The effects of genetic bottlenecks on mutation fixation and replicative capacity of the influenza A virus
Abstract
The influenza A virus is a common cause of respiratory illness in humans. Seasonal
epidemics of influenza in the United States can result in up to 40 million cases, with
annual hospitalizations and deaths reaching as high as 400,000 and 70,000, respectively.
The influenza A virus continually causes annual epidemics, despite yearly vaccines, as a
result of its high mutation rate, leading to genetically diverse viral populations within
hosts. Respiratory droplet-mediated transmission of the virus between individuals is
accompanied by a bottleneck event that decreases the diversity of the viral population
passed to new hosts. Using controlled artificial bottlenecks of different sizes during in
vitro serial passaging, the impact of these bottleneck events on patterns of mutation
fixation and replicative capacity of the influenza A virus was determined. Growth curves
and genome sequencing were used after passaging to characterize differences in
replicative capacity and identify genomic changes within the population. Serial passaging
at a bottleneck size of one virus generated virus populations with lower replicative
capacity as compared to the original parental virus. This effect was associated with
fixation of numerous mutations spread throughout the genome. An increase in replicative
capacity was evident after repeated bottlenecks of 1000 viruses, demonstrating that
sufficiently loose bottlenecks do not compromise viral replication kinetics and even allow
for improvement. This increase in replicative capacity was associated with several
mutations, clustered primarily in the hemagglutinin genome segment.
Subject
Microbiology
Avian Influenza Viruses
Mutation