Abstract
Fitness conferred by the same allele may differ between genotypes and environments, and these differences shape variation and evolution. Changes in amino acid propensities at protein sites over the course of evolution have been inferred from sequence alignments statistically, but the existing methods are data-intensive and aggregate multiple sites. Here, we develop an approach to detect individual amino acids that confer different fitness in different groups of species from combined sequence and phylogenetic data. Using the fact that the probability of a substitution to an amino acid depends on its fitness, our method looks for amino acids such that substitutions to them occur more frequently in one group of lineages than in another. We validate our method using simulated evolution of a protein site under different scenarios and show that it has high specificity for a wide range of assumptions regarding the underlying changes in selection, while its sensitivity differs between scenarios. We apply our method to the env gene of two HIV-1 subtypes, A and B, and to the HA gene of two influenza A subtypes, H1 and H3, and show that the inferred fitness changes are consistent with the fitness differences observed in deep mutational scanning experiments. We find that changes in relative fitness of different amino acid variants within a site do not always trigger episodes of positive selection and therefore may not result in an overall increase in the frequency of substitutions, but can still be detected from changes in relative frequencies of different substitutions.
Highlights
A particular amino acid at a specific position of a protein may confer different fitness in different species
In surface proteins of HIV-1 and influenza A, we find that changes in preferences detected with d-test match those observed in deep mutational scanning experiments
This can be observed as clustering of homoplasies in these groups of species, and such clustering has been interpreted as evidence for changes in fitness landscapes
Summary
A particular amino acid at a specific position of a protein may confer different fitness in different species. Such changes in amino acid propensities can occur due to substitutions at other epistatically interacting sites in the course of evolution. It has been shown to bias the phylogenetic distribution of homoplasies–repeated substitutions giving rise to the same allele: parallelisms, convergences [16,17,18,19,20] and reversals [21,22] This is because the fixation probability of a mutation, and the rate of a substitution, giving rise to an allele increases with its conferred fitness [23]. Most existing methods [16,17,18,19,20,21,22] aggregate data across multiple sites to increase power, and do not allow to track changes in amino acid propensities at individual sites
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