Rosa Rubicondior: How Science Works - Not Abandonning Evolution

A new theory of molecular evolution | University of Michigan News

A new paper in Nature Ecology & Evolution by a research team at the University of Michigan, led by evolutionary biologist, Professor Jianzhi Zhang, comprehensively, but incidentally, refutes several common creationist claims — such as that mainstream biologists are abandoning evolution because it supposedly cannot explain the evidence, that all mutations are harmful, so cannot underpin evolution, and that scientists are prevented from publishing findings that challenge orthodoxy.

The study examines a key assumption of the Neutral Theory of Molecular Evolution — namely that most amino-acid substitutions are neutral (neither beneficial nor strongly deleterious) and fix by drift rather than selection. The authors report experimental data showing that in mutational-scanning assays of over 12,000 amino-acid-altering mutations across 24 genes, >1 % of mutations were beneficial, implying a far higher beneficial-mutation rate than is conventionally assumed.

To reconcile that finding with the fact that comparative genomic data appear consistent with many substitutions being neutral, Zhang’s team propose a new model — “adaptive tracking with antagonistic pleiotropy” — in which beneficial mutations are frequently environment-specific, and when the environment changes the same mutation may become deleterious, hence failing to fix. In this way, although beneficial mutations are common, they rarely reach fixation when environments shift, and substitution patterns can appear neutral.

The paper operates fully within the framework of evolutionary theory by natural selection: it does not challenge evolution itself, but refines a subsidiary theoretical model about molecular changes. Thus, it strengthens the broader evolutionary paradigm rather than undermines it.

Average time to fixation of a mutation under different environments. To keep things simple, assume a standard Wright–Fisher population with effective size \(\small(N_e)\), diploid, with a single new copy of the allele arising in one generation.

Neutral mutation in a neutral environment
A new neutral mutation starts at frequency
\[(p_0 = 1/(2N_e)).\]
Two classic results:

Probability that a neutral mutation eventually fixes: \[(P_{\text{fix, neutral}} = p_0 = 1/(2N_e)).\]
Expected time to fixation given that it does fix (diffusion approximation): \[(\bar T_{\text{fix, neutral}} \approx 4N_e)\ \text{generations}.\]

So, for a neutral mutation that happens to win the drift lottery, the typical time-scale to drift to fixation is of order \(\small(4N_e)\) generations.
Mutation that is beneficial half the time and deleterious half the time
Now suppose the same mutation experiences:

selection coefficient (+s) in environment A,
selection coefficient (-s) in environment B,
with the population spending 50% of generations in each environment.

On average, the selection coefficient is zero:

\[(\bar s = \tfrac12(+s) + \tfrac12(-s) = 0),\]
so in a first approximation the allele is time-averaged neutral. However, it is not truly neutral – it is sometimes favoured and sometimes disfavoured. That fluctuation in selection has two important consequences:

The probability of fixation is typically lower than for a strictly neutral mutation, because periods in the “bad” environment (–s) tend to undo gains made in the “good” environment (+s).
The distribution of times to absorption (loss or fixation) is broader, and the mean time to fixation, conditional on fixation, is generally longer and more variable than the simple \(\small(4N_e)\) rule.

Crucially, there is no neat closed-form equivalent to \(\small(\bar T_{\text{fix}} \approx 4N_e)\) in this fluctuating case: the mean time to fixation depends on:

the population size \(\small(N_e)\),
the magnitude of (s), and
how fast the environment flips between A and B.

In practice, one usually estimates the fixation probability and mean fixation time in such a ±s, 50/50 scenario either by:

solving the diffusion (backward Kolmogorov) equations for allele frequency with a stochastic selection term, or
simulating a Wright–Fisher (or Moran) population in which the environment changes over time and recording how long successful mutations take to fix.

This is exactly the sort of situation considered in the Zhang et al. paper: a mutation that is advantageous in one environment but disadvantageous in another may arise fairly often, yet fail to become fixed because the population spends much of its time in the “wrong” environment.

A summary of the research is available in a University of Michigan News article.

A new theory of molecular evolution
For a long time, evolutionary biologists have thought that the genetic mutations that drive the evolution of genes and proteins are largely neutral: they’re neither good nor bad, but just ordinary enough to slip through the notice of selection.

Now, a University of Michigan study has flipped that theory on its head.
In the process of evolution, mutations occur which can then become fixed, meaning that every individual in the population carries that mutation. A longstanding theory, called the Neutral Theory of Molecular Evolution, posits that most genetic mutations that are fixed are neutral. Bad mutations will be quickly discarded by selection, according to the theory, which also assumes that good mutations are so rare that most fixations will be neutral, says evolutionary biologist Jianzhi Zhang.

The U-M study, led by Zhang, aimed to examine whether this was true. The researchers found that so many good mutations occurred that the Neutral Theory cannot hold. At the same time, they found that the rate of fixations is too low for the large number of beneficial mutations that Zhang’s team observed.

