Mutations can occur on several levels, including genetic, but can also take the form of amino acid replacements during protein synthesis. Amino acid replacements can be deleterious, neutral, or beneficial, and can have profound effects on evolution. For example, several amino acid replacements have been identified in the evolution of SARS-CoV-2.
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Types of amino acid replacements
Mutations, giving rise to new alleles, are a fundamental part of evolution. These mutations can occur on several levels, such as by directly modifying genetic code, and can have knock-on effects at the amino acid level.
One of the earlier theories regarding amino acids and evolution was that mutant proteins, which were still functional, are common to enable evolution.
So far, evidence suggests that proteins are very tolerant of amino acid replacements. Neutral amino acid replacements occur when the new amino acid does not significantly alter the protein or its function.
Deleterious amino acid replacements are likely to render the protein dysfunctional, whereas a beneficial amino acid replacement is likely to be selected for.
Predicting and managing amino acid replacements
Much regarding amino acid replacements is unknown or poorly understood. The wide variety of mutations that can occur means that predicting their effect can be difficult, although many mathematical methods have attempted to address this.
Similarly, it is argued whether amino acid replacements are beneficial for an organism’s survival. While deleterious replacements can be catastrophic, the enriched genetic variation that occurs as a result of mutations can help organisms in rapidly changing environments.
Studies attempting to quantify the probability of amino acid replacements and mutations have found that certain patterns are more likely to lead to deleterious changes. In particular, decreasing substitutions between adenine and thymine bases are associated with less deleterious effects. This is likely due to the nature of both bases when in the second position of the codon – thymine in this position is associated with hydrophobic amino acids, whereas adenine in this position is associated with hydrophilic amino acids.
Opposite to this, substitutions between cytosine and thymine are associated with a lower cost of amino acid replacements. This is also interesting considering cytosine to thymine substitutions are among the most common point mutations that can occur.
The structure of protein subunits can also play a role in their sensitivity to amino acid replacement. For example, a study on 3-methyladenine DNA glycosylase (AAG) found that β strand residues are generally less tolerant of amino acid replacements than α helices. This may be due to the 3D structure of the protein – in AAG, β sheets tend to be less solvent and thus have fewer surface residues. Surface residues tend to be more likely to tolerate substitution.
Amino acid replacements and COVID-19
Understanding amino acid replacements in the causative virus of COVID-19, SARS-CoV-2, is useful to both track its evolution and predict future variants. The amino acid sequence of SARS-CoV-2 differs from other coronaviruses, especially in the 1ab polyprotein and S-protein regions. The S-protein is associated with the virus gaining entry into cells but despite the amino acid replacements.
Comparative studies of SARS-CoV and SARS-CoV-2 have found that there have been 5 amino acid replacements between the two and their receptor-binding domain residues. Three of these showed signs of positive selection, along with 10 other amino acid replacement sites in the virus amino acid sequence.
The replacements in the receptor-binding domain residues seem to have impacted the binding affinity to ACE2 (angiotensin-converting enzyme II), with SARS-CoV-2 having a higher binding affinity for the enzyme. ACE2 has been linked to the pathogenesis and mortality of COVID-19.
On the opposite end of this, the N protein of COVID-19 has almost 90% sequence similarity with SARS-CoV. This has lead researchers to speculate that N protein antibodies of SARS-CoV can cross-react with COVID-19, but might not provide immunity to both diseases.
In terms of the evolutionary origin of SARS-CoV-2, the amino acid sequences have at times been confusing. SARS-CoV-2 and Pangolin-CoV have identical functional amino acid residues in the receptor-binding domain. Because of this, SARS-CoV-2 was at first believed to originate from Pangolin-CoV.
However, more recent evidence suggests that SARS-CoV-2 is most closely related to bat RaTG13, where the receptor-binding domain residues have changed after its divergence from SARS-CoV-2.
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