Genetic Mutations - Introductory Genetics: Alexandra D. Simmons N., PhD.

Mutations are permanent, heritable changes in DNA sequences. They are not detected as errors by DNA polymerase and won’t be repaired by normal mechanisms. Mutations can be beneficial, harmful, or neutral—most are neutral. Importantly, even a single base pair change means the entire DNA sequence is considered mutated. Image credit: “Robertsonian translocation diagram” by Splette (Wikimedia Commons), CC BY 4.0, modified with added labels.

Point mutation

Mutation that impacts a single base-pair (deletion, insertion, or base substitution).

Chromosomal Rearrangements

Change in structure of chromosome(s), may consist of many sub mutations. Can involve multiple chromosomes or even result in changes to ploidy number (number of sets of chromosomes).

Base substitution

Mutation in which one nucleotide is replaced with another. (Only one base pair has been modified)

Transition

Specific base substitution in which a pyrimidine is changed for another pyrimidine, or a purine is changed for another purine.

Transversion

Specific base substitution in which a pyrimidine is changed for a purine or vice versa.

Deletion(s)

Removal of one or more nucleotides.

Insertion

Addition of one or more nucleotides.

Indels

Either insertion or deletion of nucleotides (can range from just 1 base pair to a sequence of several Mb of genomic sequence—millions of base pairs).

In-frame

Nucleotide addition or deletion, multiples of 3 (3, 6, 9, …). Do not affect the reading frame.

Frameshift

Addition or deletion of nucleotides that changes the reading frame (not a multiple of 3 base pairs).

Dynamic repeats / Dynamic mutations

Mutation caused by unstable expansions of microsatellites, repeating units of 3 to 6 nucleotides. (Diseases caused by this show “anticipation,” where the disease manifests earlier and severity increases with each generation.)

Transposition

Mutation caused by the movement of a transposon from one genomic locus to another.

Missense mutation

Change of a codon for a non-synonymous codon.

Conservative substitution

Missense mutation that changes the original amino acid to another with similar properties.

Nonconservative substitution

Missense mutation that changes the original amino acid to another with different properties.

Neutral mutation

Missense mutation similar to a conservative substitution: the change of amino acid does not significantly impact the function of the protein.

Silent mutation

Change of a codon for a synonymous codon. Even though the DNA sequence has changed, the primary structure of the protein does not.

Nonsense mutation

Change of a sense codon for a non-sense codon (stop codon). Leads to early termination of protein synthesis, producing a truncated protein or no protein at all.

Loss of function mutation

Mutation that can: inactivate a regulatory sequence, eliminate protein synthesis, or produce a nonfunctional (or reduced-function) protein.

Gain of function mutation

Rare mutation which allows a protein to acquire a new function, often detrimental.

Lethal mutation

Mutation that leads to the death of the organism.

Dominant-negative effect

In a heterozygous individual, this mutation produces an altered protein that interferes with the function of the normal protein produced from the normal allele.

Forward mutation

Change of a normal allele (wild-type) to a mutant allele.

Reverse genetics

The method by which specific genes are mutated to observe the consequences.

Reverse mutation

Change of a mutant allele to a normal allele (counteracts forward mutation).

Intragenic suppressor

When the reverse mutation occurs at a different nucleotide in the same gene.

Intergenic suppressor

When the reverse mutation occurs in a different gene.

Somatic mutation

Mutation in any cell, with the exception of germ cells and cells that produce them.

Germline mutation

Mutations in germ cells or the cells that produce them.

Endogenous mutation

Mutation that occurs naturally in living cells.

Exogenous mutation

Mutation caused by an external agent.

Genomic rearrangement

Mutations that involve larger segments of DNA (a few to thousands of nucleotides) that may include coding regions, exons, a gene or group of genes. (Deviations from normal diploid or changes to relative location of genes.)

Genomic disorder

Genetic disease caused by a genomic

Copy number variant

Variation observed in the number of genes or DNA segments, which may be duplicated or deleted, with no apparent clinical significance.

Structural variant

Variation observed in the structure of the genome, where segments are inverted or translocated, with no apparent clinical significance.

Microduplication

Genomic rearrangement in which a segment of DNA has been duplicated.

Microdeletion

Genomic rearrangement in which a segment of DNA has been deleted.

Insertion (genomic rearrangement)

Genomic rearrangement that leads to the addition of one or more nucleotides into a specific locus.

Inversion

Genomic rearrangement in which two breaks are made in a DNA segment, and it is reinserted in the opposite orientation.

Translocation

Break of a segment of one or more chromosomes that become attached to another. Exchange of DNA segments between non-homologous chromosomes: “balanced” when no genetic material is lost; “unbalanced” when some is lost.

Robertsonian translocation

Centromere-to-centromere fusion of two acrocentric chromosomes, usually between non-homologous chromosomes. The short arms of each chromosome also merge but are lost due to lack of centromeres/kinetochores.

Aneuploidy

Loss or gain of one or more chromosomes of the diploid set. Impact on the organism is usually severe.

Nullisomy

A specific homologous pair of chromosomes is absent.

Monosomy

Loss of one chromosome of a homologous pair.

Trisomy

Having three copies of the same chromosome.

Tetrasomy

Having four copies of the same chromosome.

Uniparental disomy (UPD)

When both chromosomes of a homologous pair originate from only one parent. UPD can be partial or complete.

Polyploidy

When a cell contains more than two chromosome sets.

Alleles

Different forms of a gene (sequence variants).

Mutant allele

Variants that cause a disease or specific conditions (different from “mutant alleles”).

Wild-type allele

Most common allele in a population.

Polymorphism

Mutations resulting in a normal variant (mutant allele), expressing a phenotype variant found in that population.

Mutant alleles

Alleles from mutating a wild-type allele to produce a different phenotype (different from “mutant allele”; do not necessarily carry disease/condition).

SNPs (single nucleotide polymorphism)

A subclass of base substitution mutations with “unknown consequences.”

Knockout mutations

Subclass of loss of function: sequence or protein displays complete loss of function.

Knockdown mutations

Subclass of loss of function: function is reduced or production is insufficient for that phenotype.

Forward genetics

Altered phenotypes are studied to identify the causal mutation.

Inherited mutation

Mutant allele inherited from one or both parents.

Induced mutation

A mutation caused by an external agent or treatment (not inherited).

Spontaneous mutations

A mutation via endogenous forces.

De novo mutation

New mutation (spontaneous) not inherited from parents.

Endogenous DNA damage

Damage originating from internal cellular processes.

Exogenous DNA damage

Damage caused by external environmental factors (UV rays, ionizing radiation, toxins, etc.).