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

Abstract

Influenza A virus (IAV) is a major public health problem and a pandemic threat. Its evolution is largely driven by diversifying positive selection so that relative fitness of different amino acid variants changes with time due to changes in herd immunity or genomic context, and novel amino acid variants attain fitness advantage. Here, we hypothesize that diversifying selection also has another manifestation: the fitness associated with a particular amino acid variant should decline with time since its origin, as the herd immunity adapts to it. By tracing the evolution of antigenic sites at IAV surface proteins, we show that an amino acid variant becomes progressively more likely to become replaced by another variant with time since its origin—a phenomenon we call “senescence.” Senescence is particularly pronounced at experimentally validated antigenic sites, implying that it is largely driven by host immunity. By contrast, at internal sites, existing variants become more favorable with time, probably due to arising contingent mutations at other epistatically interacting sites. Our findings reveal a previously undescribed facet of adaptive evolution and suggest approaches for prediction of evolutionary dynamics of pathogens.

The ups and downs of amino acid co-evolution: evolutionary Stokes and anti-Stokes shifts

“…Changes in amino acid propensities are not directly observable in natural proteins. However, Popova et al (2019) recently put forward that sustained increases (or decreases) in propensities may produce a detectable signal in natural protein alignments by causing a change in the rate of amino acid replacement. They suggest that the propensity of an amino acid is inversely related to its rate of replacement: if the propensity for the resident amino acid is high, then the rate of replacement should be low, and vice versa.…”

“…Risso et al (2014) found empirical evidence of evolutionary Stokes shifts in the evolution of thioredoxins and β-lactamases; however, those shifts in propensities were minor. Interestingly, Popova et al (2019) recently observed the opposite trend where the fitness of the resident amino acids decreased with time -they termed this phenomenon "senescence". Popova et al (2019) contend that the decrease in preferences must be the result of adaptive protein evolution, and that, unlike the evolutionary Stokes shifts, mere epistatic constraints "cannot lead to a systematic reduction in fitness of the incumbent alleles".…”

“…Interestingly, Popova et al (2019) recently observed the opposite trend where the fitness of the resident amino acids decreased with time -they termed this phenomenon "senescence". Popova et al (2019) contend that the decrease in preferences must be the result of adaptive protein evolution, and that, unlike the evolutionary Stokes shifts, mere epistatic constraints "cannot lead to a systematic reduction in fitness of the incumbent alleles". Do resident amino acid preferences tend to increase, decrease, or remain relatively conserved throughout a protein's evolution?…”

Senescence and entrenchment in evolution of amino acid sites

“…We have previously revealed the acceleration of substitutions over the course of allele lifetime in the evolution of influenza A virus 41 . This pattern has been mainly observed at sites associated with avoidance of the host immune system pressure, and we interpreted it as evidence for negative frequency-dependent selection actively disfavoring the current allele 41 . Here, we show that this type of selection is not a prerequisite for senescence.…”

“…1e,f) . We term this process senescence 41 . This effect is more pronounced for the rugged landscape, when one allele is highly more beneficial than the others (Fig.…”