A mutation is a change in the DNA sequence of an organism's genetic material. In its broadest molecular sense, mutation includes alterations ranging from changes to individual nucleotide bases to large structural changes involving chromosomes or substantial genomic regions. Mutations can occur in genes, regulatory sequences, intergenic regions, mitochondrial DNA and other genomic components. A mutation may have no detectable effect, may alter a biological trait, or may substantially affect cell function or organismal fitness. Mutations are important because they create new genetic variants, making them a fundamental ultimate source of new alleles. They are not synonymous with evolution itself, because evolution involves changes in inherited variant frequencies in populations, whereas mutation is one process that generates genetic differences.
Mutations can be classified according to the molecular change involved. A substitution replaces one nucleotide with another and can be further described as a transition or transversion. Insertions add DNA sequence, while deletions remove sequence. Insertions or deletions within a protein coding region can cause a frameshift if their length is not a multiple of three, potentially changing the downstream amino acid sequence and introducing a premature stop codon.
A substitution can be synonymous, missense or nonsense depending on its effect on the encoded protein. Regulatory mutations can alter gene expression without changing the protein sequence. Larger structural mutations include duplications, inversions and translocations, and changes in chromosome number can arise through mechanisms such as nondisjunction.
Mutations can occur spontaneously as a consequence of normal cellular processes. DNA replication is highly accurate but not completely error free, and occasional copying errors can escape proofreading and repair. Chemical changes to DNA bases can also occur spontaneously, while DNA can experience damage from ordinary metabolic processes. Cells possess multiple repair systems that detect and correct many forms of DNA damage, including mismatch repair, base excision repair, nucleotide excision repair and double strand break repair pathways.
Mutation therefore reflects a balance between DNA damage and replication errors on one side and surveillance and repair mechanisms on the other. The mutation rate is generally low at individual nucleotide positions, but because genomes contain enormous numbers of nucleotide sites and organisms reproduce repeatedly, mutations continually arise across populations.
The consequences of a mutation depend strongly on where it occurs and what molecular function is affected. A mutation in a nonfunctional or redundant region may have little measurable consequence, while a mutation disrupting an essential protein can be harmful. Mutations in regulatory regions can change the amount, timing or location of gene expression. Mutations affecting splice sites can alter RNA processing, while changes to protein coding sequences can modify protein structure or function. Some mutations are beneficial in a particular environment, and others can be conditionally beneficial or harmful depending on circumstances. The same variant can therefore have different evolutionary consequences in different environments, genetic backgrounds or life stages.
Mutations in somatic cells and mutations in germline cells have different evolutionary implications. A somatic mutation occurs in a body cell and is generally transmitted only to descendant cells within that individual, not to offspring through ordinary sexual reproduction. Such mutations can contribute to processes such as cancer when they affect cell growth or genome stability. Germline mutations occur in cells that contribute genetic material to offspring, or in their precursors, and can therefore become inherited variants. In organisms with separate germline and soma, this distinction is fundamental to evolutionary inheritance. In some organisms, especially plants and organisms with different reproductive systems, the boundary between somatic and reproductive tissues can differ from the standard animal model.
Mutations are not generally directed responses to environmental need. A common misconception is that an organism exposed to a challenge develops exactly the mutation required to survive it. In evolutionary biology, mutations generally arise without regard to whether they will later prove useful. Environmental conditions then influence the reproductive success of individuals carrying different variants. This distinction is particularly important in antibiotic resistance. Resistance can arise through mutations that occur before exposure, after which antibiotic treatment selects resistant cells. Some environmental agents can increase the overall mutation rate by damaging DNA or interfering with replication, but this does not mean that they intelligently generate specific beneficial mutations.
Mutation rates and mutation spectra vary among organisms, genomic regions and environmental conditions. DNA repair capacity, replication machinery, genome composition, exposure to mutagens and cellular physiology can all influence mutation patterns. Some genomic regions are more mutable than others, and repetitive DNA can be particularly prone to certain rearrangements. Mutations can also be classified by whether they occur in protein coding sequences, regulatory regions or other genomic contexts. Modern sequencing technologies allow researchers to identify large numbers of mutations and estimate mutation rates across genomes. These measurements are important in evolutionary biology, cancer research, genetic disease studies, microbial evolution and population genetics.
Mutations have both biological costs and evolutionary significance. Most mutations are neutral or nearly neutral with respect to fitness, while a smaller proportion are deleterious and a still smaller proportion are beneficial under a particular set of conditions. Natural selection can remove strongly harmful variants, favour advantageous variants and have relatively little effect on neutral variants. Genetic drift can cause neutral and even mildly deleterious variants to change in frequency by chance.
Over long evolutionary periods, mutation supplies the raw genetic variation from which selection and other processes operate. Mutation can therefore be viewed as a source of novelty rather than a mechanism that automatically improves organisms. Without mutation, existing genetic variants could be rearranged by reproduction but genuinely new DNA sequence variants could not continually enter the population.
