Dee Denver: Shaking up mutation

© Lincoln Barbour PHOTOGRAPHY

Though it's been decades since he was a kid turning over rocks in St. Joseph, Missouri, Dee Denver, now assistant professor in the zoology department at Oregon State University, still enjoys looking at nematodes. "It's beautiful," he says, watching through a microscope in his laboratory as a tiny worm makes sinusoidal tracks through a plate of Escherichia coli. It's no coincidence that the animals that intrigue him have also allowed him to make dogma-shaking observations in evolutionary biology.

As an undergraduate at the University of Missouri, Columbia, Denver realized he could combine two of his interests - his childhood fascination with invertebrates and research he did in a cancer lab on mutation. In 1997, at the start of graduate school, Denver moved west to pick up a project in Kelley Thomas's lab at the University of Missouri, Kansas City, that colleagues had been working on for a few years: developing generation upon generation of mutation accumulation lines in Caenorhabditis elegans.

Denver looked at the nematode mutation rate in the absence of natural selection, and "I started getting a feeling that what was there in the textbooks was off," he says. Previous estimates in other animals set the mitochondrial mutation rate at 0.02 to 0.2 mutations per site per million years. But after allowing mutations to accumulate in his worms for 200 generations, Denver sequenced the mitochondrial DNA and found the mutation rate to be 14.3 mutations per site per million years - 100 times greater than former estimates. ¹

The finding raised a few eyebrows, but didn't capture as much attention as did his work as a postdoc in Mike Lynch's lab at Indiana University, where Denver started in 2002. There, Denver and his colleagues continued his mutation-accumulation experiments, this time allowing them to run 450 generations, and examined segments of the nuclear genome. He found that the mutation rate was 2.1 x 10-8 mutations per site per generation - 10 times larger than textbook estimates of C. elegans mutation. ²

"Those were all fundamental achievements in the field," says Thomas, now at the University of New Hampshire. But the findings were met with skepticism. When Denver's study was featured on National Public Radio, Jan Drake from the National Institute of Environmental Health Sciences questioned whether the results would stand up to years of evidence that has suggested a slower mutation rate. Still, Denver "handled it remarkably well," Thomas says, likely because he was prepared. "He's very thoughtful. He criticizes [his data] himself."

Denver began at Oregon State in 2006, and his present work includes collecting natural populations to compare to his mutation accumulation lines. He now plans to take advantage of the school's genome analyzer to observe mutation accumulations in whole C. elegans genomes, and capture large events such as big duplications and transposon movement. "I still don't think I have the right mutation rate," Denver says. "I still think it's underestimated."