The role of neutral mutations in adaptive evolution

Although these mutations have no direct effects on fitness, they can have far-reaching consequences.

Genetic mutations are often classified into three main categories: deleterious, advantageous and neutral. Highly deleterious mutations are swiftly eliminated from the gene pool by natural selection, while advantageous ones can quickly spread through the population. And the neutral mutations? They just fluctuate in frequency due to chance processes, such as genetic drift. This simplistic view of molecular evolution suggests that neutral mutations do not play a major role in the adaptive evolution of organisms. A recent paper in the journal Current Biology challenged this perspective: neutral mutations do contribute to adaptive evolution.

The Adaptive Landscape

Evolution can be depicted as the exploration of an adaptive landscape. Hills and mountains represent genetic combinations of high fitness (so-called adaptive peaks), while valleys correspond to regions of low fitness. Advantageous genetic variants – either from standing genetic variation or from de novo mutations – can push populations up new adaptive peaks. At first sight, neutral mutations seem unimportant. They only allow populations to wander around a fitness-plateau without any adaptive benefits. However, aimlessly strolling through a landscape can lead to unexpected discoveries. Indeed, an important contribution of neutral mutations is that they allow populations to explore the adaptive landscape. Some mutations might bring populations to base of new adaptive peaks, where advantageous mutations can take over.

A visualization of the adaptive landscape. The blue color indicates a low fitness value, while the red regions correspond to adaptive peaks. © Rhiever&action | Wikimedia Commons

Volatile Codon

This process is nicely illustrated by the effect of neutral mutations on protein evolution. As you probably remember from high school biology, proteins are strings of amino acids. Each amino acid is coded for by particular three-letter-combinations in the DNA (i.e. codons). For example, the codon GGC corresponds to glycine, while AGC represents arginine. This genetic code is redundant and some amino acids have multiple codons. Glycine, for instance, is not only linked with GGC, but also with GGT, GGA and GGG. Neutral mutations in these codons do not change the amino acid in the protein. To stick with the examples above: a mutation from GGC to GGT will still result in the addition of a glycine during protein synthesis. Such neutral mutations – also known as synonymous mutations – do not directly contribute to adaptive evolution. But they do allow proteins to explore the adaptive landscape.

The codons CGG and AGG correspond to the amino acid arginine. The first codon (CGG) is one mutational step away from five other amino acids (glycine, tryptophan, glutamine, leucine, and proline) while a mutation in the second codon (AGG) gives access to another set of amino acids (glycine, tryptophan, lysine, threonine, methionine, and serine). So, a neutral mutation from CGG to AGG opens up a new section of the adaptive landscape to explore.

Neutral mutations in codons (i.e. synonymous mutations) can give access to new sets of amino acids for consequent mutations. Here, a change from CGG to AGG (both coding for glycine) leads to a change in amino acids that are one mutational step away. From: Tenaillon & Matic (2020) Current Biology.

Mutation and Recombination

Apart from exploring unchartered territory on the adaptive landscape, neutral mutations can also affect genomic processes, such as mutation and recombination rates. Experimental evolution with bacterial strains showed that the probability of a mutation occurring is partly determined by the surrounding DNA-letters. For example, mutations affecting a G in a CGT sequence were found to be about 10 times more likely than mutations affecting G in an AGT sequence. Neutral mutations that change the genomic context can thus result in higher mutation rates, potentially speeding up adaptive evolution.

Finally, neutral mutations might also influence local recombination rates. Homologous recombination produces new combinations of DNA sequences during meiosis by swapping genomic sections between chromosome pairs. Certain enzymes, such as DNA recombinases, initiate this process at particular combination of DNA-letters (i.e. motifs). Neutral mutations can slightly change such motifs across the genome, which might result in recombination between non-identical DNA sequences. This situation leads to issues for the recombination machinery and can give rise to changes in genome structure, such as inversions or duplications.

Local reductions in recombination rate can also contribute to speciation. The authors write that “the accumulation of neutral diversity may be enough to create long-lasting barriers to genetic exchange and the further accumulation of genetic diversity.” Do not underestimate the power of neutral mutations!

References

Tenaillon, O., & Matic, I. (2020). The Impact of Neutral Mutations on Genome Evolvability. Current Biology30(10), R527-R534.

Featured image: A point mutation © Jing.fm

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