Mutations and genetic variants

A mutation is a lasting change in the DNA sequence or the organization of genetic material. “Genetic variant” is often preferred because a change is not necessarily damage or a cause of disease. Variants arise through DNA copying and repair errors and through mutagens, such as ionizing or ultraviolet radiation and certain chemicals. Some viruses can also alter a cell’s genetic material. Specialized processes, such as somatic hypermutation in immune cells, have a physiological role; normal meiotic recombination is not itself equivalent to mutation.

Changes in reproductive cells may be passed to offspring. Somatic changes arise in other cells and are usually not inherited by children. Clinical significance depends on the particular change, the cells affected and its influence on gene function.

Changes in chromosome number

A change in the number of complete chromosome sets is called polyploidy: triploidy is 3n and tetraploidy is 4n, compared with the usual diploid 2n complement. Loss or gain of individual chromosomes is called aneuploidy. This differs from changing the number of complete sets; for example, trisomy means three copies of a particular chromosome.

Structural chromosome changes

Large rearrangements may involve part of one chromosome or several chromosomes:

• Deletion: loss of a DNA segment.
• Duplication: an additional copy of a segment.
• Inversion: reversal of a DNA segment’s orientation.
• Translocation: movement of a segment, including between different chromosomes.

The consequences depend on the rearrangement’s size and location and on whether the amount of genetic material changes.

Changes within a gene

Gene variants include nucleotide substitutions, deletions, insertions, duplications and other rearrangements. Replacing one nucleotide is a single-nucleotide substitution; it can occur in coding, regulatory or other DNA regions.

Base substitutions are classified as transitions—purine to purine (A↔G) or pyrimidine to pyrimidine (T↔C)—or transversions, in which a purine replaces a pyrimidine or vice versa (A/G↔T/C).

Effects on a coding sequence include:

• Synonymous substitution (same-sense): the new codon specifies the same amino acid because the genetic code is redundant. This does not always mean no biological effect; splicing or expression regulation may sometimes change.
• Missense variant: the codon specifies a different amino acid. This may alter protein function but does not necessarily make the protein nonfunctional or cause disease.
• Nonsense variant: a premature stop codon forms, potentially producing a shortened protein or degradation of the corresponding RNA. The three messenger RNA stop codons are UAG (amber), UAA (ochre) and UGA (opal).

Uracil (U) is a normal RNA base, used instead of thymine (T), not cytosine (C); its presence is not unique to stop codons. Cytosine deamination in DNA can produce uracil and a mismatched U–G pair. If unrepaired, this damage can become a substitution after replication.

Frameshift

In a coding sequence, insertion or deletion of a number of nucleotides not divisible by three usually shifts the reading frame. Because codons are read in triplets, the grouping of subsequent nucleotides changes and a premature stop codon often appears. An insertion or deletion divisible by three usually preserves the frame but can still disrupt protein function. This classification does not cover every possible effect: changes outside coding regions may also matter.