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Genomic Techniques Shed New Light on Encephalitis Epidemic

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As an evolutionary biologist studying malaria, Susan Perkins didn't expect to find herself knee-deep in flaviviruses. But by pairing phylogenetic and molecular evolutionary analyses combined with large-scale sequencing techniques to study one in particular — the St. Louis encephalitis virus — she and her colleagues were able to make  an unexpected discovery about its past, and the route it took to get from there to here.

Working off a Department of Defense grant, Perkins' group at the Sackler Institute for Comparative Genomics at the American Museum of Natural History in New York wanted to "pair genomics and geography" to look at how geographical proximity and recombination work hand in hand. It's been assumed that in many cases, recombination is what creates mutant viral strains, which can then confer increased pathogenicity to these genetic invaders. Perkins chose the St. Louis encephalitis virus, which got its name from the first epidemic in St. Louis in 1933, mostly because it hadn't been studied that much. Previous literature showed that there was a recombination event between two strains of St. Louis encephalitis within the envelope protein gene, and Perkins figured that finding others would be likely. Thanks to whole genome sequencing, her hypothesis turned out to be wrong.

After sequencing the first 20 of an expected 200 strains from international virus repositories, they realized that in the original published sequence, the recombination breakpoint began at a primer. "It became obvious that there had just been a lab error in the initial study," Perkins says. "We didn't have the recombination story anymore; and in fact, there was no recombination between any of those strains along the entire genome."

What they did find, however, was that the virus showed a lot of negative selection, and very little positive selection. "I was surprised at how conserved some of these viral genomes were. Out of all the proteins that the virus has, there was just one codon that seems to be experiencing positive selection, and that is in the envelope protein gene," she says. "We say that with a grain of salt, of course, because all of these are of lab strains and so it's always possible that's what being positively selected is its ability to grow in cell culture, not something that's directly disease-related."

Further analysis gave Perkins a sense of the mutation rate, which, using new methods, allowed her to estimate the demographics of the viral populations in North America. The pattern she found showed that the virus did experience an expansion in the late 1800s, which correlates well with migratory birds delivering it from South America at about the same time.

Perkins says that this study is a good example of "bringing pure genomics into the realm of comparative genomics," which is where her research at the museum sits. The methods her team used, phylogenetics and molecular evolution techniques, have only recently begun to be applied to the study of viral pathogens and other diseases. Perkins says she will continue her work on malaria, while her colleagues at Sackler are using phylogenetics to examine other pathogens, including human papillomavirus and elephant tuberculosis.

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