Adaptive tracking theory of molecular evolution challenges mutation neutrality

For a long time, evolutionary biologists thought that the genetic mutations that determine the evolution of genes and proteins are largely neutral: they are neither good nor bad, but just ordinary enough to go unnoticed in the breeding notice.

Now a study from the University of Michigan has overturned that theory.

During the process of evolution, mutations occur which can then become fixed, meaning that every individual in the population carries that mutation. A long-standing theory, called the Neutral Theory of Molecular Evolution, posits that most fixed genetic mutations are neutral.

Bad mutations will be quickly eliminated by selection, according to the theory, which also assumes that good mutations are so rare that most fixations will be neutral, explains evolutionary biologist Jianzhi Zhang.

The UM study, led by Zhang, aimed to test whether this was true. The researchers found that there were so many good mutations that the neutral theory could not hold. At the same time, they found that the rate of fixations is too low for the large number of beneficial mutations Zhang’s team observed.

Mutations, adaptation and changing environments

To solve this problem, researchers suggest that mutations that are beneficial in one environment can become harmful in another environment. These beneficial mutations may not become fixed due to frequent environmental changes. The study was published in Nature ecology and evolution.

“We say the outcome was neutral, but the process was not neutral,” said Zhang, a professor of ecology and evolutionary biology at UM. “Our model suggests that natural populations are not truly adapted to their environment, because the environment changes very quickly and populations are always chasing the environment.”

Zhang says their new theory, called Adaptive Tracking with Antagonistic Pleiotropy, tells us something about how all living things are adapted to their environments.

“I think this has broad implications. For example, humans. Our environment has changed so much, and our genes may not be the best for today’s environment because we’ve gone through a lot of other different environments. Some mutations may be beneficial in our ancient environments, but don’t match today’s,” Zhang said.

“At any time you look at a natural population, depending on when the last significant change in the environment occurred, the population may be very poorly adapted or relatively well adapted. But we will probably never see a population fully adapted to its environment, because complete adaptation would take longer than almost any natural environment can remain constant.”

Historical context and research methods

The neutral theory of molecular evolution was first proposed in the 1960s. Previously, scientists studied evolution based on the morphology and physiology, or appearance, of organisms. But from the 1960s, scientists were able to begin to sequence proteins, then genes. This prompted researchers to examine evolution at the molecular level.

To measure beneficial mutation rates, Zhang and his colleagues studied large datasets of deep mutational analysis produced by his lab and others. In this type of analysis, scientists create numerous mutations on a specific gene or region of the genome in model organisms such as yeast and E. coli.

The researchers then followed the organism over several generations, comparing them to the wild type, or most common version existing in nature, of the organisms. This allowed the researchers to measure their growth and compare their growth rate to that of the wild type, which is how they estimated the effect of the mutation.

They found that more than 1% of mutations are beneficial, orders of magnitude higher than neutral theory allows. This number of beneficial mutations would lead to more than 99% of fixations being beneficial and a rate of gene evolution much higher than that observed in nature. The researchers realized they had made a mistake in assuming that an organism’s environment remained constant.

Experimental results on environmental changes

To study the impacts of a changing environment, Zhang’s research team compared two groups of yeast. One group evolved in a constant environment for 800 generations (each generation lasted three hours), while the second group evolved in a changing environment, in this case consisting of 10 different types of media, or solutions, in which the yeast grew.

The second group of yeasts grew in the first medium for 80 generations, in the second medium for another 80 generations, and so on, for a total of 800 generations as well.

The researchers found that there were far fewer beneficial mutations in the second group than in the first. Although beneficial mutations occurred, they did not have a chance to become established before the environment changed.

“This is where the inconsistency comes from. Although we observe a lot of beneficial mutations in a given environment, these beneficial mutations have no chance of being corrected because as their frequency increases to a certain level, the environment changes,” Zhang said. “These beneficial mutations in the old environment could become deleterious in the new environment.”

Limitations and future research directions

However, Zhang says there is a caveat: the data used comes from yeast and E. coli, two single-celled organisms in which it is relatively easy to measure the effects of mutations on fitness. Further mutational analysis data collected from multicellular organisms would indicate whether results from single-celled organisms apply to multicellular organisms such as humans.

Next, the researchers plan a study to understand why it takes organisms so long to fully adapt to a constant environment.

Other authors of the study include Siliang Song and Xukang Shen, former UM graduate students, and Piaopiao Chen, a former UM postdoctoral researcher.