Mutation bias interacts with composition bias to influence adaptive evolution

Author summary Mutation is often depicted as a random process due its unpredictable nature. However, such randomness does not imply uniformly distributed outcomes, because some DNA sequence changes happen more frequently than others. Such mutation bias can be an orienting factor in adaptive evolution, influencing the mutational trajectories populations follow toward higher-fitness genotypes. Because these trajectories are typically just a small subset of all possible mutational trajectories, they can exhibit composition bias-an enrichment of a particular kind of DNA sequence change, such as transition or transversion mutations. Here, we use empirical data from eukaryotic transcriptional regulation to study how mutation bias and composition bias interact to influence adaptive evolution. Mutation is a biased stochastic process, with some types of mutations occurring more frequently than others. Previous work has used synthetic genotype-phenotype landscapes to study how such mutation bias affects adaptive evolution. Here, we consider 746 empirical genotype-phenotype landscapes, each of which describes the binding affinity of target DNA sequences to a transcription factor, to study the influence of mutation bias on adaptive evolution of increased binding affinity. By using empirical genotype-phenotype landscapes, we need to make only few assumptions about landscape topography and about the DNA sequences that each landscape contains. The latter is particularly important because the set of sequences that a landscape contains determines the types of mutations that can occur along a mutational path to an adaptive peak. That is, landscapes can exhibit a composition bias-a statistical enrichment of a particular type of mutation relative to a null expectation, throughout an entire landscape or along particular mutational paths-that is independent of any bias in the mutation process. Our results reveal the way in which composition bias interacts with biases in the mutation process under different population genetic conditions, and how such interaction impacts fundamental properties of adaptive evolution, such as its predictability, as well as the evolution of genetic diversity and mutational robustness.