A mutation is a lasting change in the sequence of an organism’s DNA. It may affect a single nucleotide, a segment of a gene, or a larger region of a chromosome. Mutations arise through copying errors, exposure to DNA-damaging agents, and other processes. Their effects range from undetectable changes to substantial alterations in biological function. Mutations that enter reproductive lineages can be inherited, whereas those confined to body cells generally cannot. Mutation is a fundamental source of variation studied in genetics and evolution. (genome.gov)
Origins and molecular mechanisms
During DNA replication, the molecular machinery copying genetic material can insert an incorrect nucleotide or add or omit bases. DNA polymerases have proofreading mechanisms, and DNA repair systems correct many remaining errors. If an error escapes correction and becomes established in subsequent copies, it produces a mutation. DNA also undergoes spontaneous chemical changes, such as loss or modification of bases, that can lead to sequence alterations. (ncbi.nlm.nih.gov)
External agents that increase mutation rates are called mutagens. Examples include ultraviolet radiation, ionizing radiation, and certain chemicals. They can modify bases, interfere with copying, or break DNA strands. DNA damage is not itself synonymous with mutation: damage may be repaired accurately, while inaccurate copying or repair can convert a lesion into a lasting sequence change. Movement of transposable elements can also interrupt genes or alter surrounding sequences. (ncbi.nlm.nih.gov)
Types of mutation
Mutations can be classified by the physical change in DNA or by their consequences for gene function. These classifications overlap: an insertion, for example, may also cause a frameshift. Principal sequence changes include:
- Substitution: replacement of one nucleotide with another.
- Insertion and deletion: addition or removal of nucleotides, ranging from individual bases to extensive DNA segments.
- Duplication: copying of a sequence, creating an additional copy.
- Inversion: reversal of the orientation of a DNA segment.
- Repeat expansion: an increase in the number of copies of a repeated short sequence. (medlineplus.gov)
Within a protein-coding sequence, a substitution may be synonymous, leaving the encoded amino acid unchanged; missense, replacing one amino acid with another; or nonsense, introducing a premature stop signal. Because a codon consists of three nucleotides, an insertion or deletion whose length is not a multiple of three shifts the reading frame. Such frameshifts change the downstream instructions for producing a protein and often introduce an early stop signal. These terms describe molecular consequences rather than guaranteeing a particular effect on an organism. (ncbi.nlm.nih.gov)
Inheritance and cellular distribution
A germline mutation occurs in an egg, sperm, or their precursor lineage and can pass to offspring. A somatic mutation arises in a body cell and can be transmitted to its descendants through cell division, but ordinarily is not inherited by children. A variant inherited through fertilization is typically present in virtually every cell of the resulting individual. (medlineplus.gov)
A de novo mutation is newly identified in an offspring rather than inherited as a variant detectable in either parent’s sampled body cells. It may originate in a parental reproductive cell or during early embryonic development. Mutations arising after fertilization can produce mosaicism, in which genetically distinct cell populations coexist within one individual. Their distribution depends partly on when the change occurred and which cell lineage carries it. Germline mosaicism can allow a parent without the variant in most body cells to transmit it. (medlineplus.gov)
Functional effects
Many mutations do not cause disease. Some leave protein function unchanged; others occur in regions where the alteration has no established functional consequence. Conversely, a small sequence change can substantially affect an essential biological process. The outcome depends on the location and nature of the alteration, the role of the affected sequence, and the broader biological context. (medlineplus.gov)
Mutations need not alter a protein’s amino-acid sequence to matter. Changes in regulatory DNA can modify gene expression, causing a gene to become active in a different tissue or at a different time, or changing how much protein is produced. Other noncoding sequences encode functional RNA molecules involved in regulation or protein assembly. Alterations in these regions can therefore affect cellular function without changing a protein-coding sequence directly. (medlineplus.gov)
In cancer, certain mutations contribute to abnormal growth by affecting genes that regulate division, suppress tumors, or repair DNA. Alterations that promote cancer development are called driver changes. Distinguishing these from accompanying passenger mutations requires evidence about their biological effects; merely finding a mutation in a tumor does not establish its causal role. (cancer.gov)
Evolutionary significance
Mutation creates new genetic variants, including new alleles, that contribute to genetic diversity. Natural selection can increase the frequency of heritable variants that improve reproductive success in a particular environment. Other variants are neutral or harmful, and the same alteration may have different consequences under different environmental conditions. Mutation supplies variation; selection influences which variants become more common. (medlineplus.gov)
Genetic drift can also change allele frequencies through chance, sometimes eliminating a new variant or making it common without an adaptive advantage. An illustrative interaction between inheritance and selection involves sickle cell disease: one copy of the relevant altered HBB allele provides some protection against malaria, whereas two copies cause disease. This helps explain the allele’s persistence in some malaria-affected populations. (genome.gov)
Detection and interpretation
DNA sequencing determines nucleotide order and enables comparisons that reveal sequence differences. Detecting a difference, however, is distinct from establishing its functional significance. In clinical usage, variant is often preferred to mutation because it does not imply disease. A variant of uncertain significance is a detected change for which available evidence does not establish whether it is disease-causing or benign. (genome.gov)