Genomics
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Description
A mutation is a permanent structural alteration in DNA. In most cases, DNA changes either have no effect or cause harm, but occasionally a mutation can improve an organism's chance of surviving and passing the beneficial change on to its descendants.
Discussion
In biology, mutations are changes to the genetic material (usually DNA or RNA). Mutations can be caused by copying errors in the genetic material during cell division and by exposure to radiation, chemicals, or viruses, or can occur deliberately under cellular control during processes such as meiosis or hypermutation. In multicellular organisms, mutations can be subdivided into germline mutations, which can be passed on to descendants and somatic mutations. The somatic mutations cannot be transmitted to descendants in animals. Plants sometimes can transmit somatic mutations to their descendents asexually or sexually (in case when flower buds develop in somatically mutated part of plant).
Mutations are considered the driving force of evolution, where less favorable (or deleterious) mutations are removed from the gene pool by natural selection, while more favorable (beneficial or advantageous) ones tend to accumulate. Neutral mutations are defined as mutations whose effects do not influence the fitness of either the species or the individuals who make up the species. These can accumulate over time. The overwhelming majority of mutations have no significant effect, since DNA repair is able to revert most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise permanently mutated somatic cells.
Classification
By effect on structure
The DNA sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health, depending on where they occur and whether they alter the function of essential proteins. Structurally, mutations can be classified as:
- Small-scale mutations affecting one or a few nucleotides, including:
- Point mutations, often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another. Most common is the transition that exchanges a purine for a purine (A ↔ G) or a pyrimidine for a pyrimidine, (C ↔ T). A transition can be caused by nitrous acid, base mispairing, or mutagenic base analogs such as 5-bromo-2-deoxyuridine (BrdU). Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). A point mutation can be reversed by another point mutation, in which the nucleotide is changed back to its original state (true reversion) or by second-site reversion (a complementary mutation elsewhere that results in regained gene functionality). These changes are classified as transitions or transversions. An example of a transversion is adenine being converted into a cytosine. There are also many other examples that can be found. Point mutations that occur within the protein coding region of a gene may be classified into three kinds, depending upon what the erroneous codon codes for:
- Silent mutations: which code for the same amino acid.
- Missense mutations: which code for a different amino acid.
- Nonsense mutations: which code for a stop, which can truncate the protein.
- Insertions add one or more extra nucleotides into the DNA. They are usually caused by transposable elements, or errors during replication of repeating elements (e.g. AT repeats). Insertions in the coding region a gene may alter splicing of the mRNA, or cause a shift in the reading frame (frameshift), both of which can significantly alter the gene product. Insertions can be reverted by excision of the transposable element.
- Deletions remove one or more nucleotides from the DNA. Like insertions, these mutations can alter the reading frame of the gene. They are irreversible.
- Large-scale mutations in chromosomal structure, including:
- Amplifications (or gene duplications) leading to multiple copies of chromosomal regions, increasing the dosage of the genes located within them.
- Deletions of large chromosomal regions, leading to loss of the genes within those regions.
- Mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct fusion genes (e.g. bcr-abl). These include:
- Chromosomal translocations: interchange of genetic parts from nonhomologous chromosomes.
- Interstitial deletions: removing regions of DNA from a single chromosome, thereby apposing previously distant genes (e.g. fig-ros).
- Chromosomal inversions: reversing the orientation of a chromosomal segment.
- Loss of heterozygosity: loss of one allele, either by a deletion or recombination event, in organisms which previously had two.
By effect on function
- Loss-of-function mutations are the result of gene product having less or no function. When the allele has a complete loss of function (null allele) it is often called an amorphic mutation. Phenotypes associated with such mutations are most often recessive. Exceptions are when the organism is haploid, or when the reduced dosage of normal gene product is not enough for normal phenotype (this is called haploinsufficiency).
- Gain-of-function mutations change the gene product such that it gains a new and abnormal function. These mutations usually have dominant phenotypes.
- Dominant negative mutations (also called antimorphic mutations) have an altered gene product that acts antagonistically to the wild type allele. These mutations usually result in an altered molecular function (often inactive) and are characterised by a dominant or semi-dominant phenotype.
- Lethal mutations are mutations that lead to a phenotype incapable of effective reproduction.
By effect on gene expression
- Hypomorphic mutations are mutations that cause reduced function of the gene product, or a negative change in expression of the gene.
- Hypermorphic mutations are the opposite of hypomorphic mutations; they cause increased activity or expression of the gene product.
- Neomorphic mutations cause a novel molecular function or expression of the gene product.
