Mutation Bias

The mutation is a skewed stochastic process in which certain mutations are more common than others. Synthetic genotype-phenotype landscapes have been employed in the past to investigate how mutation bias influences adaptive evolution. To investigate the impact of mutation bias on the adaptive evolution of higher binding affinity, we looked at 746 empirical genotype-phenotype landscapes, each of which defines the binding affinity of target DNA sequences to a transcription factor. We just need to make a few assumptions regarding landscape topography and DNA sequences in each landscape when we use empirical genotype-phenotype landscapes. The latter is particularly essential since the sorts of mutations that might occur along a mutational path to an adaptive peak are determined by the sequences that make up a landscape. That is, landscapes can show a composition bias—a statistical enrichment of a certain kind of mutation compared to a null expectation throughout a whole landscape or along specific mutational paths—that is independent of any mutational bias. 

Our findings show how composition bias interacts with mutation process biases under various population genetic settings, and how this interaction affects essential features of adaptive evolution such as predictability, genetic diversity evolution, and mutational resilience.

Due to its unexpected character, the mutation is sometimes represented as a random process. However, because certain DNA sequence changes occur more frequently than others, such randomness does not imply equally distributed results. In adaptive evolution, mutation bias can operate as an orienting force, driving populations’ mutational paths toward higher-fitness genotypes. Because these trajectories are often a limited fraction of all conceivable mutational trajectories, composition bias—an enrichment of a certain type of DNA sequence alteration, such as transition or transversion mutations—can occur. We investigate how mutation bias and composition bias combine to impact adaptive evolution using empirical data from eukaryotic transcriptional regulation.

Transition-transversion bias

Two purines (A and G) and two pyrimidines make up the canonical DNA nucleotides (T and C). Transition is used in the molecular evolution literature to describe nucleotide changes within a chemical class, while transversion is used to describe transitions from one chemical class to another. Each nucleotide undergoes one transition (for example, T to C) as well as two transversions (e.g., T to A or T to G).

Because a site (or a sequence) experiences twice as many transversions as transitions, the overall rate of transversions for a sequence may be larger even if the per-path rate of transitions is higher. The per-path rate bias is commonly indicated by (kappa) in the molecular evolution literature, meaning that if the rate of each transversion is u, the rate of each transition is u. R = (1 * u) / (2 * u) = / 2 is the aggregate rate ratio (transitions to transversions). For example, in yeast, the aggregate bias is R = 1.2 / 2 = 0.6, but in E. coli, the aggregate bias is R = 4 / 2 = 2.

Transition mutations occur many times more frequently than predicted under homogeneity in a range of species. In animal viruses, the bias can be even more strong; for example, in a recent analysis of HIV, 31 of 34 nucleotide changes were transitions. As previously stated, yeast has a modest bias toward transitions, which appears to be absent in the grasshopper Podisma pedestris.

Male Mutation Bias

Male-Driven Evolution is another term for male mutation bias. Male germline mutations are more common than female germline mutations. Male mutation bias has been documented in a variety of animals. Takashi Miyata and colleagues devised a method to verify Haldane’s idea in 1987. 

If Y and X are indicated as Y and X-linked sequence mutation rates, he includes that the ratio of Y-linked sequence mutation rate to X-linked sequence mutation rate is:

Y/X = 3α/(2+α)

In higher primates, the average Y/X ratio is 2.25. Using the equation, we were able to calculate the male-to-female mutation rate ratio of 6. Males have a higher mutation rate than females in certain creatures with a shorter generation time than humans. Males’ cell divisions are typically not as massive as females’. In males and females, the number of germ-cell divisions from one generation to the next is lower than in humans. Other theories have been proposed to explain the male mutation bias. They believe it is due to a greater mutation rate in the Y-linked region than in the X-linked sequence. Male germline genomes are extensively methylated and more prone to mutation than female germline genomes. 

On hemizygous chromosomes, X chromosomes encounter higher purifying selection mutations. People investigate the mutation rate of birds to explore this notion. Bird males are homogametic (WW), whereas females are heterogametes (WW) (WZ). The researchers discovered that the male-to-female ratio in avian mutation rates varies from 4 to 7. It was also established that the mutation bias is mostly due to higher male germline mutation than female germline mutation.

A heritable alteration in the genetic information of a brief section of DNA sequences is known as a mutation. Replication-dependent mutations and replication-independent mutations are the two types of mutations. As a result, there are two types of mutation processes that might explain male mutation bias.

• Replication-dependent mechanism

Females have a constant number of germ-cell divisions, which is significantly less than men. The majority of primary oocytes in females are produced before birth. In the formation of a mature ovum, the number of cell divisions is constant. During the process of spermatogenesis, more cell divisions are required in men. Not only that, but spermatogenesis is a never-ending process. Throughout the male’s productive life, spermatogonia will continue to divide. Male germline cell divisions at the production are not only higher than female germline cell divisions, but they are also increasing as the male’s age rises. One would think that the pace of male germline cell divisions would be equivalent to the rate of male mutations. However, only a few species agree with the male mutation rate estimate. Even in these species, the male-to-female mutation rate is less than the male-to-female number of germline cell divisions ratio.

• Replication-independent mechanism

The skew estimates of the male-to-female mutation rate ratio reveal another major process that has a significant impact on male mutation bias. A C-to-T transition occurs when CpG sites are mutated. These C-to-T nucleotide substitutions occur 10-50 times quicker in DNA sequences than at rest sites and are most likely seen in male and female germlines. Because of the independence of replication, the CpG mutation has no sex bias and effectively lowers the male-to-female mutation rate ratio. Furthermore, neighbour-dependent mutations can generate mutation rate biases and may have no bearing on DNA replication. For example, if mutations caused by mutagens exhibit a weak male mutation bias, such as from UV radiation exposure.

In conclusion, male mutation bias is mostly owing to replication-dependent mutations occurring more frequently in the male germline than in the female germline, although replication-independent mutations also help to mitigate the disparity.

Conclusion

While it will be important to test the degree and extent of mutation bias in organisms other than Arabidopsis, the adaptive mutation bias described here offers an alternative explanation for many previous observations in eukaryotes, such as reduced genetic variation in constrained loci and the genomic distributions of widely used population genetic statistics. Because mutational biases are a result of evolution, they may vary between organisms, which might explain disparities in the distribution of fitness consequences of novel mutations among species.

Finally, because epigenetic traits are malleable, epigenome-associated mutation bias may play a role in environmental mutation effects. Our study provides a fresh understanding of the mechanisms that drive natural variation patterns, contradicting a long-held assumption about mutation’s randomness and pointing the way forward for theoretical and practical research on mutation in biology and evolution.