Mutations are changes in an organism’s DNA sequence. They can arise when DNA is copied, repaired, or otherwise altered, and they can also result from exposure to certain environmental factors. Some mutations have no noticeable effect, some alter a trait or cellular function, and others can contribute to disease.
The word mutation covers many different kinds of genetic changes. The simplest involve a single DNA base, while others affect stretches of DNA, whole genes, or even chromosome structure. Understanding the type of mutation helps explain what happened to the DNA and, in many cases, what biological consequences might follow.
What is a mutation?
DNA is built from four bases: adenine (A), thymine (T), cytosine (C), and guanine (G). The order of these bases stores genetic information. A mutation occurs when the DNA sequence differs from the original sequence.
Mutations can occur in DNA in any cell, but their significance depends partly on where they happen. A mutation in a body cell, called a somatic mutation, generally affects only that cell and the cells descended from it. A mutation in a sperm or egg cell, or in a cell that gives rise to them, is a germline mutation. Germline mutations can be passed to offspring.
Mutations also differ in scale. A single DNA letter may change, or a large DNA segment may be inserted, deleted, duplicated, inverted, or moved to another location.
Substitution: one DNA base is replaced by another
A substitution occurs when one DNA base is replaced with a different base. For example, a sequence containing A might acquire G at the same position.
Substitutions are sometimes called point mutations, although the terms are not perfectly interchangeable. A point mutation refers broadly to a change affecting a single nucleotide position, while substitution specifically describes replacing one base with another.
The effect of a substitution depends on where it occurs and what it changes. In a protein-coding gene, the altered DNA may change the corresponding codon—the three-base sequence used to specify an amino acid.
Silent, missense, and nonsense substitutions
A silent mutation changes a DNA codon without changing the amino acid it encodes. This is possible because multiple codons can specify the same amino acid. A silent change therefore does not necessarily alter the resulting protein, although changes outside the protein-coding sequence or changes that affect RNA processing can still have biological effects.
A missense mutation changes a codon so that it specifies a different amino acid. The resulting protein may function normally, work differently, work less effectively, or fail to function, depending on the location and properties of the altered amino acid.
A nonsense mutation changes a codon into a stop codon. This can cause protein production to end prematurely, often producing a shortened protein that does not function properly.
Not every substitution falls neatly into one of these categories. A substitution in a regulatory region, for example, may affect how strongly or when a gene is expressed without changing the protein’s amino-acid sequence.
Insertion: extra DNA is added
An insertion occurs when one or more DNA bases are added to a sequence.
The consequences depend heavily on the number of bases inserted and where the insertion occurs. In a protein-coding region, adding one or two bases changes how the sequence is grouped into codons from the insertion onward. This is known as a frameshift mutation.
For example, if DNA is read in groups of three bases, inserting a single base shifts the reading frame. The altered grouping can change many subsequent amino acids and may eventually create a premature stop codon.
Insertions involving three bases—or another multiple of three—do not necessarily cause a frameshift because the original grouping into three-base codons can be maintained. Such an insertion can still add one or more amino acids to the protein and potentially affect its structure or function.
Larger insertions can involve much longer DNA segments, including portions of genes or other genomic regions.
Deletion: DNA is removed
A deletion occurs when one or more bases are removed from DNA.
Like insertions, deletions can have very different effects depending on their size and location. Removing one or two bases from a protein-coding sequence can cause a frameshift, altering the codons that follow. Removing three bases may eliminate a single amino acid without shifting the remaining reading frame.
Large deletions can remove part or all of a gene, multiple genes, or regulatory DNA. Their effects can therefore range from subtle to substantial.
Insertions and deletions are often grouped together as indels. Small indels are especially important because they can alter protein-coding sequences, regulatory regions, or other functional parts of the genome.
Frameshift mutations change the genetic reading frame
A frameshift mutation occurs when an insertion or deletion changes the grouping of bases into codons in a protein-coding sequence.
Consider a simplified sequence divided into codons:
THE CAT ATE THE…
If one character is removed, the grouping after that point can change:
THC ATA TET HE…
DNA does not literally use words like these, but the example illustrates the underlying principle: changing the number of bases by an amount that is not divisible by three can alter every codon downstream.
Frameshifts can have major effects because they may change many amino acids and introduce a premature stop codon. However, the actual consequence depends on the specific sequence and whether the altered RNA or protein is subsequently processed or degraded.
Duplication: a DNA segment is copied
A duplication occurs when a segment of DNA is repeated, producing an extra copy of that sequence.
