The Impact of Non-Neutral Synonymous Mutations When Inferring Selection on Non-Synonymous Mutations

-


The study of evolutionary forces shaping genomes relies heavily on identifying mutations under selection. A key distinction is made between synonymous and non-synonymous mutations. Synonymous mutations alter the DNA code but not the resulting amino acid sequence in the protein, while non-synonymous mutations change the amino acid, potentially affecting protein function. 


Traditionally, synonymous mutations are considered selectively neutral – meaning they offer no fitness advantage or disadvantage. This assumption forms the basis for many methods that infer selection on non-synonymous mutations by comparing their frequency to synonymous mutations. 

However, a recent study published on bioRxiv by Martinez et al. (2024) challenges this notion, highlighting the potential impact of non-neutral synonymous mutations on our understanding of selection.

The core message of the study is that synonymous mutations are not neutral. These "non-neutral synonymous mutations" can influence fitness in significant ways, mimicking the effects of weak selection on non-synonymous mutations. This creates a problem for traditional methods that rely on the neutrality of synonymous mutations as a baseline. When non-neutral synonymous mutations exist, they can skew the interpretation of selection pressure on non-synonymous mutations. The authors propose that these effects can lead to misinterpretations of evolutionary forces acting on protein-coding genes.

Here's a deeper dive into the concepts presented in the study:

  • Synonymous vs. Non-synonymous Mutations: DNA encodes proteins through codons, which are three-nucleotide sequences. Multiple codons can specify the same amino acid (degeneracy of the genetic code). A synonymous mutation changes the DNA sequence within a codon but maintains the same amino acid. Conversely, a non-synonymous mutation alters the DNA sequence, leading to a different amino acid and potentially impacting protein function.

  • Inferring Selection: Researchers use various methods to identify mutations under selection. One common approach compares the frequency of non-synonymous mutations with synonymous mutations.

If non-synonymous mutations are more frequent than expected based on the synonymous mutation rate, it suggests positive selection. Conversely, a scarcity of non-synonymous mutations compared to synonymous mutations hints at negative selection.

The study by Martinez et al. (2024) argues that the assumption of strict neutrality in synonymous mutation does not hold true. Here are some potential mechanisms for non-neutral synonymous mutations:

  • RNA Structure: Changes in codon usage can alter the folding of messenger RNA (mRNA), which carries the genetic information from DNA to ribosomes for protein synthesis. 


Specific RNA structures might be crucial for efficient translation or mRNA stability. A synonymous mutation disrupting a vital RNA structure could have a negative impact on protein production.

  • Codon Bias: 


Organisms exhibit a preference for using certain codons over others for the same amino acid. This codon bias is thought to be linked to the efficiency and accuracy of translation. Synonymous mutations that shift codon usage away from the preferred codons might subtly hinder translation, impacting fitness.

  • Regulatory Elements: Mutations in non-coding regions flanking a gene can act as regulatory elements, influencing gene expression. Synonymous mutations within these regions could inadvertently disrupt regulatory elements, impacting the level of protein production.

The authors of the study highlight the potential consequences of neglecting non-neutral synonymous mutations. When these mutations exist, they can:

  • Mask Positive Selection: If a non-synonymous mutation is beneficial but accompanied by a non-neutral synonymous mutation with a negative fitness effect, the combined impact might appear neutral compared to synonymous mutations. This could lead to underestimating the strength of positive selection acting on the non-synonymous mutation.

  • Mimic Negative Selection: A non-neutral synonymous mutation with a negative fitness effect might be misinterpreted as a non-synonymous mutation under negative selection, even if the non-synonymous mutation itself is neutral.

The study emphasizes the need for more sophisticated methods that account for the potential influence of non-neutral synonymous mutations when inferring selection on protein-coding genes. The authors propose incorporating additional data, such as information about RNA structure and codon bias, into existing methodologies. Additionally, developing new approaches specifically designed to identify non-neutral synonymous mutations could improve our understanding of the subtle forces shaping protein evolution.

Looking Forward:

The study by Martinez et al. (2024) opens new avenues for investigating the complexities of selection at the molecular level. It underscores the importance of considering all potential influences when analyzing mutations within genes. Future research will likely delve deeper into the mechanisms and prevalence of non-neutral synonymous mutations. 


