Coordinated Evolution of Influenza A Surface Proteins

Abstract

The surface proteins hemagglutinin (HA) and neuraminidase (NA) of human influenza A virus evolve under selection pressures to escape adaptive immune responses and antiviral drug treatments. In addition to these external selection pressures, some mutations in HA are known to affect the adaptive landscape of NA, and vice versa, because these two proteins are physiologically interlinked. However, the extent to which evolution of one protein affects the evolution of the other one is unknown. Here we develop a novel phylogenetic method for detecting the signatures of such genetic interactions between mutations in different genes -that is, inter-gene epistasis. Using this method, we show that influenza surface proteins evolve in a coordinated way, with mutations in HA affecting subsequent spread of mutations in NA and vice versa, at many sites. Of particular interest is our finding that the oseltamivir-resistance mutations in NA in subtype H1N1 were likely facilitated by prior mutations in HA. Our results illustrate that the adaptive landscape of a viral protein is remarkably sensitive to its genomic context and, more generally, that the evolution of any single protein must be understood within the context of the entire evolving genome. Author SummaryThe fitness of an organism depends on the coordinated function of many genes. Thus, how a mutation in one gene affects fitness often depends on what mutations are present in other genes. This dependence is called "genetic interaction" or "epistasis". The prevalence and type of such interactions are not well understood. Epistasis can be inferred from timeseries sequencing data when a mutation in one gene is observed to facilitate the spread of a mutation in another gene. However, the situation is much more complicated when new combinations of genes are formed by processes such as recombination or reassortment. In such cases, deducing the time and order of genetic changes is difficult. Here, we devise a method to infer pairs of mutations in different genes which closely follow one another in the presence of reassortment. We apply it to evolution of two surface proteins of influenza A virus, hemagglutinin and neuraminidase, which are important targets for the human immune system and drugs. We show that mutations in one of these proteins are often facilitated by prior mutations, or compensated by subsequent mutations, in the other protein. In particular, drug-resistance mutations in neuraminidase were likely made possible by prior mutation in hemagglutinin. Knowledge of such interactions is necessary to fully understand and predict evolution.

Deconvolving mutational patterns of poliovirus outbreaks reveals its intrinsic fitness landscape

“…These non-antigenic mutations seemingly hitchhike with the antigenic mutation that potentially escapes population immunity and facilitates an outbreak in a particular region. This is reminiscent of the evolution of influenza virus 61,62 , in which multiple neutral or deleterious mutations linked to an antigenic mutation, which enables escape from population immunity, have been observed to proceed to fixation collectively.…”

Allele-specific nonstationarity in evolution of influenza A virus surface proteins

“…First, it may be caused by direct antigenic selection, which is supported by enrichment of NA epitopes with senescence; second, it may be promoted by changes in HA, which in turn, are driven by antigenic selection. Indeed, changes in NA can compensate for HA affinity fluctuations (13,35). Apart from being antigenic, sites 339, 331, and 253 of NA, each of which harbors a senescing allele, are also known to affect NA specificity or activity (35)(36)(37).…”

“…The 2 surface proteins of influenza A virus (IAV), hemagglutinin (HA) and neuraminidase (NA), are textbook examples of adaptive evolution. They experience elevated rates of nonsynonymous substitutions evident of positive selection (8)(9)(10), and which substitutions spread is affected by epistatic interactions between sites (11)(12)(13). However, whether and how the fitness of a variant changes during the time between when it is gained and lost are unknown.…”

Mutation landscape of SARS-CoV-2 reveals five mutually exclusive clusters of leading and trailing single nucleotide substitutions

“…Leading and trailing mutations have been previously described in virus genomes (41,42). We define leading mutations as mutations that are documented in SARS-CoV-2 at an earlier time point and their presence is a pre-requisite for the origination of trailing mutations.…”