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Reappraising the role of damaged DNA

by Rowan Hooper

Outside of comic books, when you are exposed to radiation, your DNA is damaged and you get ill. Sometimes very ill: just witness the terrible effects of the radiation released in the Chernobyl nuclear disaster 20 years ago.

But if only life were like it is in the comics! Spiderman got his powers when bitten by an irradiated spider. The supernatural powers of the X-Men are a result of environmental genetic changes. Bruce Banner’s green alter-ego, the Incredible Hulk, bursts into life after he is exposed to gamma radiation.

In reality, changes to our DNA — mutations — occur randomly in our genome and only rarely have a beneficial effect. This is why natural selection proceeds gradually. Only those rare mutations with beneficial effects, say on our muscle strength or ability to speak, will produce something that natural selection can work on. Most mutations have an effect that is neutral with respect to evolution.

The recognition that most of the differences in the genomes of different individuals are neutral is one of the greatest contributions a Japanese scientist has made to evolutionary theory. Nearly 40 years ago, in 1968, Motoo Kimura introduced the neutral theory of evolution. The neutral theory posits that most of the differences in the genetic code between me and you, for example, don’t exert much influence on how we look or how our bodies work.

Kimura’s theory provoked much discussion, and argument, but is now generally accepted to be compatible with natural selection.

And now from Japan there comes another provocative theory.

Yusaku Nakabeppu and colleagues from Kyushu University have produced evidence suggesting that environmentally damaged DNA may contribute to human genetic diversity. It’s not quite the same as saying that the mutations of the X-Men are plausible, but it is the first time that environmental mutations have been found to be non-random, and, possibly, able to exert a widespread beneficial effect.

Human DNA is constantly barraged by a variety of environmental agents, including UV light and chemicals, as well as by reactive oxygen species (ROS), which are produced as byproducts of normal metabolic reactions or as molecular agents of host defense. These agents may cause the chemical bases in DNA — the building blocks of DNA — to spontaneously undergo a chemical transformation known as oxidation.

Nakabeppu and his team looked at the DNA base guanine, which gets oxidized into a form called 8-oxoguanine (8-oxoG). The sites in which 8-oxoG occurs were found to be evolutionary “hot spots”; sites where recombination happens with greater frequency. Recombination is the result of DNA sequences being “shuffled” when eggs are produced in females and sperm in males.

“Recombination increases the chance of shuffling the genome sequence between the mother and father,” Nakabeppu told The Japan Times.

When DNA is copied in a cell containing 8-oxoG instead of guanine, the oxidized form pairs with the wrong base pair. Normally, guanine pairs with cytocine, but the oxidized form pairs with thymine. The result is a permanent nucleobase change in the DNA sequence.

You would expect the aberrant 8-oxoG form to be randomly distributed throughout the genome, but Nakabeppu has demonstrated otherwise. His team looked at human chromosomes where the 8-oxoG was fluorescently labeled and found that it was concentrated in areas where recombination is highest. Furthermore, the distribution and intensity of 8-oxoG was remarkably similar in different individuals.

“8-oxoG is unevenly distributed in the normal human genome and the distribution pattern is conserved among different individuals,” says Nakabeppu. “We suggest that 8-oxoG accumulation in a particular region of a chromosome causes recombination.”

This is a big deal. Sunlight causes oxidation. Chemicals in the environment to which we are exposed everyday cause oxidation.

“Our theory is supported by studies showing that enzymes involved in the repair of oxidative DNA damage can also induce recombination,” Nakabeppu says.

The team also suggest that recombination rates in women are higher than in men, because eggs are bigger than sperm and are exposed to oxidative stress for longer periods of time. One amazing conclusion is that women are more important in driving evolution than are men.

But why the special clustering of 8-oxoG in the genome? That is still unknown. “One can certainly argue that there must be another factor that coincidentally increases the recombination rate,” says Nakabeppu. “Further analysis is required to fully understand the mechanistic relationship between 8-oxoG, recombination, and mutagenesis.”

Nakabeppu’s work, published in the journal Genome Research, is another example from Japan of a surprising and enriching way of looking at evolution. The X-Men are unlikely to take over the world anytime soon. But we might have to reappraise how the environment drives evolutionary change.