In the Robert Frost poem “The Road Not Taken,” a traveler recalls a time when his forest path forked and wonders where he would have ended up had he chosen the other path. Some viruses encounter analogous evolutionary divergence points, and they may not all take linear paths to inevitable outcomes.
For instance, a novel avian influenza A (H7N9) virus has emerged in China.1 Because all known pandemic and other human, mammalian, and poultry influenza A viruses have descended from wild-bird viruses, it seems logical that any avian influenza A virus that becomes pandemic must have serially acquired signature mutations known to be associated with circulation in humans. It would follow that mutations distinguishing “avian-like” from “human-like” viruses must be milestones on a fixed evolutionary pathway to potential pandemicity, including mutations affecting the hemagglutinin (HA) receptor–binding domain associated with efficient binding to human epithelial cells, polymerase mutations associated with efficient replication in human cells, and others. The fact that H7N9 isolates have some of these mutations1 has led to predictions of its evolution toward pandemicity….
