Evolution of influenza A Rachel Albert Craig Bland Evolution of influenza A

Influenza A Responsible for 20,000 American deaths annually. Genome consists of 8 RNA strands that code for 11 proteins including coat proteins. Divided into 16 Hemagglutinin (H1-H16) and 9 neuraminidase (N1-N9) subtypes (H1N1). H1 & H3 infect humans Hemagglutinin has five antigenic sites that allow for the host’s immune system to recognize, attack, and remember.

Why has Influenza been such an effective virus? Lack enzymes that check for replication errors. Antigenic drift has strong influence. Positive selection- more nonsilent mutations than silent. Host immune system forces virus to evolve.

Arthur Chun-Chieh Shih et al Wanted to determine the rate at which the flu evolves and how it evolves. Frequency Switch- replacement of one major amino acid by another between successive years. Effective Switch- when new amino acid becomes fixed in a population for 1 year. Total Switches:130 Effective Switches:95 57 out of the 95 occurred at known antigenic epitopes. Including 8 that are also receptor binding sites.

Effective switches. 130 switches and the sites at which they occurred. Shih A C et al. PNAS 2007;104: ©2007 by National Academy of Sciences

Transition Time

Walter Fitch and Colleagues Hypothesized that flu strains with novel antigenic sites would have a selective advantage. Examined frozen hemagglutinin genes over a 20 year span. Two patterns emerged :  Nucleotide Substitutions at 6.7 X per nucleotide per year  Most of the frozen flu strains were extinct by the 1980’s

Why did some lineages survive while others perished? Nucleotide substitutions resulting in amino acid replacements in hemagglutinin’s antigenic sites rather then nonantigenic sites In antigenic sites In nonantigenic sites Surviving Lineages 3310 Extinct Lineages3135

Robin M. Bush and colleagues (1999) Wanted to understand influenza evolution. Hypothesized the neutral theory of molecular evolution  1) mutations that alter amino acid replacements are deleterious  2) silent mutations may become fixed in population. Looked at 331 nucleotide substitiutions 58% were silent 42% replacement. Results consistent with neutral theory.

However, some areas did not fit neutral theory. Found that 18 codons had nonrandom mutations (hypervariable regions) These codons had 9 silent, and 123 nonsilent substitutions. All of the 18 codons determined which amino acid would be present in a HA antigenic site. Determined that host immune system forces strong selection on HA genes.

Predicting the Evolution of Influenza (Bush et al. 1999) Wanted to develop a method to predict future viral strains of Influenza. Identified a small set of 18 rapidly evolving codons (5.7 X ) which improves viruses fitness. They found a significant overlap between the positively selected codons and the codons in or near antibody binding sites. Their methods can be used to monitor the viruses currently in the population to help identify positively selected codons which may have a predictive value for determining future progeny.

Why important? Understanding flu evolution allows us to better predict vaccines. /

Future Research More Research performed to better predict Influenza A virus Investigate the use of chicken eggs and its effect on deadly Avain flu virus showing up in human populations.

Works Cited Bush, Robin M.,Catherine A. Bender, Kanta Subbarao, Nancy J. Cox, Walter M. Fitch. “Predicting the Evolution of Human Influenza A.”Science 286 (1999): Bush, Robin M., and Walter M. Fitch. "Positive Selection on the H3 Hemagglutinin Gene of Human Influenza." Molecular Biology and Evolution (1999): Freeman, Scott, and Jon C. Herron. Evolutionary Analysis. Upper Saddle River, NJ: Pearson Prentice Hall, Shih, A. C.-C., T.-C. Hsiao, M.-S. Ho, and W.-H. Li. "Simultaneous Amino Acid Substitutions at Antigenic Sites Drive Influenza A Hemagglutinin Evolution." Proceedings of the National Academy of Sciences (2007):