The term mutation simply means a change or alteration. In genetics, a mutation is a change in the genetic material – DNA sequence – of an organism. By extension, a mutant is the organism in which a mutation has occurred. But what is the change compared to? The answer to this question is that it “depends”. The comparison can be made with the direct progenitor (cell or organism) or to patterns seen in a population of the organism in question. It mostly depends on the specific context of the discussion. Since genetic studies often look at a population (or key subpopulations) of individuals we begin by describing the term “wild-type”. Different forms of a gene, including those associated with “wild type” and respective mutants, in a population are termed alleles.

While the term “mutation” has colloquially negative connotations we must remember that change is not inherently “bad”. Indeed, mutations (changes in sequences) should not primarily be thought of as “bad” or “good”, but rather simply as changes and a source of genetic and phenotypic diversity on which evolution by natural selection can occur. Natural selection ultimately determines the long-term fate of mutations. If the mutation confers a selective advantage to the organism, the mutation may eventually become very common in the population. Conversely, if the mutation is deleterious, natural selection will ensure that the mutation will be lost from the population. If the mutation is neutral, that is it neither provides a selective advantage nor disadvantage, then it may persist in the population.

For an individual, the consequence of mutations may mean little or it may mean life or death. Some deleterious mutations are null or knock-out mutations which result in a loss of function of the gene product. These mutations can arise by a deletion of either the entire gene, a portion of the gene, by a point mutation in a critical region of the gene that renders the gene product non-functional, through a nonsense mutation early in the coding sequence, or through a frame-shift mutation. These types of mutations are also referred to as loss-of-function mutations. Alternatively, mutations may lead to a modification of an existing function (i.e. the mutation may change the catalytic efficiency of an enzyme, a change in substrate specificity, or a change in structure). In rare cases a mutation may create a new or enhanced function for a gene product; this is often referred to as a gain-of-function mutation. Lastly, mutations may occur in non-protein-coding regions of DNA. If these mutations occur in regions of the gene that are non-coding, but still important for gene expression (such as a promoter), they can also strongly affect gene function.

Types of mutations

Most mutations arise from mistakes made during the process of DNA copying (replication) when the DNA polymerase enzyme might incorrectly pair nucleotides. While DNA polymerase, the enzyme responsible for replicating DNA, has proofreading capabilities to correct mistakes, it is not perfect. Occasionally, it inserts incorrect nucleotides into the new DNA strand, resulting in point mutations. Mutations that result from DNA replication are called spontaneous mutations. Spontaneous mutations occur without any exposure to any external or environmental agent; they are a result of spontaneous biochemical reactions taking place within the cell, including errors of replication). Another source of spontaneous mutations is oxidative damage from cellular respiration. Highly reactive molecules called “free radicals” are byproducts of normal cellular metabolism, but can damage DNA by modifying nucleotide bases.

Another category of mutations is induced mutations, which arise due to exposure to external agents known as mutagens. These mutations occur when cells are exposed to environmental factors such as chemicals, ultraviolet (UV) radiation, X-rays, or other physical and chemical agents that can alter the DNA structure. For example, UV rays cause the formation of thymine dimers, where adjacent thymine bases bond to each other instead of to their complementary adenine bases, disrupting normal DNA replication and potentially leading to errors. Chemical mutagens, such as nitrosamines or alkylating agents, can modify the chemical structure of DNA bases, leading to mispairing during replication. X-rays and other forms of ionizing radiation can break DNA strands, causing large-scale mutations like deletions or chromosomal rearrangements if the damage is not properly repaired. Induced mutations are significant because they increase the mutation rate beyond what would occur naturally and can lead to genetic disorders, cancer, or other diseases if they affect critical genes involved in cell regulation or function.

Mutations may have a wide range of effects. Some mutations have no effect on gene function; these are known as silent mutations. Point mutations are those mutations that affect a single base pair. The most common nucleotide mutations are substitutions, in which one base is replaced by another. Mutations can also be the result of the addition of a nucleotide, known as an insertion, or the removal of a base, also known as deletion. Sometimes a piece of DNA from one chromosome may be joined to another chromosome or to another region of the same chromosome; this is known as translocation.

When a mutation occurs in a protein coding region it may have several effects. Nucleotide substitutions may lead to no change in the protein sequence (known as silent mutations), change the amino acid sequence (known as missense mutations), or create a stop codon (known as a nonsense mutation). Insertions and deletions in protein coding sequences lead to frameshift mutations. Missense mutations that lead to conservative changes result in the substitution of similar but not identical amino acids. For example, the acidic amino acid glutamate substituted for the acidic amino acid aspartate would be considered conservative- they have the same charge. In general we do not expect these types of missense mutations to be as severe as a non-conservative amino acid change; such as a glutamate substituted for a valine (changing from charged to hydrophobic). Drawing from our understanding of functional group chemistry we can correctly infer that this type of substitution may lead to severe functional consequences, depending upon location of the mutation.

Mutations are the ultimate source of variation

Mutations are randomly created in the genome of every organism, and this in turn creates genetic diversity and a plethora of different alleles per gene per organism in every population on the planet. If mutations did not occur, and chromosomes were replicated and transmitted with 100% fidelity, how would cells and organisms evolve? Whether mutations are retained in a population depends largely on whether the mutation provides selective advantage (meaning, increases the frequency of reproduction of that allele), poses some selective cost or is at the very least, not harmful. Indeed, mutations that appear neutral may persist in the population for many generations and only be meaningful when a population is challenged with a new environmental challenge. At this point the apparently previously neutral mutations may provide a selective advantage.