Duplications can range from a small stretch of DNA to a large genomic region. An extra copy of a gene can sometimes affect how much of its product is made. In other cases, duplicated genetic material may have little immediate effect or can provide raw material for evolutionary change because copies of genes can accumulate different mutations over time.
A duplication is distinct from an insertion in terms of origin: an insertion adds DNA to a location, while a duplication specifically involves an additional copy of an existing DNA segment. The two can sometimes occur together.
Inversion: a DNA segment is reversed
An inversion occurs when a DNA segment is removed, reversed in orientation, and returned to the same chromosome.
The DNA letters within the affected segment are therefore reversed in orientation relative to the surrounding sequence. An inversion does not necessarily add or remove genetic material, but it can disrupt a gene or alter regulatory relationships if the breakpoints occur in functionally important regions.
Inversions can also affect chromosome pairing and recombination during the formation of eggs or sperm, depending on their structure and location.
Translocation: DNA moves between chromosome locations
A translocation occurs when a DNA segment moves from one chromosome location to another. In a reciprocal translocation, segments from two chromosomes exchange places.
Some translocations have little or no obvious effect when they do not disrupt important genes or regulatory sequences. Others can alter gene function or regulation. In some cancers, for example, chromosome rearrangements can place genes in abnormal regulatory environments or create abnormal fusion genes that contribute to uncontrolled cell growth.
Translocations are therefore an example of how a mutation can involve chromosome structure rather than simply changing individual DNA bases.
Repeat expansions: DNA sequences become unusually long
Some regions of DNA contain short sequences that are repeated. A repeat expansion occurs when the number of repeats increases beyond the usual range.
The biological effects depend on the sequence, its location, and how large the expansion becomes. Expansions can interfere with gene expression, RNA processing, or protein production. Certain inherited neurological and other genetic disorders are associated with repeat expansions.
Repeat expansions also illustrate why mutations are not always simple substitutions, insertions, or deletions of arbitrary sequences. The structure and repetitive nature of the DNA itself can influence how mutations arise and how they affect cells.
Mutations can occur in different parts of a gene
A mutation’s location can matter as much as its basic type.
A change in a coding region can alter the amino-acid sequence of a protein. A change in a regulatory region can affect when, where, or how much a gene is expressed. Mutations near splice sites can interfere with the processing of RNA after a gene is transcribed, potentially causing parts of the RNA to be incorrectly included or excluded.
Mutations can also occur in noncoding regions that have important biological functions. The term “noncoding” does not mean “useless”; much of the genome participates in regulation, chromosome organization, RNA production, or other cellular processes.
Are all mutations harmful?
No. Mutations can be harmful, beneficial, or neutral, depending on the biological context.
A mutation is neutral when it has little or no detectable effect on the organism under particular conditions. Many mutations fall into this category, although determining whether a particular genetic change is truly neutral can be difficult.
A mutation is harmful when it interferes with normal biological function. Some mutations cause inherited disorders, while others contribute to diseases that develop during a person’s lifetime.
A mutation can also be beneficial if it improves survival or reproduction in a particular environment. A change that is advantageous under one set of conditions may be neutral or disadvantageous under another.
Importantly, a mutation itself is not inherently “good” or “bad.” Its consequences depend on the gene or genomic region involved, the nature of the change, the individual’s genetic background, and the environment.
How do mutations arise?
Mutations can arise through errors in DNA replication or repair. DNA-copying machinery is highly accurate, and cells have repair systems that correct many errors, but some changes escape correction.
DNA can also be altered by mutagens, which are physical or chemical agents that increase the likelihood of genetic changes. Examples include certain forms of radiation and some chemicals. Biological processes can contribute as well; for example, errors involving repeated DNA sequences or chromosome recombination can produce structural changes.
A mutation does not necessarily result from an external exposure. Mutations can occur spontaneously as part of the normal challenges of maintaining and copying DNA.
A mutation’s effect depends on more than its name
Knowing that a change is a substitution, insertion, deletion, or inversion is useful, but it does not by itself determine what the mutation does.
A single-base substitution in an unimportant region may have little consequence, while a single-base change in a critical part of a gene can substantially alter a protein. Conversely, a relatively large deletion may have little effect if it occurs in a region with limited functional significance, whereas deletion of an essential gene can be severe.
The same principle applies to inherited and acquired mutations. An acquired mutation in one body cell may remain limited to a small population of descendant cells, while a germline mutation can be present throughout the body and potentially be inherited by the next generation.
The most useful way to think about mutation types is therefore as descriptions of what changed in the DNA. Determining what that change means biologically requires looking at where the change occurred, how it affects genetic information, and how the affected cells respond.