June 8, 2022 | David F. Coppedge

Mutations Are Not Neutral

It should be obvious that random mistakes cannot be good.
A new study confirms that intuition.



Does shooting at a computer make it run better? Let’s cut to the chase, and let the University of Michigan announce a rethink about mutations:

Most ‘silent’ genetic mutations are harmful, not neutral, a finding with broad implications (University of Michigan News, June 8, 2022). Neo-Darwinian theory relies on mutations to get from molecules to man. Before looking into the implications of the new study, let’s learn some terminology:

Occasionally, single-letter misspellings in the genetic code, known as point mutations, occur. Point mutations that alter the resulting protein sequences are called nonsynonymous mutations, while those that do not alter protein sequences are called silent or synonymous mutations.

Most mutations are harmful, evolutionists will admit, but once in awhile a beneficial mutation comes along that can lift a molecule on its way to personhood. Between the good and bad mutations is a vast field of “silent” or neutral mutations – ones that don’t change the protein, but lie in wait for their opportunity to contribute variations to the evolutionary Tinker Toy shop. Enough silent mutations, they think, might actually come together in serendipitous combinations to produce something novel. Such innovations are the feed stock of evolutionary progress. Everything from sponges to trilobites to dinosaurs and eagles came about this way—including us. So the story goes.

Sanford’s book examines the impact of near-neutral mutations that are invisible to selection.

Others, like former Cornell geneticist John Sanford, PhD, have argued that neutral mutations burden the genome. They accumulate like typos in a book. A book can still be read with some typos, but eventually, the book becomes unreadable. Over time, this “genetic entropy” drives populations toward extinction. It is a false hope, he says, to expect even neutral mutations to do anything good. Human beings, he said in his book Genetic Entropy, accumulate about 100 mutations per generation. Modern medicine can help overcome the effects of some genetic errors, but the inexorable process of mutational load cannot be stopped. It will drive Homo sapiens extinct, Sanford argues.

Now, scientists at the University of Michigan make Sanford’s prediction look overly optimistic!

Between one-quarter and one-third of point mutations in protein-coding DNA sequences are synonymous. Ever since the genetic code was cracked, those mutations have generally been assumed to be neutral, or nearly so.

But in a study published online June 8 in the journal Nature that involved the genetic manipulation of yeast cells in the laboratory, University of Michigan biologists show that most synonymous mutations are strongly harmful.

Did you catch that? Not just harmful. Strongly harmful.

The strong nonneutrality of most synonymous mutations—if found to be true for other genes and in other organisms—would have major implications for the study of human disease mechanisms, population and conservation biology, and evolutionary biology, according to the study authors.

My, what implications could it have for evolutionary biology? It’s not hard to figure that one out. Synonymous or silent mutations “have been generally thought to be benign,” says one author of the study in Nature, George Zhang. “We now show that this belief is false.” Zhang is not mincing words. Silent mutations are not benign. That belief is false.

Shen, Song, Li and Zhang: Synonymous mutations in representative yeast genes are mostly strongly non-neutral, Nature 8 June 2022.

In the paper, the authors describe how they calculated the effects of mutations. Using yeast, which grow and reproduce easily in the lab, “They used CRISPR/Cas9 genome editing to construct more than 8,000 mutant yeast strains, each carrying a synonymous, nonsynonymous or nonsense mutation in one of 21 genes the researchers targeted,” the press release explains.

Then they quantified the “fitness” of each mutant strain by measuring how quickly it reproduced relative to the nonmutant strain. Darwinian fitness, simply put, refers to the number of offspring an individual has. In this case, measuring the reproductive rates of the yeast strains showed whether the mutations were beneficial, harmful or neutral.

To their surprise, the researchers found that 75.9% of synonymous mutations were significantly deleterious, while 1.3% were significantly beneficial.

Mutations lead to genetic disease and ultimately to genomic meltdown. (Illustra Media)

(See commentary below for reaction to these criteria.) One thing they found is that synonymous mutations alter gene expression levels. Previous studies have shown that synonymous mutations can act as rheostats to fine-tune expression of genes. In that respect, synonymous mutations can serve a function. But all things being equal, if the initial yeast cells were healthy, the number of offspring produced by the mutant yeast strains gives a quick measure of health as a consequence of mutations.

Shocking Results

Were the four scientists expecting this result? They knew from other studies that so-called “neutral” mutations from synonymous codons could lean toward the dark side.

But we were shocked by the large number of such mutations,” he said. “Our results imply that synonymous mutations are nearly as important as nonsynonymous mutations in causing disease and call for strengthened effort in predicting and identifying pathogenic synonymous mutations.”

The press release never got back to discussing implications of this finding for evolutionary theory. The paper in Nature ignored that entirely. In the same issue of Nature, Nathaniel Sharp sent this headline: “Mutations matter even if proteins stay the same.”

Here’s one evolutionary implication of the study: it moves most “neutral” mutations from the “possibly helpful” column into the “deleterious” column. Darwin just lost a caboodle of dice in his quixotic game of chance.

As we have said often, measuring fitness by reproduction is a tautology (see “Fitness for Dummies,” 19 June 2014). Measuring how many yeast cells divide to determine which ones are “fit” can only give ambiguous results. If the initial stock normally divided at a particular rate, however, and the mutant strains all were slower to reproduce, that gives a first-order estimate that something has gone wrong in 75.9% of them.

The claim that 1.3% were “significantly beneficial” also needs scrutiny. More cell division is not necessarily better (e.g., cancer cells). The mutant offspring were all carrying a defect. It may have increased reproduction rate but caused harm in other ways. Evolutionists should not look to the 1.3% as feed stock for innovation and progress, therefore, without careful analysis of all the physiological consequences of the mutations.

Take-home message: Natural selection theory just took a big hit.

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