Table of Contents
Overview: How Mutations Are Classified
In the parent chapters, mutation was introduced as a permanent change in genetic information and its general causes were described. Here, the focus is on how we classify mutations into different types.
Mutations can be grouped according to:
- The size of the change (small vs. large)
- The kind of change in the DNA sequence
- The effect on gene products (proteins)
- The cells in which they occur
- The level at which we view them (DNA, gene, chromosome, genome)
These different perspectives overlap. The same mutation can belong to several categories at once (e.g., “point mutation, missense, somatic”).
Below, the most important categories are structured from small-scale (molecular) to large-scale (chromosomal, genomic), and finally by biological context (somatic vs. germline).
Point Mutations (Base Substitution Mutations)
Point mutations affect one single base pair or just a few closely neighboring bases in the DNA.
Types by Nucleotide Change
Transitions and Transversions
- Transition: a purine is replaced by another purine (A ↔ G) or a pyrimidine by another pyrimidine (C ↔ T).
- Transversion: a purine is replaced by a pyrimidine or vice versa (A or G ↔ C or T).
This distinction is often important for understanding mutation mechanisms, but for effects on proteins, we more commonly use the categories below.
Types by Effect on the Coding Sequence
When a point mutation occurs in the coding region of a protein-coding gene, it can change the encoded protein in different ways.
Silent (Synonymous) Mutation
- Definition: A base is changed, but the resulting codon still encodes the same amino acid.
- Reason: The genetic code is degenerate (several codons can specify the same amino acid).
- Consequences:
- The amino acid sequence of the protein remains unchanged.
- Often no visible phenotypic effect.
- Can still subtly influence protein production (e.g., mRNA stability, translation speed), but these finer points are not part of basic classification.
Missense Mutation
- Definition: A base change leads to a codon that encodes a different amino acid.
- Consequences depend on:
- Position within the protein (active site vs. unimportant region).
- Chemical properties of the old vs. new amino acid (similar vs. very different).
- Subtypes (conceptual):
- Conservative missense: replaced by a chemically similar amino acid; often mild effects.
- Nonconservative missense: replaced by a very different amino acid; often stronger functional changes.
- Many single–amino acid genetic diseases are caused by missense mutations.
Nonsense Mutation
- Definition: A base change converts a codon for an amino acid into a stop codon (UAA, UAG, UGA).
- Consequences:
- Premature termination of translation.
- Protein is shorter (truncated) and usually nonfunctional or unstable.
- Severity depends on how far “upstream” the new stop codon lies.
Small Insertions and Deletions (Indels)
Insertions add one or more nucleotides into the DNA.
Deletions remove one or more nucleotides from the DNA.
Frameshift Mutations
- Occur when the number of inserted or deleted bases is not a multiple of 3.
- The reading frame of the mRNA (grouping into triplets) is shifted from the mutation onward.
- Consequences:
- All codons downstream are read differently.
- The amino acid sequence after the mutation is changed dramatically.
- Often a premature stop codon appears soon after, creating a truncated protein.
- Typically has severe functional consequences if within the coding region.
In-Frame Insertions and Deletions
- Occur when nucleotides are added or removed in multiples of 3.
- The reading frame remains intact, but one or more entire amino acids are added or lost.
- Consequences:
- Protein is slightly shorter or longer.
- Effect can be mild or severe, depending on which amino acids and regions are affected.
Larger-Scale Gene and Chromosomal Mutations
Mutations at higher levels involve larger DNA segments. These are often visible at the chromosomal level and frequently affect multiple genes at once.
Gene-Level Deletions and Duplications
These can be small (a few bases) or large (entire genes).
- Gene deletion:
- One or more genes are completely removed.
- Leads to loss of gene function, sometimes called a null mutation if no functional product is made.
- Gene duplication:
- One or more gene copies are added.
- Important for evolution (extra copies can accumulate new mutations and functions).
- In an individual, can cause dosage effects (too much of a gene product).
Chromosome Structure Mutations (Structural Aberrations)
Here, a segment of a chromosome is rearranged. These are often detectable under a microscope.
Deletion (Chromosomal)
- A piece of a chromosome is lost.
- Multiple genes may be removed.
- Can cause severe developmental problems.
Duplication (Chromosomal)
- A segment of a chromosome is copied and inserted next to the original or elsewhere in the genome.
