may reflect the fact that MutM recognizes formamidepyrimidine derivatives as well as 8-oxoG (Boiteux et al. 1987
Genome-wide distribution of 8-oxoG in the human genome
An averaged 8-oxoG score per megabase in a given region of each chromosome except for the Y chromosome was calculated and its distribution was mapped on a connected physical map of chromosomes 1–22 and X (Supplemental Fig. 2a). The distribution of chromosomal regions with a high density of 8-oxoG across the entire genome was statistically compared among four subjects. The Kruskal-Wallis test revealed that there was no significant difference among the four subjects (P = 0.54, Supplemental Fig. 2a), and moreover, there was a strong correlation between any pair of the four subjects (coefficient >0.7, P < 0.0001, Spearman’s rank correlation test, Supplemental Fig. 2b). These analyses revealed that the genome-wide distribution of 8-oxoG, in terms of its chromosomal region and frequency, was highly similar among the four individuals, suggesting that 8-oxoG at steady state is generally distributed in distinct regions of human chromosomes. Thus, results from the four subjects were combined to obtain a comprehensive map of chromosomal regions with a high density of 8-oxoG (Fig. 3). These high-density regions were distributed throughout the genome, and at least a single region was mapped on each arm of all chromosomes. The high densities of 8-oxoG were found in regions corresponding to GC-rich R-bands and GC-very-rich T-bands or near boundaries between R and G bands more frequently than in those corresponding to AT-rich G-bands. The total 8-oxoG score per chromosome increased with increasing chromosomal length (Supplemental Table 1a). However, the 8-oxoG density in each chromosome (total 8-oxoG score per megabase) varied among the chromosomes, and the shorter chromosomes tended to exhibit a higher 8-oxoG density (Supplemental Table 1a). Chromosomes 18 and 19, whose sizes are very close to each other, exhibit a similar level of 8-oxoG density, regardless of the difference in their GC content; i.e., 40% in chromosome 18 and 48% in chromosome 19, suggesting that another factor(s) in addition to the GC content may have control over the distribution of 8-oxoG in the human genome.
8-oxoG and meiotic recombination rate in the human genome In recent years, it has been shown that each human chromosome has different features in terms of certain sequence parameters revealed by the human genome project (Venter et al. 2001 ). To determine the factors involved in the distinct distribution of 8-oxoG in human chromosomes, we first performed simple regression analyses considering the 8-oxoG density as the response and eight different genomic parameters as the predictor (Fig. 4; Table 1). The strongest correlation was found between the 8-oxoG density and the meiotic recombination rate (data from Kong et al. 2002) (coefficient = 0.79, R2 = 0.6, P < 0.0001, Table 1). We also noticed its significant positive correlation with GC content, CpG-island density, poly(A) or poly(T) fraction and gene density (coefficient = 0.53, 0.51, 0.45, 0.39, respectively, Table 1). Since it is well known that CpG-island density, the poly(A) or poly(T) fraction and gene density strongly correlate with the GC content, the GC content can be considered as one of the factors determining the distribution of 8-oxoG in the human genome. There is a significant negative correlation between the 8-oxoG density and chromosomal length as we noted above. On the other hand, the multiple regression analysis with the six predictors, which showed a significant correlation with the 8-oxoG density in simple regression analyses, indicated that only the recombination rate has a significant correlation with the 8-oxoG density (P = 0.0127, Table 1).
To further examine whether the intrachromosomal distribution of 8-oxoG has any correlation with that of recombination-prone sites, we compared locations of regions with a high density of 8-oxoG and regions with a high frequency of recombination on chromosome 11. As shown in Figure 5A, most of the recombination peaks were located within regions with a high density of 8-oxoG. Statistical analysis revealed that regions with the high 8-oxoG density exhibited a significantly higher recombination rate in comparison with regions lacking this high density (Fig. 5B). The same results were obtained from a genome-wide analysis using data from all autosomes (Supplemental Table 2).
8-oxoG and SNPs in the human genome Since some of the base substitutions that occurred in the human genome in the past are preserved as SNPs in the current population, we hypothesized that regions with a high density of 8-oxoG may be colocalized with a high density of SNPs. To evaluate our hypothesis, we compared both the distributions and frequencies across the entire genome. From the SNP database at NCBI (build 33), we selected SNPs with only two reported differences in bases at the same position (A/G, C/T, G/T, A/C, C/G, A/T), and frequencies of the six types of substitutions were calculated. The chromosomal position and frequency of each type of substitution were expressed on an ideogram as bar plots (Fig. 5C for chromosome 11, Supplemental Fig. 3 for all autosomes). All types of substitutions were distributed throughout the genome, and their frequencies varied from place to place. All chromosomes possess multiple regions with a significantly higher frequency of each base substitution spectrum compared with surrounding regions. In general, regions with a high density of 8-oxoG tend to exhibit a higher frequency of SNPs (Supplemental Fig. 3). Statistical analyses clearly showed that the frequencies of all substitutions except the A/T substitution were significantly higher in regions with a high density of 8-oxoG in chromosome 11 than in the regions without this high density (Fig. 5D). The same results were obtained from genome-wide analysis using data from all autosomes (Supplemental Table 3). We also performed the same analysis against the SNP data set obtained from shotgun sequencing, and the results were similar (Supplemental Table 4).
