In my undergraduate evolution course my teacher gave me a paper by biologist Motoo Kimura, who is known for introducing the neutral theory of molecular evolution. I became his follower as he explained how “Junk DNA” could have more mutations than neo-Darwinism could explain. Kimura’s observations may have finally been explained, though in an unexpected way.
In June 2022, a team of University of Michigan biologists published an article called “Synonymous Mutations in Representative Yeast Genes Are Mostly Strongly Non-neutral.”1 The words “strongly non-neutral” suggest far more than what happens in yeast genes—they carry significant implications for a scientific paradigm.
In fact, the authors claimed that 60 years of neo-Darwinism, aka the modern synthesis, has been challenged by the discovery that most “silent” (synonymous) mutations were not neutral but harmful. I’ll explain why, but first I’ll provide some background on the genetic code of life.
Codons and Amino Acids
The discovery of the genetic code in 1961 allowed scientists to learn how information in DNA molecules is translated into proteins, which are the working parts of living cells. Scientists noted that DNA had four nucleotides that “code” for 20 amino acids that make up proteins. Three-letter DNA units called “codons” code each of the 20 amino acids. DNA has 64 codon combinations for 20 amino acids (see figure 1).
Figure 1: Amino Acid Codon Table
Credit: Wikimedia Commons
Why was this the case? Why a “redundant” 64 to 20 “code” and not simply a 20 to 20 ratio? Molecular biologist Francis Crick, the codiscoverer of the DNA helix, said it was simply a “frozen accident,” meaning that the genetic code was not designed for optimality but was functional and became frozen in place (with the redundant codons) as the mode of genetic inheritance.
Occasional errors in the genetic code, called point mutations, can be either “synonymous” or “nonsynonymous.” Synonymous mutations are “silent,” meaning that they don’t alter the protein sequences. Nonsynonymous mutations alter the protein sequences. The research team learned that redundant synonymous codons accommodate synonymous (the same) mutations with no change in amino acid production. They reasoned that “neutral” evolution protects organisms from too many mutations (hence, harm).
However, scientists now know that neo-Darwinian mutations and protein production do not adequately explain how organisms pass along fitness to survive. Other factors are involved in non-Darwinian adaptation.
If a mutation makes a nonsynonymous (not the same) codon, then a different protein is produced. This is how natural selection drives evolution. In support of this neo-Darwinian model, Crick proposed the central dogma of molecular biology, which is an explanation of the flow of genetic information within a biological system.
Figure 2: Central Dogma of Molecular Biochemistry
Credit: Wikipedia (author’s note included next to black arrows)
Does the Central Dogma Explain Genetics?
The central dogma proposes that the genetic flow of information is as follows: DNA makes RNA and RNA makes protein. The central dogma supports the nonsynonymous/synonymous neo-Darwinian model. It focuses on the “gene”-centric view of genetics with an oversimplification of the mechanisms at hand, mainly that the phenotype (protein) was entirely dependent on the DNA. On this view, we are reduced to our genes, and random favorable nonsynonymous mutations drive our destiny via natural selection.
The researchers measured the differences in protein production per the nonsynonymous/synonymous selective mechanism, and it seems to have verified their neo-Darwinian model. Yet, while true on one level, the central dogma does not account for numerous factors that the UM researchers (among others) discovered. The central dogma assumption of DNA transferring to protein doesn’t fully explain what happens in genetic mutations. Fitness and non-Darwinian adaptation have a role.
Other researchers have sequenced these mutations and derived simple formulas; for example, the Ka/Ks ratio of nonsynonymous to synonymous mutations, to calculate the strength of natural selection. Thousands of research efforts over the decades have used such methods that appear to support the notion that “natural selection did it,” meaning that natural selection randomly selected which mutations would be synonymous and which would be nonsynonymous.
However, many scientists, including me, doubted that so many favorable nonsynonymous mutations could perfectly line up over time. Simple probability worked against it.
About 20 years ago, many researchers noted that synonymous codons were not random. Instead, they were “biased” in their usage. What this means is that the genetic codes of different organisms are often biased toward using one (and not others) of the several codons that encode the same amino acid. This observation was different from evolution theory assumptions that focused on protein production.2 Now, this codon bias underpins fundamental research efforts in genetics, including the UM researchers’ findings.
So what changed over 60 years since the discovery of the genetic code and synonymous codons?
The metagenomic era began. Researchers developed inexpensive sequencing machines that resulted in massive DNA data for comparison. The codon bias was confirmed across all life. This confirmation promoted a race to discover why there are biased usages and to expand the question past the neo-Darwinian nonsynonymous/synonymous models, which yielded no firm answers to this question. In addition, strong computer models could measure not just protein output (per neo-Darwinism) but the “fitness effect” or non-Darwinian adaptation of these mutations on the organism.