Rethinking Neutrality: How Synonymous Mutations Upend Decades of Selection Inference

For the past 50 years, the Ka/Ks ratio has been a cornerstone in measuring natural selection acting on protein-coding genes. 


Ka refers to the rate of non-synonymous mutations (amino acid changes), and Ks represents the rate of synonymous mutations (mutations that don't change the amino acid). The underlying assumption? Synonymous mutations are effectively neutral, unaffected by selection pressures. This allows scientists to isolate the impact of selection on protein function by comparing the rates of these two mutation types.

However, the article throws a wrench into this long-held belief. The authors argue that recent evidence suggests  synonymous mutations can influence fitness, challenging the assumption of neutrality. This has significant implications for how we interpret Ka/Ks ratios.

Here's how non-neutral synonymous mutations can mislead Ka/Ks:

  • Misinterpreting Demographic History: Traditionally, Ka/Ks is used to infer selection alongside estimates of demographic parameters like population size changes. If synonymous mutations are not truly neutral, these estimates become skewed, leading to inaccurate conclusions about selection acting on non-synonymous mutations.

  • Inflated Deleterious Effects: The authors used simulations to show that selection on synonymous mutations can inflate the estimated proportion of highly deleterious non-synonymous mutations. This creates a misleading picture where selection appears to be stricter than it actually is.

These challenges highlight the need to abandon the Ka/Ks method. Researchers must acknowledge the potential influence of non-neutral synonymous mutations. 

In conclusion, the concept of non-neutral synonymous mutations compels us to revisit our understanding of Ka/Ks ratios if not replace it.

Comments

Post a Comment

Popular posts from this blog

No, the EES is not just a add on to Neo-Darwinism aka the Modern Synthesis

-
Image
" The summary of the state of affairs on the 150th anniversary of the Origin is somewhat shocking: in the post-genomic era, all major tenets of the Modern Synthesis fthe theory of evolution) are, if not outright overturned replaced by a new and incomparably more complex vision of the key aspects of evolution (EES). So, not to mince words , the Modern Synthesis is gone" -Eugene Koonin, an evolutionary biologist (Cited by over 270,000 evolutionary scientists.) The Extended Evolutionary Synthesis (EES) represents a significant departure from the traditional neo-Darwinian framework, also known as the Modern Synthesis . While both theories aim to explain evolutionary change, they differ fundamentally in their underlying mechanisms and the roles they assign to various biological processes. A crucial point of divergence lies in the interpretation and application of the term " evolutionary ," particularly concerning the incorporation of epigenetic mechanisms....
Read more

Is the random mutational model of evolution on its way out?

-
Image
While the random mutational model of evolution has long been a cornerstone of evolutionary biology, the Extended Evolutionary Synthesis (EES) and the study of epigenetics are challenging its core assumptions. The Random Mutational Model and Its Limitations The traditional view of evolution, often called the Modern Synthesis or neo-Darwinism , emphasizes random genetic mutations as the primary source of variation. Natural selection then acts upon this variation, favoring individuals with advantageous traits. This model has been successful in explaining some evolutionary phenomena, but it also has limitations: It struggles to explain complex adaptations: The idea that complex features like the eye or the immune system arose solely through random mutations seems statistically improbable. It overlooks the role of the environment: The traditional model treats the environment as a selective force, but it doesn't fully consider how organisms can actively respond to and s...
Read more

ERVs and Common Descent: A Reassessment in Light of Recent Findings

-
Image
Endogenous retroviruses (ERVs) have long been considered strong evidence for the common descent of humans and chimpanzees. These remnants of ancient viral infections, embedded in the genomes of both species, were once thought to be non-functional "junk DNA." The premise was that the shared presence of these seemingly random insertions in corresponding genomic locations could best be explained by a shared evolutionary history. However, recent research, such as the "Switching Sides" article published in May 2021, has challenged this assumption by demonstrating that ERVs play a functional role in the development of the human embryo and immune system. This discovery raises questions about the validity of using ERVs as primary evidence for common descent. The Traditional Argument for Common Descent The traditional argument for common descent based on ERVs rests on the following points: Random Insertion: Retroviral insertions are thought to occur randomly in...
Read more