Mutation

In biology, a mutation is a heritable alteration in the nucleotide sequence of the genetic material of an organism, virus, or extrachromosomal element. Mutations form the fundamental source of genetic variation, allowing evolutionary processes to shape populations over time. They arise through diverse molecular mechanisms and can have effects ranging from negligible to highly consequential for the organism’s physiology, development, and fitness.

Nature of mutations and distinction from DNA damage

Mutations differ fundamentally from DNA damage. DNA damage refers to structural irregularities in the molecule such as single- or double-strand breaks, modified bases, or bulky adducts. These lesions are recognised by cellular repair systems and are typically corrected using the undamaged complementary strand or, in diploid organisms, the homologous chromosome.
In contrast, a mutation represents an alteration in the base sequence that has become fixed in both DNA strands. Once established, it is no longer recognised as abnormal and therefore cannot be corrected through standard repair pathways. While DNA damage can block transcription or replication and may result in cell death, mutations are faithfully replicated when the cell divides. They accumulate in populations of cells or organisms according to their impact on survival and reproduction.

Mechanisms and types of mutation

Mutations can take many forms, depending on the underlying molecular process.
Point mutations involve changes at single nucleotide positions.

• Substitutions replace one base with another.
• Insertions and deletions add or remove small numbers of nucleotides, sometimes altering the reading frame of a gene.

Larger-scale mutations encompass structural changes in chromosomes.

• Gene duplication results in the copying of entire genes or substantial genomic segments, creating redundant genetic material.
• Inversions, translocations, and chromosome fusions rearrange genomic architecture.
• Changes in chromosome number such as aneuploidy or polyploidy alter the genetic complement of cells or organisms.

Mobile genetic elements, including transposable elements, can move within the genome, causing insertions, deletions, or regulatory changes. Many plant and animal genomes contain vast numbers of such elements; for example, Alu sequences constitute a significant portion of the human genome.
At the molecular level, a variety of spontaneous events can introduce mutations. Proton repositioning in nucleotides can give rise to tautomeric forms that pair incorrectly during DNA replication. Loss of purine bases creates apurinic sites, and hydrolytic reactions may convert bases to atypical forms, some of which are recognised and repaired while others persist. During replication, misalignment or ‘slippage’ between template and nascent strands can generate small insertions or deletions.
Mutations can also arise through error-prone translesion synthesis, a process in which specialised polymerases bypass lesions in the template strand at the cost of increased replication errors. Errors introduced during DNA repair itself, particularly during repair of double-strand breaks by mechanisms such as microhomology-mediated end joining, also contribute to mutational load.
Environmental agents, known as mutagens, including ultraviolet radiation, ionising radiation, and certain chemicals, produce DNA damage that may convert to fixed mutations if not accurately repaired.

Mutations and evolutionary processes

Mutation provides the primary raw material on which natural selection and genetic drift act. Although most mutations are neutral or deleterious, a small proportion confer advantageous traits that improve reproductive success. These beneficial mutations can spread through populations, enabling adaptation.
Gene duplication plays a particularly significant role in evolution. When a gene is duplicated, one copy typically retains the original function while the other acquires mutations that may lead to new functions. Such duplications have produced extensive gene families in animals and plants. In humans, for instance, the genes responsible for colour and night vision arose through successive duplications of an ancestral photoreceptor gene.
Chromosomal rearrangements can promote speciation by reducing gene flow between populations. For example, the fusion of two ancestral ape chromosomes produced human chromosome 2, a structural change absent in other extant apes. This and comparable rearrangements alter patterns of chromosomal pairing and recombination, potentially accelerating genetic divergence.
Mobile elements also contribute to evolutionary innovation. Some transposable element insertions have been co-opted as regulatory sequences influencing gene expression. Others create structural variation or serve as substrates for recombination, thereby generating diversity.

Mutations and genetic variation within populations

Within population gene pools, mutations accumulate as long as they do not reduce fitness severely. Neutral mutations, which do not affect survival or reproduction, can increase in frequency through genetic drift. The vast majority of mutations in organisms with large genomes are believed to be neutral or nearly neutral, consistent with theoretical models. Non-lethal but mildly deleterious mutations may persist at low frequencies, counterbalanced by selection.
Mutation rates vary between organisms and even between sexes. In humans, an average of around sixty new mutations is passed to each offspring, with paternal age contributing significantly to the number due to continual sperm production and associated replication cycles.

Mutations and disease

Mutations underpin many diseases, including cancer, in which somatic mutations disrupt normal regulatory pathways governing cell proliferation. Studies suggest that a substantial portion of cancer-associated mutations arise from intrinsic replication errors, with environmental and inherited factors accounting for the remainder. Many organisms possess mechanisms such as apoptosis, which eliminate cells carrying harmful mutations, thereby protecting tissues from further damage.
Some mutations are beneficial, notably those affecting immune cell receptors, which contribute to antibody diversity and enhance pathogen recognition. Such programmed mutational mechanisms underlie key components of adaptive immunity.

Classes and causes of mutation

Mutations can be categorised into four broad classes based on their origin:

• Molecular decay, encompassing spontaneous hydrolysis, depurination, and tautomeric shifts.
• Error-prone bypass of damaged bases during DNA replication.
• Errors introduced during DNA repair, especially those arising from pathways that operate without a high-fidelity template.
• Induced mutations caused by exposure to mutagens or deliberate experimental manipulation.

Each class contributes to the overall mutational burden experienced by organisms.

Spontaneous mutation dynamics

Spontaneous mutations occur continually, even in healthy cells free from external stress. Oxidative damage alone is estimated to strike human DNA tens of thousands of times per cell per day. Although most lesions are repaired, a fraction leads to permanent sequence changes. Some spontaneous processes, such as proton tunnelling between base pairs, have been proposed as quantum-level contributors to replication errors, illustrating the complexity of molecular events underpinning mutation.
Mutational mechanisms emphasise the dynamic and continually changing nature of genomes. By generating new genetic combinations and altering existing sequences, mutations underpin biological diversity, drive evolutionary change, and shape the capacity of organisms to adapt to their environments.