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CAMBRIDGE, England, April 16 -- Seasonal influenza starts in east and southeast Asia and follows a highly predictable path to infect the rest of the world, researchers here said.

The finding solves a long-standing mystery of where seasonal flu viruses originate and how they migrate throughout the world, according to Colin Russell, Ph.D., of Cambridge University, and colleagues.

The flu arrives in Europe and North America six to nine months after the viruses infect Asia, and finally ends its travels in South America after another six to nine months, the researchers reported in the April 18 issue of Science.

Dr. Russell said in a telephone press conference that flu viruses die out after they cause an epidemic -- mainly because their human targets have acquired immunity -- but are continually being replaced by new ones evolving in what he called a "circulating network" in east and southeast Asia.

Every year, one or two strains emerge, cause seasonal epidemics throughout the world, enter the "evolutionary graveyard" of South America, and disappear after causing one last burst of disease, he said.

The Science finding arises from a study of the hemagglutinin gene of more than 13,000 influenza A H3N2 isolates from 2002 through 2007, Dr. Russell and colleagues said.

A separate study, in the April 17 issue of Nature, also suggests that seasonal flu strains arise from a central source and eventually peter out in a "sink."

That study, by Edward Holmes, Ph.D., of Pennsylvania State University, and colleagues, hypothesizes that the source for the viruses is in the tropics, but does not pin the location down.

The studies are "beautifully complementary," said Derek Smith, Ph.D., also of Cambridge University, who was senior author of the Science study. Among other things, both show clearly that flu viruses do not persist in any region, but are constantly being replaced by new ones.

One implication of the two studies, he said, is that stronger surveillance collaborations in east and southeast Asia may be able to do a better job of predicting what flu viruses will escape the region and cause disease elsewhere.

That, in turn, may improve selection of strains for the annual vaccine, he said.

"Knowing how the virus migrates around the world is one big step" toward improving the annual vaccines, he said.

Dr. Russell painted a picture of east and southeast Asia as cauldron of competing influenza strains. In tropical and semi-tropical areas, he said, the flu season is the rainy season, but in east and southeast Asia, rainy seasons may be different even in places that are geographically close.

For instance, Dr. Russell said, Bangkok and Kuala Lumpur are only 700 miles apart, but have rainy seasons -- and flu epidemics -- at different times of the year.

In the region as a whole, the result is a series of flu epidemics that overlap in time, with different strains causing disease in different places. When that's combined with easy air travel within the region, the result is a quickly evolving group of influenza strains, he said.

On the other hand, "once viruses leave east and southeast Asia, they rarely return," he said. That's because a virus carried back into the region, after infecting a resident of North America, for instance, faces a population that has already developed immunity.

In the Science study, the researchers developed a family tree of H3N2 viruses based on the antigenic properties of the hemagglutinin protein. They then used a technique dubbed "antigenic cartography" to create a two-dimensional plot of how the virus changed over time.

They were then able to plot that data on a world map and show that the viruses began in east and southeast Asia before "seeding" the rest of the world.

The data show that the ancestors of strains in temperate regions typically

originate in east and southeast Asia, with the "trunk" of the phylogenetic tree typically made up of strains from that region.

On average, strains from east and southeast Asia are significantly closer to the trunk of the tree (at P<0.001) than are strains from other regions.

The analysis rules out several other hypotheses about how the flu evolves, Dr. Russell said.

For instance, if China were the source, as one theory proposes, strains from that country would tend to be closer to the trunk of the viral family tree, but they aren't.

Similar considerations rule out the idea that the flu viruses ping-pong back and forth between the north and south temperate zones, Dr. Russell and colleagues said.

The study also rules out the idea that flu strains persist in some regions and then are resurrected later. "Our study suggests that influenza viruses don't circulate continuously in any country," Dr. Russell said. "Rather, they go extinct."

The Nature study reached similar conclusions through an analysis of the entire genome of 1,302 H3N2 and H1N1 influenza A strains.

"We propose the existence of a continuous reservoir or source population" of flu strains, Dr. Holmes and colleagues said, adding that the evolution of influenza is "shaped by a complex interplay" among factors such as rapid mutation, frequent reassortment, natural selection, and global epidemiology.

The Science study was supported by the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Netherlands Influenza Vaccine Research Centre, the Australian Department of Health and Aging and the United Kingdom Medical Research Council. The researchers did not report any conflicts. The Nature study was supported by the NIH, the National Institute of Allergy and Infectious Diseases, the National Institute of General Medical Sciences and the Royal Society of London. The researchers did not report any conflicts.

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