Biased DNA Copying

Copying billions of base pairs every time a cell divides demands high fidelity. Now it appears that all DNA is not recreated equal--one strand of the helix is copied more reliably than the other, according to a report in the current Proceedings of the National Academy of Sciences. The researchers say this finding may indicate that cells use one strand to keep genes intact and the other to evolve new, potentially advantageous features.

Many biologists suspect that this copying bias may result from the way double-stranded DNA molecules are arranged; each strand has the same sequence of bases, but one is backwards. The enzyme that copies DNA, called polymerase, can move in only one direction along a strand, adding bases one by one as it goes. When the helix unzips, a polymerase molecule continuously slides down one strand (called the leading strand). But as the other strand (the lagging strand) splits away, the polymerase working this strand must move backwards--toward the free end--as it copies, then jump back to the split when it finishes each section. Some evolutionary biologists had suggested that if one strand was copied more faithfully, it would preserve genes, while extra mutations on the other strand might allow new and possibly advantageous features to spring up.

To explore the difference in copying accuracy, Roel Schaaper of the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, and colleagues at the Polish Academy of Sciences in Warsaw modified versions of the Escherichia coli bacteria's circular genome. They created a single-base mutation in a spot that mutates readily, then inserted this gene into each strand. They found that when the gene was on the leading strand, the polymerase gaffed the copying up to 6 times more often than when the gene was on the lagging strand. "It was very clear that the lagging strand was more accurate," Schaaper says.

The next task for Schaaper's team is to figure out the exact cause of the errors. One idea is that the lagging strand polymerase is quicker to stop copying and let go of the DNA when it makes a mistake, whereas the polymerase on the leading strand never needs to release its hold and so is more likely to push on through a mismatched spot.

"This is a particularly nice paper, because it's a simple assessment of the natural process of replication," says Richard Sinden, a molecular biologist at Texas A&M University in College Station. However, he adds, the difference between the strands may depend on which type of mutation you look at. Sinden says his group has done experiments that show the lagging strand can produce 50 times more deletion mutations than the leading strand.