60 years of evolutionary theory challenged
In June 2022, Nature journal published an article called "Synonymous mutations in representative yeast genes are mostly strongly non-neutral." The authors claimed that 60 years of neo-darwinism, aka the modern synthesis, is challenged by declaring that most “silent” (synonymous) mutations were not neutral but harmful. The discovery of the genetic code in 1961 noted DNA had four nucleotides coding for only 20 amino acids that make up proteins.
Three-letter DNA units called "codons" code each of the 20 amino acids. DNA has 64 (3^4) codon combinations for 20 amino acids.
Figure codon table
Why was this the case? Why a "redundant" 64 to 20 "code?" Francis Crick, the co-discoverer of the DNA helix, said it was simply a "frozen accident." Redundant Synonymous codons accommodate "synonymous" (the same) mutations with no change in amino acid production. They reasoned that "neutral" natural selection may protect organisms from too many mutations. We now know that neo Darwinian mutations and protein production is far from the whole answer. Other factors are involved in non Darwinian adaptation.
If a mutation makes a nonsynonymous (not the same) codon, then a different protein is produced falling under natural selection thus driving evolution. Supporting this neo-Darwinian model, Francis Crick proposed the Central Dogma.
It proposed that DNA>RNA>protein. While true on one level, it ignored numerous factors the Nature researchers (among others) discovered. The Central Dogma supported the nonsynonymous/synonymous neo-Darwinian model. It focused on the "gene" centric view of genetics with an oversimplification of the mechanisms at hand, mainly that the phenotype (protein) was slave to the DNA. We are reduced to our genes, and random favorable nonsynonymous mutations drive our destiny via natural selection. Researchers measured the differences in the protein production per the nonsynonymous/synonymous selectorate, and it seems to have verified their neo-Darwinian model.
Yet the Central Dogma assumption of DNA>protein was not the whole issue. "Fitness" and non darwinian adaptation have a role. Researchers sequenced these mutations and derived simple formulas, e.g., the Ka/Ks ratio of nonsynonymous to synonymous mutations, to calculate the strength of natural selection. Thousands of articles over decades used such methods, exclaiming, "natural selection did it." Many, including myself, doubted so many "happy" nonsynonymous mutations could perfectly line up over time, even with typical "arm waving'' and billions of year's arguments. Simple probability was against it. Roughly 20 years ago, many researchers noted that synonymous codons were not "random." Instead, they were "biased" in their usage. This was different from evolution theory assumptions that focused on protein production. This "codon bias" is the fundamental research culminating in the Nature article.
So what changed over 60 years since the discovery of the genetic code and synonymous codons? The development of inexpensive sequencing machines which resulted in massive DNA data for comparison - the mega genomic era began. The "codon bias" was confirmed across all life. This promoted a race to discover why and 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 researchers show. These effects were not so much at the DNA level as the Central Dogma claimed but at the RNA level. But this 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 parenthesis as many 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.
These researchers used a new tool. In 2000 the CRISPR/Cas9 system was discovered. It allows "genetic engineering" to a level never contemplated. Nature researchers 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 non mutant fitness. Surprisingly, 76% of synonymous mutations were significantly deleterious, while only 1.3% were especially beneficial. This has significant implications for studying human disease mechanisms and evolutionary theory. They 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.” As 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 might require a "rethink" of genetics in medicine. As important as this is, was their data met with accolades? 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. Isn't that great!? To demonstrate the neo-Darwinian "pushback," I defer to Jerry Coyne on his widely read Sandwalk blog site. Referring to a hasty "pushback" non-peer-reviewed article, he said, "the Nature paper failed to exercise the proper scrutiny of a report that contradicted many previous {neo darwinian} studies. I suspect this reflects a desire among Nature editors to publish "breakthrough" papers. Or, maybe Nature has bad editors and bad reviewers." "Breakthrough" papers and "bad editors!?" Nature is THE most respected journal in evolution and biology today. But they committed the "unpardonable sin"- they allowed the questioning of neo-Darwinian theory. Interestingly enough, Darwin would have agreed with the paper. He looked at natural selection at the " fitness" level, unlike the hardened gene-centric neo-Darwinian view. Darwin would not 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 a mechanism of natural selection?
Shen, Zhang
Synonymous mutations in representative yeast genes are mostly strongly non-neutral
Nature June (2022)
doi.org/10.1038/s41586-022-04823-w
Fragata, Bank
The fitness landscape of the codon space across environments
Nature Heredity, August (2018)
doi.org/10.1038/s41437-018-0125-7
Plotkin & Kudla
Synonymous but not the same: the causes and consequences of codon bias
Nature Reviews Genetics November,(2011)
doi.org/10.1038/nrg2899
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