Phylogeny inference, or tree building, is used to deduce the history of entities related by common descent, whether they're genes, populations, or species. Ultimately, it can reveal the evolutionary relationships between these entities, even if we don't have access to the intermediate steps.

But it's a method that has to be used cautiously. "Erroneous conclusions can show strong statistical support," warns a new paper, published in Nature. Andrew Rambaut's lab, which wrote the paper, issued that warning because phylogenetic studies can have serious practical implications: "This is a serious problem given that such results are widely used to infer when, where, and how pandemic and panzootic viruses have emerged."

The "pandemic and panzootic" virus in question is the influenza A strain that swept the globe in 1918, killing millions. The new analysis by Rambaut's lab suggests that previous work on the 1918 flu was fundamentally flawed.

The problem is that viral genes mutate at different rates depending on which host species the virus is infecting. Researchers know that different species, and even different genes within a species, mutate at different rates; hence, during phylogenic analysis they usually use a "relaxed clock model" that allows for the mutation rate to vary over time and between organisms.

Rambaut himself used this relaxed clock in a 2006 paper he titled (probably without irony) "Relaxed Phylogenetics and Dating with Confidence." But this new paper says that an older one of his "very seriously underestimates the time to the most recent common ancestor," probably because the older one only looked at human flu viruses.

The flu viruses they have now examined anew include equine, porcine, avian, and human strains. This most recent phylogenomic analysis, using a new host-specific local clock, indicates that their most recent common ancestor dates very recently—to the latter half of the nineteenth century.

That's when avian influenza viruses underwent a global selective sweep, a process in which DNA sequences tag along with a beneficial mutation that's under positive selection. Even though these nearby sequences confer no benefit themselves, they become more prominent in a population, along with the gene that is actually useful.

The net result of a selective sweep is reduced genetic diversity as the beneficial mutation spreads through the population, dragging nearby genetic sequences along with it. The authors speculate that one of the most dramatic recorded outbreaks of flu in animals, the equine influenza of 1872 and 1873, may have somehow precipitated the sweep. During this period, the same genes spread into related viruses in other species—the virus was panzootic—including all of those that tend to make the jump to humans.

The new analysis suggests that this set the stage for the 1918 flu, which they conclude arose in North America and originated in birds. The prevailing hypothesis—that it came from a reassortment of human and swine viruses—"arises erroneously from a failure to accommodate differences in [mutation] rates between hosts."

The HA and NA genes, which encode proteins on the virus' surface, are more diverse than the genes for the proteins that are encapsulated inside the virus. This had always been attributed to a higher rate of evolution, as the virus hangs on to mutations that let it escape immune attack. But Rambaut now thinks that it may be a vestige of the ancestral diversity that existed in all avian strains before the global selective sweep of the late 1800s.

Human flu viruses undergo selective sweeps that serve to replace their genomic diversity every few years. In 1918, it took only months for the new deadly variant to replace existing strains. The authors are still not sure what drove the global selective sweep that they are suggesting occurred in avian viruses in the 1870s, but they note that figuring it out might be important in understanding the risks that bird flu might pose for us in the future.

PLoS Biology, 2014. DOI: 10.1371/journal.pbio.0040088 (About DOIs).

Nature, 2006. DOI: 10.1038/nature13016 (About DOIs).