To resolve this, the researchers suggest that mutations that are beneficial in one environment may become harmful in another environment. These beneficial mutations may not become fixed because of frequent environmental changes. The study, supported by the U.S. National Institutes of Health, was published in Nature Ecology and Evolution.

We’re saying that the outcome was neutral, but the process was not neutral. 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.

Professor Jianzhi Zhang, corresponding author Department of Ecology and Evolutionary Biology
University of Michigan
Ann Arbor, MI, USA.

Zhang says their new theory, called Adaptive Tracking with Antagonistic Pleiotropy, tells us something about how well 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 went through a lot of other different environments. Some mutations may be beneficial in our old environments, but are mismatched to today.

At any time when you observe a natural population, depending on when the last time the environment had a big change, the population may be very poorly adapted or it may be relatively well adapted. But we’re probably never going to see any population that is fully adapted to its environment, because a full adaptation would take longer than almost any natural environment can remain constant.

Professor Jianzhi Zhang.

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 starting in the 1960s, scientists were able to start sequencing proteins, and later, genes. This prompted researchers to look at evolution at the molecular level.

To measure beneficial mutation rates, Zhang and colleagues investigated large deep mutational scanning datasets produced by his and other labs. In this kind of scanning, the scientists created many 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 many generations, comparing them against the wild type, or the most common version existing in nature, of the organisms. This allowed the researchers to measure their growth and compare their growth rate to 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 greater than what the Neutral Theory allows. This amount of beneficial mutations would lead to more than 99% of fixations being beneficial and a rate of gene evolution that is much higher than the rate that is observed in nature. The researchers realized they had made a mistake in assuming an organism’s environment remained constant.

To investigate 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 3 hours), while the second group evolved in a changing environment, in this case composed of 10 different kinds of media, or solution, that the yeast grew in. The second yeast group grew in the first media for 80 generations, in the second media 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 compared to the first. Although the beneficial mutations occurred, they didn’t have a chance to become fixed before the environment shifted.

This is where the inconsistency comes from. While we observe a lot of beneficial mutations in a given environment, those beneficial mutations do not have a chance to be fixed because as their frequency increases to a certain level, the environment changes. Those beneficial mutations in the old environment might become deleterious in the new environment.

Professor Jianzhi Zhang.

However, Zhang says there is a caveat: The data they used came from yeast and E. coli, two unicellular organisms in which it’s relatively easy to measure the fitness effects of mutations. Deep mutational scanning data collected from multicellular organisms would tell whether their findings from unicellular organisms apply to multicellular organisms such as humans. Next, the researchers are planning a study to understand why it takes so long for organisms to fully adapt to a constant environment.

Other authors of the study include former U-M graduate students Siliang Song and Xukang Shen and former U-M postdoctoral researcher Piaopiao Chen.

Publication:
Song, S., Chen, P., Shen, X. et al.
Adaptive tracking with antagonistic pleiotropy results in seemingly neutral molecular evolution.
Nat Ecol Evol (2025). https://doi.org/10.1038/s41559-025-02887-1

Abstract
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 fuelled 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 and the tempo and mode of evolution.

Song, S., Chen, P., Shen, X. et al.
Adaptive tracking with antagonistic pleiotropy results in seemingly neutral molecular evolution.
Nat Ecol Evol (2025). https://doi.org/10.1038/s41559-025-02887-1

© 2025 Springer Nature Ltd.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.

Apart from the obvious point that the researchers show absolutely no sign of finding the Theory of Evolution unfit for purpose—let alone turning to creationism, as creationist leaders have been assuring their followers is just about to happen - for more than half a century — there are other less obvious aspects of this paper that should give creationists pause.

First, the study highlights the close relationship between the environment and whether a mutation is beneficial, deleterious or truly neutral. These terms describe how well an organism survives and reproduces under particular conditions: change the environment, and exactly the same mutation can have an entirely different effect. This is precisely what Darwin proposed.

As with all good science, the need for slight adjustment doesn't invalidate the entire science, it strengthens it. The Theory of Evolution is strengthened rather than weakened by refinements like this that improve our understanding of the details. Minor adjustments to subsidiary theories help clarify the details of how evolution works; they do not threaten the foundations of the overarching theory on which modern biology depends, and they do nothing to justify the creationist tactic of falsely presenting the dichotomy of their superstition as the only alternative choice to that of an allegedly 'failed' scientific theory, without providing the slightest scrap of testable evidence.

As Thomas Henry Huxley is reputed to have exclaimed on reading Darwin’s Origin of Species for the first time: “How stupid not to have thought of it oneself!” Nearly 170 years later, how much more foolish it is to cling to a fairy tale that explains nothing, makes no testable predictions and is unfalsifiable because it relies on magic, essentially because it happens to be the belief you were raised with, when the Theory of Evolution provides a coherent, predictive and experimentally supported account of the living world.

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