U.S. scientists join international team to discover paradigm-shaking role of mutation in natural selection

An international team of plant biologists and geneticists from Germany, the United States, Sweden, and France have found evidence overturning the commonly held assumption that mutations are entirely random across the genome.

The discovery explains why mutations are found considerably less often within essential genes and considerably more often in noncoding regions of the genome. The lower frequency of mutations found within certain regions of the genome had been known for some time, but previously was explained to be the result of a natural selection process that occurred after the mutation took place.

Through their extensive studies of the model organism Arabidopsis thaliana, a small flowering plant  found in Eurasia and Africa and commonly known as thale cress, the international team was able to show that mutations simply did not occur as often inside functionally constrained regions of the genome due to physical features of DNA structure and the epigenome.

The authors reported their work, which was published online Jan. 12 in the journal Nature.

“With independent genomic mutation datasets, including from the largest Arabidopsis  mutation accumulation experiment conducted to date, we demonstrate that epigenomic and physical features explain over 90% of variance in the genome-wide pattern of mutation bias surrounding genes,” they wrote.

Mutation bias refers to the tendency of mutations to occur in one part of the organism and not another. The prevailing view of evolution, known as the “modern synthesis,” denies the existence of a mutation bias.

These new findings refute the commonly given explanation that the lower frequency of appearance of “non-synonymous mutations” within the genome is caused by higher selective pressures within the genome. A non-synonymous mutation is a change or substitution in the DNA helix that causes it to produce a different sequence of amino acids. Different amino acid sequences often result in malfunctioningy proteins, which do not work properly in the cell.

A new paradigm

The results presented in the new study are paradigm shaking.

As the authors explain, “The random occurrence of mutations with respect to their consequences is an axiom upon which much of biology and evolutionary theory rests. This simple proposition has had profound effects on models of evolution developed since the modern synthesis, shaping how biologists have thought about and studied genetic diversity over the past century.

“From this view, for example, the common observation that genetic variants are found less often in functionally constrained regions of the genome is believed to be due solely to selection after random mutation," they wrote. "This paradigm has been defended with both theoretical and practical arguments. [These include] that selection on gene-level mutation rates cannot overcome genetic drift, that previous evidence of non-random mutational patterns relied on analyses in natural populations that were confounded by the effects of natural selection and that past proposals of adaptive mutation bias have not been framed in the context of potential mechanisms that could underpin such non-random mutations.”

Mutations are not random

The authors challenge the prevailing assumption that evolutionary change is random and instead show that the mechanisms of mutation lead on the one hand to a conservation of basic species characteristics, and on the other hand to the ability of organisms to adapt to and change their nature in response to environmental conditions.

“Since the first half of the 20th Century,” the authors explain in their Abstract, “evolutionary theory has been dominated by the idea that mutations occur randomly with respect to their consequences.

"Here we test this assumption with large surveys of de novo mutations in the plant Arabidopsis thaliana. In contrast to expectations, we find that mutations occur less often in functionally constrained regions of the genome—mutation frequency is reduced by half inside gene bodies and by two-thirds in essential genes. ..."

To explain why this is necessary they say, “the adaptive value of this bias can be conceptualized by the analogy of loaded dice with a reduced probability of rolling low numbers (that is, deleterious mutations), and thus a greater probability of rolling high numbers (that is, beneficial mutations).”

Summarizing their unexpected conclusions, the authors note, “Finally, we find that genes subject to stronger purifying selection have a lower mutation rate. We conclude that epigenome-associated mutation bias reduces the occurrence of deleterious mutations in Arabidopsis, challenging the prevailing paradigm that mutation is a directionless force in evolution [emphasis added].”

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Monroe, J.G., Srikant, T., Carbonell-Bejerano, P. et al. Mutation bias reflects natural selection in Arabidopsis thaliana, Nature. (12 Jan 2022).   DOI: https://doi.org/10.1038/s41586-021-04269-6