Axiom of Evolution "Random" mutations are found to be wrong


Since the first half of the twentieth century, evolutionary theory has been dominated by the idea that mutations occur randomly with respect to their consequences.

In contrast to expectations, we find that mutations occur less often in functionally constrained regions of the genome.

The random occurrence of mutations with respect to their consequences is an axiom upon which much of biology and evolutionary theory rests. 

Our discovery yields a new account of the forces driving patterns of natural variation, challenging a long-standing paradigm regarding the randomness of mutation.

The article "Mutation bias reflects natural selection in Arabidopsis thaliana" by Monroe et al. (2022) challenges the prevailing paradigm that mutation is a directionless force in evolution. The authors show that mutations are less likely to occur in functionally constrained regions of the genome, such as gene bodies and essential genes. This mutation bias is mediated by a link between mutation rate and the epigenome, and it reduces the occurrence of deleterious mutations in Arabidopsis.

The authors first used two independent genomic mutation datasets to map the genome-wide pattern of mutation bias in Arabidopsis. They found that mutations occur less often in functionally constrained regions of the genome, such as gene bodies and essential genes. This mutation bias is not explained by differences in DNA replication or repair, but it is correlated with epigenomic features, such as DNA methylation and histone modification.

The authors then used an experimental approach to test the functional significance of mutation bias. They generated a mutant strain of Arabidopsis with a reduced mutation rate, and they found that this strain had a lower frequency of deleterious mutations. This suggests that mutation bias plays a role in protecting Arabidopsis from the accumulation of deleterious mutations.

The findings of this study have important implications for our understanding of evolution. They suggest that mutation is not a random process. This mutation bias can help to protect organisms from the accumulation of deleterious mutations, and it can also drive the evolution of new traits.

Here are some additional thoughts on the article:

  • The findings of this study suggest that mutation bias is a widespread phenomenon that occurs in many different organisms. This is supported by the fact that the authors found similar patterns of mutation bias in both the model organism Arabidopsis and in natural populations of Arabidopsis.

  • The findings of this study have implications for our understanding of the evolution of complex traits. Mutations in functionally constrained regions of the genome are more likely to be deleterious, so mutation bias can help to prevent the evolution of harmful mutations.

  • The findings of this study have implications for our understanding of the role of DNA repair in evolution. DNA repair can help to remove deleterious mutations from the genome, but it can also reduce mutation bias. This suggests that DNA repair can have both positive and negative effects on evolution.

Overall, the article "Mutation bias reflects natural selection in Arabidopsis thaliana" is a significant contribution to our understanding of the role of mutation in evolution. The findings of this study challenge the prevailing paradigm that mutation is a random process, and they suggest that mutation bias is a widespread phenomenon that can have both positive and negative effects on evolution.

Article snippets 

mutation frequency is reduced by half inside gene bodies and by two-thirds in essential genes.

we demonstrate that epigenomic and physical features explain over 90% of variance in the genome-wide pattern of mutation bias surrounding genes.

That mutation bias is the primary force behind patterns of sequence evolution around genes in natural accessions is supported by analyses of allele frequencies.

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

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.

This paradigm has been defended with both theoretical and practical arguments: 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.

Yet, emerging discoveries in genome biology inspire a reconsideration of classical views. It is now known that nucleotide composition, epigenomic features and bias in DNA repair can influence the likelihood that mutations occur at different places across the genome

At the same time, we have learned that specific gene regions and broad classes of genes, including constitutively expressed and essential housekeeping genes, can exist in distinct epigenomic states.

This could in turn provide opportunities for adaptive mutation biases to evolve by coupling DNA repair with features enriched in constrained loci. Indeed, evidence that DNA repair is targeted to genic regions and active genes has been

We found no evidence of selection on these mutations.

Therefore, as expected, non-synonymous changes and premature stop codons accounted for a greater share of variants than in natural populations, and their frequencies were indistinguishable from a null model of random mutation.

Finally, we confirmed that observed mutation biases could not be explained by variation in read depth, mappability, the distribution of false positives or selection on mutations

These data also provided evidence for genetic variation in mutation bias, raising the possibility of mutation bias evolvability

Since only 20–30% of gene body sites are estimated to be subject to selection, mutation bias in genic regions could affect sequence evolution around genes more than selection.

In conclusion, evolution around genes in Arabidopsis appears to be explained by mutation bias to a greater extent than by selection.

By contrast, genes with environmentally conditional functions had the highest mutation rates. Intron mutations showed the same pattern, confirming that these results are not due to selection on coding sequences

Comparing predicted mutation rates with signatures of evolutionary constraint revealed that genes subject to purifying selection are enriched for epigenomic features associated with low mutation rate.

These patterns were replicated in analyses of mutations in introns, where selection is weaker than in exons, further indicating that results are not due to selection biasing our mutation datasets

These findings demonstrate that genes subject to stronger purifying selection are maintained in epigenomic states that underlie a significant reduction in their mutation rate

In conclusion, mutation bias acts to reduce levels of deleterious variation in Arabidopsis by decreasing mutation rate in constrained genes.

Our findings reveal adaptive mutation bias that is mediated by a link between mutation rate and the epigenome. This is mechanistically plausible in light of evidence that DNA repair factors can be recruited by specific features of the epigenome8

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)

Thus, while perhaps initially surprising, our synthesis between epigenomics and population genetic theory predicts that the observed biases could readily arise via natural selection.

While it will be important to test the degree and extent of mutation bias beyond Arabidopsis, the adaptive mutation bias described here provides an alternative explanation for many previous observations in eukaryotes, including reduced genetic variation in constrained loci and the genomic distributions of widely used population genetic statistics.

Since mutational biases are a product of evolution, they could differ between organisms, potentially explaining differences in the distribution of fitness effects of new mutations among species.

Finally, because epigenomic features are plastic, epigenome-associated mutation bias could even contribute to environmental effects on mutation.

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