Even great mutations need a little help from their friends

Researchers have discovered that, in the influenza virus, being the most beneficial mutation is no guarantee of long-term genetic success.
Positive selection over time of a single mutation affects the entire gene.

Wellcome Trust Sanger Institute scientists have used computer modelling to understand why some mutations in a virus gene rise to dominance and become 'fixed' in the genome of the virus, while others die out. Their findings were based upon real-world observations of the evolution of a human flu virus, using genome sequences collected over many years by researchers worldwide.

The team studied mutations in the haemagglutinin gene of the human influenza virus A/H3N2, which latches the virus on to human cells during an infection. Using a computer model, the team identified three key factors that determine the long-term survival of a mutation.

The three factors are -  the benefit the mutation confers to the virus; the background of other mutations that were present in the gene when the mutation appeared; and the effect of subsequent competition from different versions of the same gene in sibling viruses. To test the influence of each of these factors, they applied their model to the changes seen in the haemagglutinin gene between 1996 and the present day.

"We are keen to understand how evolutionary selection within the flu virus works over time and around the world," says Dr Chris Illingworth, first author of the study, from the Sanger Institute. "In some ways, the flu virus is very simple. When a person catches flu, their cells become incubators for the virus. Within each cell, the virus produces copies of itself. However, the evolution of the virus is not so simple. The copying process is highly error-prone, so that the new viruses often contain mutations. New mutations can either help or hinder the virus from spreading. But having the best mutation doesn't guarantee evolutionary success.

"Previous approaches to studying viral evolution have often thought about mutations one at a time, in isolation from each other. But at any one time, a large number of mutations exist. Viruses with different sets of mutations compete against each other, and the combined effect of all of the mutations must be taken into account."