Spontaneous oxidative DNA damage appears to induce genetic changes, fueling human diversity
By Melissa Lee Phillips | May 2, 2006
Spontaneous oxidative DNA damage may drive much of human genomic diversity by inducing single nucleotide polymorphisms (SNPs) and meiotic recombination, according to a new study in Genome Research. These findings reveal a mechanism by which environmental insults and oxidative metabolism may cause genetic mutations.
The authors found that an oxidized form of the DNA base guanine called 8-oxoguanine (8-oxoG) was distributed unevenly across the genome, and regions dense in 8-oxoG showed abnormally high levels of recombination and SNPs. The paper does not provide absolute proof that 8-oxoG promotes SNPs or recombination, but "it's a very reasonable speculation," said John Drake of the National Institute of Environmental Health Sciences, who did not participate in the research. "They back up their speculations with reasonable bits of evidence."
Levels of DNA damage and polymorphism vary considerably across different regions of the human genome, but very little is known about what makes a region prone to damage, senior author Yusaku Nakabeppu of Kyushu University in Japan told The Scientist in an Email. One major cause of DNA damage is oxidation by reactive oxygen species, which result from both oxidative metabolism and from exposure to ionization radiation and other environmental insults.
Oxidation of DNA or nucleotides generates 8-oxoG, which allows guanine to pair aberrantly with adenine, causing a GC to TA transversion mutation. Many species have enzymes that prevent this type of mutation by hydrolyzing 8-oxoG, or by excising it or the adenine that pairs with it.
To determine where 8-oxoG is found in the human genome, the researchers -- led by Mizuki Ohno, also of Kyushu University -- stained metaphase chromsomes from human lymphocytes with an antibody to 8-oxoG. They saw concentrated regions of fluorescence, corresponding to regions dense in 8-oxoG -- which was something of a surprise. "We rather expected random distribution" of 8-oxoG, Nakabeppu said.
The researchers found very similar 8-oxoG patterns across the chromosomes of four different individuals, suggesting that 8-oxoG is consistently found in the same distinct chromosomal regions. And when they pooled together the results from all four people, they found that regions dense in 8-oxoG largely matched regions unusually prone to meiotic recombination and to SNPs.
Oxidated guanine's known mutagenic action could produce SNPs, according to Nakabeppu, and several studies have shown "that the repair process of certain DNA damage actually induces homologous recombination," he said. "We can strongly suggest that 8-oxoG accumulated in a particular region of a chromosome causes meiotic recombination." If 8-oxoG does cause both SNPs and recombination, it could explain a previously seen correlation between genomic regions with high levels of SNPs and those prone to meiotic recombination, Nakabeppu said.
A causal connection between 8-oxoG and recombination or SNPs, however, is "still in the realm of speculation," said Sankar Mitra of the University of Texas Medical Branch. "This is a correlative conclusion. There's no direct proof."
Also, 8-oxoG is just one type of DNA damage resulting from oxidative stress, Mitra said, and others have been linked to recombination as well. According to Nakabeppu, more than 50 types of oxidized bases have been identified so far. "I think there are more oxidized or damaged bases which contribute to either SNP or recombination in humans," he said.
Why exactly 8-oxoG accumulates in specific regions is still something of a mystery, Nakabeppu said. As expected, he and his co-workers found that GC-rich regions were high in 8-oxoG -- but this may not entirely explain why 8-oxoG accumulates where it does. Evidence from other studies has suggested that "factors like chromatin structure or transcription status affect 8-oxoG density in different genomic regions," he said.
Melissa Lee Phillips
Links within this article
M. Ohno et al., "A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome," Genome Research, May 1, 2006.
M.B. Kastan, "DNA damage responses: Cancer and beyond," The Scientist, October 10, 2005.
E.J. Spek et al., "Nitric oxide-induced homologous recombination in Escherichia coli is promoted by DNA glycosylases," Journal of Bacteriology, July 2002.
M.J. Lercher, L.D. Hurst, "Human SNP variability and mutation rate are higher in regions of high recombination," Trends in Genetics, July 2002.