A nonsynonymous mutation is an alteration in a gene’s DNA sequence that leads to a change in the amino acid sequence of the corresponding protein. Genes contain the instructions for building proteins, and when a nonsynonymous mutation occurs, the resulting protein can have a different structure and function. This type of genetic change is a source of variation within populations and can have effects ranging from being harmless to causing disease.
The Genetic Code and Protein Synthesis
To understand genetic mutations, it is necessary to comprehend how cells use DNA to create proteins. The instructions within a gene are written in nucleotides: adenine (A), cytosine (C), guanine (G), and thymine (T). This information is read in three-letter “words” known as codons, and each codon specifies one of the 20 amino acids that are the building blocks for proteins. The set of rules detailing which codon corresponds to which amino acid is the genetic code.
The process begins with transcription, where DNA is copied into a messenger RNA (mRNA) molecule. This mRNA then travels to a ribosome, the cell’s protein-synthesis machinery. During translation, the ribosome reads the mRNA codons in sequence, and for each codon, a transfer RNA (tRNA) molecule brings the corresponding amino acid. These amino acids are added to a growing chain to form a complete protein.
The sequence of codons in a gene directly dictates the sequence of amino acids in a protein. This amino acid sequence, in turn, determines the protein’s three-dimensional shape and its function. Any change to the underlying DNA sequence has the potential to alter this process.
Defining Nonsynonymous vs. Synonymous Mutations
Mutations are changes to the DNA sequence, categorized by their effect on the final protein. The distinction between nonsynonymous and synonymous mutations lies in whether the DNA change alters the amino acid sequence. This is possible because the genetic code is redundant, as most amino acids are coded for by more than one codon. For example, both the mRNA codons CUU and CUC specify the amino acid Leucine.
A nonsynonymous mutation occurs when a nucleotide change alters a codon to specify a different amino acid. For instance, if a mutation changes the mRNA codon GAG (which codes for Glutamic acid) to GUG (which codes for Valine), a nonsynonymous mutation has occurred. This substitution introduces a new amino acid into the protein chain, which can affect its structure and function.
Conversely, a synonymous mutation is a DNA change that does not alter the amino acid sequence. Because the genetic code is redundant, certain nucleotide changes can result in a new codon that still codes for the same amino acid. If the mRNA codon UCU (Serine) is mutated to UCC, the amino acid remains Serine. These are often called “silent” mutations as they do not change the protein sequence.
Types of Nonsynonymous Mutations
Nonsynonymous mutations are classified into two main categories based on their consequence: missense and nonsense mutations. Each type has a different impact on the protein being synthesized.
A missense mutation is the most common type, where a single nucleotide change results in a codon that codes for a different amino acid. If the new amino acid has chemical properties similar to the original, it is a conservative mutation, and the protein might still function normally. A non-conservative mutation occurs when the new amino acid has very different properties, which is more likely to disrupt the protein’s structure and function.
A nonsense mutation arises when a nucleotide change results in a codon that previously coded for an amino acid becoming a “stop” codon. These stop signals, such as UAG, UAA, and UGA, instruct the ribosome to terminate protein synthesis. This causes translation to halt prematurely, resulting in a shortened, incomplete protein that is often non-functional.
Impact on Organisms
The consequences of a nonsynonymous mutation are tied to the change in the resulting protein’s function. An altered protein can lead to a “loss-of-function,” where it is less effective or non-functional, or a “gain-of-function,” where it takes on a new activity. These functional changes are the basis for many genetic disorders.
Sickle cell anemia is an example of a disease caused by a missense mutation. A single nucleotide change in the hemoglobin gene alters one codon, causing the amino acid glutamic acid to be replaced by valine. This substitution is enough to change the shape of red blood cells under certain conditions, leading to the disease’s symptoms.
Nonsense mutations can also have severe consequences. Certain forms of cystic fibrosis are caused by nonsense mutations in the CFTR gene. The premature stop codon leads to a truncated and non-functional CFTR protein, which disrupts ion transport across cell membranes, causing the thick mucus buildup characteristic of the disease.
Significance in Evolutionary Biology
Nonsynonymous mutations are a source of the genetic variation upon which natural selection acts. While many are harmful and are removed from a population through purifying selection, some can be neutral or beneficial. A beneficial mutation can lead to a new trait that increases an organism’s survival or reproductive success, and may become more common through positive selection.
To study these evolutionary forces, scientists compare the rate of nonsynonymous substitutions (dN) to the rate of synonymous substitutions (dS) in a gene. The dN/dS ratio serves as an indicator of the selective pressure acting on a protein-coding gene. Synonymous mutations are assumed to be neutral, providing a baseline rate of mutation.
A dN/dS ratio less than one suggests purifying selection is removing nonsynonymous changes to maintain protein function. A ratio equal to one suggests neutral evolution, where changes accumulate by random genetic drift. A ratio greater than one signals positive selection, where nonsynonymous changes have been favored, often indicating adaptation to a new environment.