It became evident that even though synonymous mutations produced the same protein, different synonymous codons via codon bias could change the organism’s fitness, as these biologists show in their yeast studies. These effects were seen not so much at the DNA level as the central dogma claimed, but at the RNA level. But this observation implies that there is another code outside of the central dogma and this code deflects attention from the “force” of natural selection. (I put “force” in quotes because many people treat natural selection as a force where it’s better qualified as a passive negative “filter.”)
It’s been discovered that there are numerous other steps between DNA and proteins affected by synonymous codons and that synonymous mutation can strongly affect them outside of the central dogma.
New Technique Shows High Rate of Harmful Mutations
At this point, scientists have ascertained that only measuring protein production by natural selection operating within with the central dogma and beneficial nonsynonymous mutations has left much to be discovered. Before this UM study, there had been several studies on synonymous mutations showing a range of adaptation effects, primarily deleterious.3
These UM biologists used a new tool. In 2000, the CRISPR/Cas9 system was developed. It allowed genetic engineering to achieve a level never contemplated. The team used it to induce mutations precisely to notice non-Darwinian fitness or adaptive effects, not just protein production.
They stated that one-quarter to one-third of protein-coding DNA sequence point mutations are synonymous. They quantified the fitness of each mutant strain by measuring how quickly it adaptively reproduced relative to the nonmutant fitness. Surprisingly, 76% of synonymous mutations were significantly deleterious (recall the words “strongly non-neutral” in the title), while only 1.3% were especially beneficial.
This high percentage of harmful mutations has significant implications for studying human disease mechanisms and evolutionary theory. If 76% of synonymous (silent) mutations are harmful to an organism, how have organisms survived?
The team concluded, “Since the genetic code was solved in the 1960s, synonymous mutations have generally been thought benign. We now show that this [neo-Darwinian] belief is false.”4
Since many biological conclusions rely on neutral synonymous mutations, their results have huge implications. They point out that synonymous mutations are generally ignored in the study of disease-causing mutations. This advance might require a rethink of genetics in medicine.
Does Evidence Point to Evolution or Design?
As important as this research is, was the biological team’s data met with accolades? No. After all, it stood to correct 60 years of evolutionary theory and possibly change genetics in medicine. Further, it explains new aspects of the “frozen” accident of the genetic code for the first time. Rather than a random accident, it appears that something else is responsible for freezing the genetic code in its universal form.
There’s been neo-Darwinian pushback. Biochemist Larry Moran claims, “the Nature paper failed to exercise the proper scrutiny of a report that contradicted many previous [neo-Darwinian] studies.”5
I would argue that Moran sidesteps the fact that Nature is the most respected journal in evolution and biology today. But it seems that from Moran’s perspective, the researchers committed the “unpardonable sin”—they questioned neo-Darwinian theory.
Interestingly enough, Darwin would most likely have agreed with the paper. He looked at natural selection at the fitness level, unlike the hardened gene-centric neo-Darwinian view. I don’t think Darwin would have been a neo-Darwinist.
Could it be that a 170-year quasi-religious commitment to natural selection caused evolutionists to stop asking important questions at the first discovery of the genetic code? Could the genetic code have been frozen for a reason? Could it have been designed for adaptation rather than as a mechanism of natural selection?
The Psalmist says, “How many are your works, Lord! In wisdom you made them all; the earth is full of your creatures” (Psalm 104:24).
I might add, “you made them able to adapt from the beginning.”
Xukang Shen et al., “Synonymous Mutations in Representative Yeast Genes Are Mostly Strongly Non-Neutral,” Nature 606 (June 8, 2022): 725–31, doi:10.1038/s41586-022-04823-w.
Inês Fragata et al., “The Fitness Landscape of the Codon Space across Environments,” Nature Heredity 121 (August 20, 2018): 422–37, doi:10.1038/s41437-018-0125-7.
Joshua B. Plotkin and Grzegorz Kudla, “Synonymous But Not the Same: the Causes and Consequences of Codon Bias,” Nature Reviews Genetics (November 23, 2010): 32–42, doi:10.1038/nrg2899.
“Study: Most ‘Silent Genetic Mutations Are Harmful, Not Neutral, a Finding with Broad Implications,” Michigan News, University of Michigan, June 8, 2022.
Larry Moran, “Are Synonymous Mutations Mostly Neutral or Are They Deleterious?” Sandwalk blog, August 23, 2022, https://sandwalk.blogspot.com/2022/08/are-synonymous-mutations-mostly-neutral.html?m=1
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