In the present study, we detected and mapped positions of 8-oxoG in human chromosomes by means of in situ immunodetection to clarify its genome-wide distribution. The chromosomal distribution of 8-oxoG, detected as clusters of several residues at steady state, is uneven in the total genome of a single human cell in terms of position and frequency, while there are many common regions with a high density of 8-oxoG in the human genome, even in cells of different individuals. Chromosomal regions with a high density of 8-oxoG contain peaks of recombination, as do those with a high density of SNPs.
To elucidate the underlying cause for genomic diversity in humans, it is essential to determine why 8-oxoG preferentially locates within distinct regions of the human genome. In the in situ immunodetection, MutM, which excises 8-oxoG opposite cytosine, largely abolished the immune signals for 8-oxoG, thus suggesting that most 8-oxoG present in the normal human genome is a product of oxidation of a G:C pair. Our results clearly indicate that the GC content or GC content-related factors are one of the determinants for 8-oxoG density in autosomes. However, we are still speculating as to whether there is another factor(s) that more strongly influences the local 8-oxoG density. The steady-state level of 8-oxoG in the normal human genome reflects its generation and repair; thus, in regions with a high density of 8-oxoG, the generation of this lesion exceeds its removal by repair. The results of in situ detection of 8-oxoG indicate that the genome may not be a homogeneous target for oxidation and repair. It has been pointed out that various factors contribute to the outcome of oxidative damage to DNA (Beckman and Ames 1997 We showed that chromosomal regions associated with peaks in meiotic recombination are preferentially located within regions with a high density of 8-oxoG. In the present study, we compared the chromosomal distribution of 8-oxoG observed in somatic lymphocytes with that of meiotic recombination, which occurs in meiotic germ cells. In meiotic cells in mouse testis as well as in cultured human cell lines, we observed a similar number of chromosomal regions with a high density of 8-oxoG (M. Ohno and Y. Nakabeppu, unpubl.). Thus, we may assume that there should be the same chromosomal distribution of 8-oxoG in germ cells as observed in somatic lymphocytes.
One can argue that there must be another factor that coincidentally increases the recombination rate in addition to the accumulation of 8-oxoG in a particular region of chromosome, implying that there is no causality between the two events, and we do not have any data at present to deny this possibility. On the contrary, it is also possible that there is causality between the two events. However, we can eliminate the possibility that meiotic recombination itself causes an increased accumulation of 8-oxoG within the recombinogenic site, because we detected 8-oxoG accumulation in the long arms of both X chromosomes in females, which undergoes meiotic recombination only during oogenesis, as well as in the long arm of the Y chromosome which has no counterpart for homologous recombination (see Supplemental Fig. 1) (Burgoyne 1982
As in other eukaryotes, meiotically programmed double-strand breaks by the enzyme SPO11, a member of the type II-like topoisomerase family of proteins, are essential for initiating meiotic recombination in the mouse (Romanienko and Camerini-Otero 2000
Areas with a higher density of SNPs are predominantly distributed within regions with a high density of 8-oxoG, suggesting that 8-oxoG may contribute to the generation of SNPs because of its mutagenic potential. SNPs are unevenly distributed across the human genome; however, the cause(s) of these base substitutions and the factor(s) determining their distribution are still largely unknown. The transition from C:G to T:A, for example, is believed to be largely induced by deamination of 5-methylcytosine at the CpG sequence, but this accounts for only part of the substitution (Venter et al. 2001
Blood samples and cell culture Peripheral blood samples were obtained from healthy adult volunteers (four unrelated Japanese, two males and two females). We obtained informed consent from all volunteers. Lymphocytes were cultured in RPMI1640 (Gibco-BRL) medium supplemented with 10% FBS, antibiotics and PHA-M (Sigma) for 72 h under normal conditions according to a standard cytogenetic method (Barch 1991 ).
HPLC–MS/MS analysis of 8-oxoG
In situ immunodetection of 8-oxoG
MutM-dependent in situ end-labeling assay
Image analysis
Chromosomal mapping of 8-oxoG
Calculation of the recombination rate and SNP frequency
We are grateful to Drs. Toshimichi Ikemura and Kenshi Hayashi for valuable discussions. We thank N. Adachi for HPLC MS/MS analysis and A. Matsuyama and S. Kitamura for technical support. We also acknowledge laboratory coworkers for their involvement in many discussions. This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant nos. 16012248 and 17014070), and the Japan Society for the Promotion of Science (grant no. 16390119).
4 Corresponding author.
E-mail yusaku{at}bioreg.kyushu-u.ac.jp; fax +81-92-642-6791. [Supplemental material is available online at www.genome.org.] Article is online at http://www.genome.org/cgi/doi/10.1101/gr.4769606
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Received October 6, 2005; accepted in revised format March 9, 2006.  CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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ABSTRACT
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. J. Biol. Chem. 274: 15920–15926.