Adaptive tracking with antagonistic pleiotropy results in seemingly neutral molecular evolution

The neutral theory of molecular evolution, positing that most amino acid substitutions in protein evolution are neutral, is supported by vast comparative genomic data. However, here we report that the key premise of the theory—beneficial mutations are extremely scarce—is violated. Deep mutational scanning data from 12,267 amino acid-altering mutations in 24 prokaryotic and eukaryotic genes reveal that >1% of these mutations are beneficial, predicting that >99% of amino acid substitutions would be adaptive. This observation demands a new theory that is compatible with both the high beneficial mutation rate and the comparative genomic data considered consistent with the neutral theory. We propose such a theory named adaptive tracking with antagonistic pleiotropy. In this theory, virtually all beneficial mutations observed are environment-specific. Frequent environmental changes and mutational antagonistic pleiotropy across environments render most of the beneficial mutations seen at one time deleterious soon after and hence rarely fixed. Consequently, despite the occurrence of adaptive tracking—continuous adaptation to a changing environment fueled by beneficial mutations, neutral substitutions prevail. We show that this theory is supported by population genetics simulation, empirical observations, and experimental evolution, and has implications for the adaptedness of natural populations as well as the tempo and mode of evolution.