- Increases gene dosage in that region.
Inversion
- A chromosome segment breaks out, rotates 180°, and reinserts.
- Two types:
- Paracentric inversion: does not involve the centromere.
- Pericentric inversion: includes the centromere.
- Gene content stays the same, but order is reversed.
- Functional consequences:
- Breakpoints can disrupt genes.
- Can lead to problems during meiosis (abnormal gametes).
Translocation
- Exchange or movement of chromosome segments between non-homologous chromosomes.
- Two main forms:
- Reciprocal translocation: exchange of fragments between two chromosomes.
- Robertsonian translocation: fusion of whole long arms of acrocentric chromosomes.
- Often no effect in carriers if no genes are broken and dosage is preserved, but can cause:
- Infertility or recurrent miscarriages (unbalanced gametes).
- Misregulation of genes at the junction sites.
Genomic Mutations (Changes in Chromosome Number)
While “types of mutations” can be defined at many scales, very large-scale changes to chromosome number are also included as mutation types at the genomic level.
- Aneuploidy:
- Gain or loss of individual chromosomes.
- Examples (humans): trisomy (2n + 1), monosomy (2n − 1).
- Results from nondisjunction during meiosis or mitosis.
- Polyploidy:
- Entire chromosome set is duplicated (e.g., 3n, 4n).
- Common and often beneficial in plants; usually lethal or severely disruptive in animals.
(Details and human examples of chromosomal and genomic mutations are covered elsewhere; here the focus is on their classification as mutation types.)
Types of Mutations by Effect on Gene Function
The same structural change can have different functional effects. Common functional categories:
- Loss-of-function mutation:
- Reduces or abolishes the activity of a gene product.
- Can be hypomorphic (reduced activity) or null/amorphic (no activity).
- Gain-of-function mutation:
- Creates a gene product with new or enhanced activity, or inappropriate activity (e.g., always “on”).
- Often associated with dominance (a single mutant allele can be sufficient for an effect).
- Dominant-negative mutation:
- The mutant gene product interferes with the function of the normal product (often when proteins form complexes).
These labels describe what the mutation does to gene function, not its size or shape at the DNA level.
Types of Mutations by Origin and Cell Type
Spontaneous vs. Induced Mutations
- Spontaneous mutations:
- Arise without an identifiable external mutagen.
- Result from natural processes such as replication errors, spontaneous base changes, or endogenous DNA damage.
- Induced mutations:
- Caused by external mutagens, such as certain chemicals or radiation.
- Specific patterns of DNA change often reflect the type of mutagen.
(The mechanisms and examples of mutagens are part of the “Causes of Mutations” chapter.)
Somatic vs. Germline Mutations
- Somatic mutations:
- Occur in body cells (non-reproductive cells).
- Affect only the organism in which they occur.
- Can contribute to cancers and mosaicism, but are not passed to offspring in sexually reproducing organisms.
- Germline mutations:
- Occur in gametes or their precursor cells.
- Can be transmitted to the next generation.
- Form the basis for heritable genetic variation and genetic diseases.
In genetic inheritance studies, germline mutations are usually the main focus.
Neutral, Deleterious, and Beneficial Mutations
In an evolutionary and phenotypic context, mutations can also be categorized by their effect on fitness (reproductive success in a given environment):
- Neutral mutations:
- No measurable effect on fitness.
- Can still spread in a population through genetic drift.
- Deleterious mutations:
- Reduce fitness.
- Often removed by natural selection.
- Beneficial mutations:
- Increase fitness in a particular environment.
- Can increase in frequency by positive selection.
These categories describe the consequences for the organism and population, not the molecular form of the mutation itself.
Summary
- Mutations differ in scale (from single bases to whole genomes), molecular form (substitutions, insertions, deletions, rearrangements), functional effect (silent, missense, nonsense, frameshift; loss- or gain-of-function), and biological context (somatic vs. germline; spontaneous vs. induced; neutral vs. selected).
- A full description of a mutation often combines several labels, for example:
“germline, induced, point mutation, missense, loss-of-function” or
“somatic, spontaneous, chromosomal deletion, loss-of-function.” - This classification framework helps connect molecular changes in DNA with their effects on proteins, cells, organisms, and populations.