Adaptive tracking with antagonistic pleiotropy generates seemingly neutral molecular evolution

Whether the evolution of genes and proteins is largely neutral or adaptive is a fundamental question. Although comparative genomic data generally conform to predictions of the neutral theory, we here show from deep mutational scanning data that the proportion of beneficial mutations far exceeds what the neutral theory permits. We propose that mutational antagonistic pleiotropy across temporally varying environments render the bulk of beneficial mutations seen at one time harmful soon after, hindering their fixation. Consequently, despite the occurrence of adaptive tracking fueled by advantageous mutations, neutral substitutions prevail. This model reconciles the prevalence of advantageous mutations with patterns of neutral evolution, is supported by population genetics simulations, empirical observations, and laboratory evolution experiments, and has broad implications for the tempo and mode of evolution.