For decades, many evolutionary biologists have observed that much of molecular evolution is surprisingly quiet. The idea was that many of the genetic changes that spread throughout a population were neither beneficial nor harmful. They just float around in nature without getting much attention from natural selection.
A University of Michigan study casts doubt on this situation. The study, led by evolutionary biologist Jiangji Zhang, suggests that useful mutations may be far more common than long-standing theory predicted. But there’s a catch. Many of these useful mutations may not last long enough to become permanent.
Major evolutionary theories face new challenges
Mutations occur by chance during the evolutionary process. Some disappear. Others spread until all members of the population possess them. This is a process known as colonization.
For more than half a century, one of the most influential ideas in molecular evolution has been the neutral theory of molecular evolution. First proposed in the 1960s, this theory asserts that most genetic changes fixed at the level of genes and proteins are neutral. In this view, most persistent molecular changes would be expected to be neutral, since deleterious mutations are usually removed by natural selection, but truly beneficial mutations are very rare.
Zhang and his colleagues set out to investigate the key assumptions behind the theory. Are there really so few beneficial mutations?
Their results suggest the answer may be no.
Useful mutations may be surprisingly common
The research team used large-scale deep mutation scanning datasets from their own lab and others to examine the effects of many mutations in model organisms such as yeast and E. coli. In deep mutation scans, scientists create many mutations in genes or regions of the genome and measure how those changes affect an organism.
The researchers tracked the organisms over many generations and compared them to the wild type, the version most commonly found in nature. By measuring growth, they could estimate whether mutations were helpful, harmful, or had little effect.
They found that more than 1% of the amino acid change mutations they examined were beneficial. That may sound small, but in evolutionary terms it’s huge. If so many mutations are helpful, the researchers calculated that more than 99% of amino acid substitutions should be adaptive. Genetic evolution should occur much faster than scientists actually observe in nature.
This discrepancy forced the researchers to reconsider one of their hypotheses. They concluded that the problem may be that the environment is not static.
Evolution follows a moving target
Mutations can be helpful in one environment and harmful in another. If the environment changes before a beneficial mutation can spread through the population, the mutation loses its advantage and may even become a disadvantage.
“We’re saying that the outcome was neutral, but the process was not,” said Zhang, a UM professor of ecology and evolutionary biology. “Our model suggests that natural populations are not truly adapted to the environment because the environment changes so rapidly and the population is constantly chasing the environment.”
The research team calls this framework adaptive tracking with antagonistic pleiotropy. In layman’s terms, this means that while many mutations have environment-dependent trade-offs, populations can always react to changes in the environment.
A mutation that increases fitness today can decrease fitness tomorrow. As a result, evolution can be filled with beneficial changes that never become permanent.
Yeast experiments that show what happens when conditions change
To test this idea, Zhang’s team compared two groups of yeast over 800 generations. One group evolved in a stable environment. The other evolved in a changing environment consisting of 10 different growth media.
The environmental change group repeated 80 generations on the first medium, then 80 generations on the next medium, and so on, completing 800 generations. (Each generation lasted 3 hours)
The researchers found that the groups exposed to changing conditions had far fewer beneficial mutations. Useful mutations still emerged, but often did not have enough time to spread through the population before the situation changed again.
“This is the source of the paradox. We observe many beneficial mutations in a particular environment, but those beneficial mutations do not have a chance to be corrected, because when their frequency increases to a certain level, the environment changes,” Zhang said. “Beneficial mutations in the old environment can be harmful in the new environment.”
Why perfect adaptation is impossible
The findings point to a more restless view of evolution. Populations may often become bogged down in pursuit of ever-changing conditions, rather than steadily progressing towards a perfect fit between organism and its environment.
Chan said the idea has far-reaching implications for living things, including humans.
“I think this has broad implications. Humans, for example. Our environment has changed a lot, but we’ve experienced many other different environments, so our genes may not be optimal for our current environment. Some mutations may be beneficial in older environments, but they’re mismatched today,” Zhang said.
He added that the degree of adaptation seen in any given population may depend on how recently its environment has changed.
“Whenever you look at a natural population, it may be very poorly adapted or relatively well adapted, depending on the last time there was a major change in the environment. But it takes longer to fully adapt than it would take for almost any natural environment to remain constant, so you’ll probably never see a population that is perfectly adapted to its environment.”
Big changes in how scientists study mutations
Neutral theory emerged at a turning point in biology. Before the 1960s, scientists often studied evolution by examining the shape, structure, and physical characteristics of living things. Once researchers began sequencing proteins and later genes, they were able to study evolution at the molecular level.
This change has revealed patterns that neutral theories better explain, such as why many genetic differences appear to accumulate steadily over time. The Michigan study does not erase that history. Instead, it offers a way to reconcile two seemingly contradictory observations.
On the other hand, when scientists compare genomes, many fixed molecular changes still appear neutral. On the other hand, experiments suggest that certain environments may be rich in beneficial mutations. Zhang’s team argues that both could be true, given that beneficial mutations are often temporary.
Recent research in evolutionary genetics continues to emphasize the importance of environmental change. A 2026 review on adaptation in rapidly changing situations highlighted how allele frequencies and trait changes are highly dependent on available genetic variation. Other yeast studies have also shown that adaptations can be shaped by environmental stress, and that mutations that are helpful in one environment can have costs in others.
Taken together, these findings strengthen a growing theme in evolutionary biology. The effects of mutations cannot always be understood in isolation. It can depend on the environment, the history of the organism, and the rate of change in conditions.
Points to note and next questions
Zhang pointed out an important limitation. Much of the data used in the study was based on yeast and Escherichia colia unicellular organism that facilitates measuring the fitness effects of mutations. More detailed mutation scan data from multicellular organisms will be needed to see if the same pattern holds true for animals, plants, and humans.
The researchers will also investigate why it takes so long for organisms to fully adapt, even when the environment remains constant.
The study was supported by the National Institutes of Health and published in the journal Nature Ecology and Evolution. Other authors include former UM graduate students Siliang Song and Xukang Shen, and former UM postdoctoral fellow Piaopiao Chen.
So far, this research shows surprising promise. Evolution may be more like chasing a world in motion than a steady climb towards perfection.