By aspect of phenotype affected
- Morphological mutations usually affect the outward appearance of an individual. Mutations can change the height of a plant or change it from smooth to rough seeds.
- Biochemical mutations result in lesions stopping the enzymatic pathway. Often, morphological mutants are the direct result of a mutation due to the enzymatic pathway.
Special classes
- Conditional mutation is a mutation that has wild-type phenotype under certain environmental conditions and a mutant phenotype under certain selective conditions. Conditional mutations may also be lethal.
Causes of mutation
Two classes of mutations are spontaneous mutations (molecular decay) and induced mutations caused by mutagens.
Spontaneous mutations on the molecular level include:
- Tautomerism - A base is changed by the repositioning of a hydrogen atom.
- Depurination - Loss of a purine base (A or G).
- Deamination - Changes a normal base to an atypical base; C → U, (which can be corrected by DNA repair mechanisms), or spontaneous deanimation of 5-methycytosine (irreparable), or A → HX (hypoxanthine).
- Transition - A purine changes to another purine, or a pyrimidine to a pyrimidine.
- Transversion - A purine becomes a pyrimidine, or vice versa.
Induced mutations on the molecular level can be caused by:
- Chemicals
- Nitrosoguanidine (NTG)
- Base analogs (e.g. BrdU)
- Simple chemicals (e.g. acids)
- Alkylating agents (e.g. N-ethyl-N-nitrosourea (ENU)) These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can only mutate the DNA when the analog is incorporated in replicating the DNA. Each of these classes of chemical mutagens has certain effects that then lead to transitions, transversions, or deletions.
- Methylating agents (e.g. ethane methyl sulfonate (EMS))
- Polycyclic hydrocarbons (e.g. benzpyrenes found in internal combustion engine exhaust)
- DNA intercalating agents (e.g. ethidium bromide)
- DNA crosslinker (e.g. platinum)
- Oxidative damage caused by oxygen radicals
- Radiation
- Ultraviolet radiation (nonionizing radiation)- excites electrons to a higher energy level. DNA absorbs one form, ultraviolet light. Two nucleotide bases in DNA - cytosine and thymine-are most vulnerable to excitation that can change base-pairing properties. UV light can induce adjacent thymine bases in a DNA strand to pair with each other, as a bulky dimer.
- Ionizing radiation
DNA has so-called hotspots, where mutations occur up to 100 times more frequently than the normal mutation rate. A hotspot can be at an unusual base, e.g., 5-methylcytosine.
Mutation rates also vary across species. Evolutionary biologists have theorized that higher mutation rates are beneficial in some situations, because they allow organisms to evolve and therefore adapt more quickly to their environments. For example, repeated exposure of bacteria to antibiotics, and selection of resistant mutants, can result in the selection of bacteria that have a much higher mutation rate than the original population (mutator strains).
Mutation and disease
Changes in DNA caused by mutation can cause errors in protein sequence, creating partially or completely non-functional proteins. To function correctly, each cell depends on thousands of proteins to function in the right places at the right times. When a mutation alters a protein that plays a critical role in the body, a medical condition can result. A condition caused by mutations in one or more genes is called a genetic disorder. However, only a small percentage of mutations cause genetic disorders, most have no impact on health. For example, some mutations alter a gene's DNA base sequence but don’t change the function of the protein made by the gene.
If a mutation is present in a germ cell, this can give rise to offspring that carries the mutation in all of its cells. This is the case in hereditary diseases. On the other hand, a mutation can occur in a somatic cell of an organism. Such mutations will be present in all descendants of this cell, and certain mutations can cause the cell to become malignant, and thus cause cancer.
Often, gene mutations that could cause a genetic disorder are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, the process of DNA repair is an important way in which the body protects itself from disease.
A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. For example, a beneficial mutation could result in a protein that protects the organism from a new strain of bacteria. Once the bacteria has its error of copying the sequence, the mutation will successfully develope in 5 days. This sequence is done on the head.
Mutagenesis
Mutagenesis (the creation or formation of a mutation) can be used as a powerful genetic tool. By inducing mutations in specific ways and then observing the phenotype of the organism the function of genes and even individual nucleotides can be determined.
References
- Maki H. 2002. Origins of spontaneous mutations: specificity and directionality of base-substitution, frameshift, and sequence-substitution mutageneses. Annual Review of Genetics 36:279-303.
- Taggart R. Starr C. Biology The Unity and Diversity of Life: Mutated Genes and Their Protein Products. 14.4:227. Thompson Brooks/Cole 2006.
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