Mutational Robustness in the Flu Virus: Manifestation of Low Level Fitness Effects at the Population Level

Abstract

Influenza, commonly referred to as the flu, is a common and important source of morbidity and mortality worldwide. The annual resurgence and success of influenza depends upon its rapid and continual evolution. Antigenic variation, evolution of the sites on the virus recognized by the immune system, results from rapid mutations due to low RNA polymerase fidelity and lack of proofreading mechanisms. These mutations cannot always be tolerated. Mutational robustness is the balance between beneficial mutations, that generate genetic variation while preserving the phenotype, and tolerating detrimental mutations. In the lab, decreased fitness from the redirection of virus evolutionary trajectories towards a point-nonsense mutation has been observed, but it is unknown whether these fitness effects are also salient in natural populations resulting in avoidance of 1-to-Stop codons, codons that are one point mutation away from a Stop codon, which is often detrimental for the virus. This project, based on a novel analysis, examines the impact of flu mutational robustness based on level of selection for novelty. It crosses scales by examining the manifestation of low level fitness effects at the population level. While there is only a secondary fitness effect from a 1-to-Stop codon in any particular influenza virus protein, at a population level, a reduction in the overall usage proportion of 1-to-Stops would theoretically result in fewer deleterious Stop mutations, and a consequently more successful virus. The proportion of 1-to-Stop codons being overrepresented in the HA protein of the human influenza virus for glycine and arginine but lack of significance in representation of serine and leucine is contrary to what would be expected from the in 6 vitro findings of Moratorio et al. (2017). Overrepresentation of 1-to-Stop codons for NA and NP proteins hints at the positive selection pressure from immune system evasion. However, overrepresentation in the PB2 proteins indicates an unknown mechanism promoting 1-to-Stops. The risk of cross-species recombinant strains of influenza, such as between human hosts and swine or avian hosts, is particularly dangerous as virus evolution occurs before being transmitted resulting in the receiving species having none of the appropriate antibodies. Climatic changes are resulting in altered disease dynamics. Increasing attention towards sustainable farming practices, including free range livestock, could also increase risk of transmission between domestic and wild animals (Dumont et al. 2013). Thus, the similarity of constraints in the animal reservoir of influenza is also interesting.