ANN ARBOR — A University of Michigan study challenges the Neutral Theory of Molecular Evolution by demonstrating that more than 1% of amino acid-changing mutations are beneficial, though most fail to become fixed in populations due to environmental change. The research, led by Jianzhi Zhang, professor of ecology and evolutionary biology, offers a new explanation for why many molecular changes appear neutral despite the prevalence of beneficial mutations.

The Neutral Theory of Molecular Evolution, first proposed in the 1960s, holds that most fixed genetic changes at the molecular level are neutral—neither beneficial nor harmful—because natural selection removes deleterious mutations and beneficial ones are exceedingly rare. The University of Michigan team used large deep mutational scanning datasets from their own lab and others to analyze mutations in model organisms such as yeast and E. coli. In deep mutational scanning, scientists generate numerous mutations in a gene or genomic region and measure their effects on organismal fitness.

Researchers tracked organisms over many generations, comparing them with wild-type strains by measuring growth rates to determine whether mutations were beneficial, harmful, or neutral. They calculated that if more than 1% of amino acid-changing mutations are beneficial, then over 99% of amino acid substitutions should be adaptive—an observation at odds with Neutral Theory. However, their experiments revealed that environmental instability prevents most beneficial mutations from reaching fixation.

In one key experiment, Zhang’s team compared two groups of yeast over 800 generations—approximately 2,400 hours—where one group evolved in a stable environment and the other cycled through 10 different growth media, spending 80 generations in each. The group exposed to shifting conditions showed far fewer fixed beneficial mutations than the stable-environment group. "We're saying that the outcome was neutral, but the process was not neutral," Zhang said.

"Our model suggests that natural populations are not truly adapted to their environments because environments change very quickly, and populations are always chasing the environment," he said. The team calls their framework "Adaptive Tracking with Antagonistic Pleiotropy," emphasizing that populations continuously adapt to shifting conditions while many mutations carry environment-dependent tradeoffs.

The study does not dispute that fixed molecular changes often appear neutral but argues that beneficial mutations are abundant yet transient. Mutations beneficial in one setting may become deleterious in another, preventing long-term fixation.