The mutation spectrum shapes the spectrum of adaptive substitutions
Alejandro Cano, Hana Rozhonova, Arlin Stoltzfus, David McCandlish, Joshua Payne
Evolutionary adaptation can be conceived as a series of substitutions representing mutation-fixation events. The changes that are more likely will appear more frequently in the aggregate spectrum of adaptive substitutions. Recent studies establish that this spectrum reflects specific mutation biases. Yet, little is known about the generality of this effect, and its dependence on mutation supply, demographics, or other conditions. Here we address how the mutation spectrum shapes the spectrum of adaptive amino acid substitutions using a general approach combining three large data sets, a regression method covering the spectrum of nucleotide substitution mutations, and computer simulations to explore the influence of different regimes of population genetics. The data sets include thousands of amino acid changes identified in natural and experimental adaptation in Saccharomyces cerevisiae, E. coli, and M. tuberculosis. By applying negative binomial regression to a codon-based model of these data, we find that the mutation spectrum has a strong and roughly proportional influence on the spectrum of adaptive substitutions: in each of the three data sets, the regression coefficient is close to and not significantly different from 1 (proportional effect), but is significantly different from 0 (no effect). The mutation spectra determined by actual mutation-accumulation experiments provide better model fits than the vast majority of randomly generated mutation spectra, demonstrating their relevance outside of the controlled laboratory conditions in which they were measured. Simulations and empirical results suggest the importance of the breadth of the mutational target: when mutation supply is not high, the mutation spectrum has a roughly proportional influence on the spectrum of adaptive substitutions, but the significance of this influence depends on whether the biological basis of adaptation implicates a narrow or broad set of mutational paths to higher fitness.