Inference of population genetic parameters from an irregular time series of seasonal influenza virus sequences

Abstract

Basic summary statistics that quantify the population genetic structure of influenza virus are important for understanding and inferring the evolutionary and epidemiological processes. However, the sampling dates of global virus sequences in the last several decades are scattered non-uniformly throughout the calendar. Such temporal structure of samples and the small effective size of viral population hampers the use of conventional methods to calculate summary statistics. Here, we define statistics that overcome this problem by correcting for the sampling-time difference in quantifying a pairwise sequence difference. A simple linear regression method jointly estimates the mutation rate and the level of sequence polymorphism, thus providing an estimate of the effective population size. It also leads to the definition of Wright’s FST for arbitrary time-series data. Furthermore, as an alternative to Tajima’s D statistic or the site-frequency spectrum, a mismatch distribution corrected for sampling-time differences can be obtained and compared between actual and simulated data. Application of these methods to seasonal influenza A/H3N2 viruses sampled between 1980 and 2017 and sequences simulated under the model of recurrent positive selection with metapopulation dynamics allowed us to estimate the synonymous mutation rate and find parameter values for selection and demographic structure that fit the observation. We found that the mutation rates of HA and PB1 segments before 2007 were particularly high and that including recurrent positive selection in our model was essential for the genealogical structure of the HA segment. Methods developed here can be generally applied to population genetic inferences using serially-sampled genetic data.

Effects of host and pathogenicity on mutation rates in avian influenza A viruses

“… Comparison of the estimated mutation rates (synonymous substitution rates) of viruses infecting domestic duck, chicken, wild duck ( Anseriformes ), and shorebird ( Charadriiformes ). Mutation rate estimates from human H3N2 viruses ( Croze and Kim 2021 ) are shown for comparison. …”

“…Whether chickens and shorebirds have much smaller effective population sizes than ducks, compatible with their larger mutation rate estimates, needs to be investigated in the future. However, short external branches of phylogeny (coalescent tree, to be exact) observed in all avian hosts suggests that they all have small effective population sizes, as in the case of human H3N2 viral population ( Croze and Kim 2021 ), leaving very small room for difference in the effective population size leading to substitution rate difference.…”

“…at nonsynonymous sites on the same segment) ( Birky and Walsh 1988 ). For example, based on synonymous site substitutions only, the mutation rate of subtype H3N2 in humans was estimated to be about 0.005 per year per nucleotide site ( Croze and Kim 2021 ).…”