For other uses, see Mutation (disambiguation).
In biology, a mutation is the permanent alteration of the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA or other genetic elements.
Mutations result from errors during DNA replication or other types of damage to DNA (such as may be caused by exposure to radiation or carcinogens), which then may undergo error-prone repair (especially microhomology-mediated end joining), or cause an error during other forms of repair, or else may cause an error during replication (translesion synthesis). Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements. Mutations may or may not produce discernible changes in the observable characteristics (phenotype) of an organism. Mutations play a part in both normal and abnormal biological processes including: evolution, cancer, and the development of the immune system, including junctional diversity.
The genomes of RNA viruses are based on RNA rather than DNA. The RNA viral genome can be double stranded (as in DNA) or single stranded. In some of these viruses (such as the single stranded human immunodeficiency virus) replication occurs quickly and there are no mechanisms to check the genome for accuracy. This error-prone process often results in mutations.
Mutation can result in many different types of change in sequences. Mutations in genes can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. Mutations can also occur in nongenic regions. One study on genetic variations between different species of Drosophila suggests that, if a mutation changes a protein produced by a gene, the result is likely to be harmful, with an estimated 70 percent of amino acidpolymorphisms that have damaging effects, and the remainder being either neutral or marginally beneficial. Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as DNA repair to prevent or correct mutations by reverting the mutated sequence back to its original state.
Mutations can involve the duplication of large sections of DNA, usually through genetic recombination. These duplications are a major source of raw material for evolving new genes, with tens to hundreds of genes duplicated in animal genomes every million years. Most genes belong to larger gene families of shared ancestry, known as homology. Novel genes are produced by several methods, commonly through the duplication and mutation of an ancestral gene, or by recombining parts of different genes to form new combinations with new functions.
Here, protein domains act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties. For example, the human eye uses four genes to make structures that sense light: three for cone cell or color vision and one for rod cell or night vision; all four arose from a single ancestral gene. Another advantage of duplicating a gene (or even an entire genome) is that this increases engineering redundancy; this allows one gene in the pair to acquire a new function while the other copy performs the original function. Other types of mutation occasionally create new genes from previously noncoding DNA.
Changes in chromosome number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the Homininae, two chromosomes fused to produce human chromosome 2; this fusion did not occur in the lineage of the other apes, and they retain these separate chromosomes. In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into new species by making populations less likely to interbreed, thereby preserving genetic differences between these populations.
Sequences of DNA that can move about the genome, such as transposons, make up a major fraction of the genetic material of plants and animals, and may have been important in the evolution of genomes. For example, more than a million copies of the Alu sequence are present in the human genome, and these sequences have now been recruited to perform functions such as regulating gene expression. Another effect of these mobile DNA sequences is that when they move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity.
Nonlethal mutations accumulate within the gene pool and increase the amount of genetic variation. The abundance of some genetic changes within the gene pool can be reduced by natural selection, while other "more favorable" mutations may accumulate and result in adaptive changes.
For example, a butterfly may produce offspring with new mutations. The majority of these mutations will have no effect; but one might change the color of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chance of this butterfly's surviving and producing its own offspring are a little better, and over time the number of butterflies with this mutation may form a larger percentage of the population.
Neutral mutations are defined as mutations whose effects do not influence the fitness of an individual. These can accumulate over time due to genetic drift. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness.[better source needed] Also, DNA repair mechanisms are able to mend most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise-permanently mutated somatic cells.
Beneficial mutations can improve reproductive success.
Main article: Mutationism
Mutationism is one of several alternatives to evolution by natural selection that have existed both before and after the publication of Charles Darwin's 1859 book, On the Origin of Species. In the theory, mutation was the source of novelty, creating new forms and new species, potentially instantaneously, in a sudden jump. This was envisaged as driving evolution, which was limited by the supply of mutations.
Before Darwin, biologists commonly believed in saltationism, the possibility of large evolutionary jumps, including immediate speciation. For example, in 1822 Étienne Geoffroy Saint-Hilaire argued that species could be formed by sudden transformations, or what would later be called macromutation. Darwin opposed saltation, insisting on gradualism in evolution as in geology. In 1864, Albert von Kölliker revived Geoffroy's theory. In 1901 the geneticistHugo de Vries gave the name "mutation" to seemingly new forms that suddenly arose in his experiments on the evening primrose Oenothera lamarckiana, and in the first decade of the 20th century, mutationism, or as de Vries named it mutationstheorie, became a rival to Darwinism supported for a while by geneticists including William Bateson,Thomas Hunt Morgan, and Reginald Punnett.
Understanding of mutationism is clouded by the mid-20th century portrayal of the early mutationists by supporters of the modern synthesis as opponents of Darwinian evolution and rivals of the biometrics school who argued that selection operated on continuous variation. In this portrayal, mutationism was defeated by a synthesis of genetics and natural selection that supposedly started later, around 1918, with work by the mathematician Ronald Fisher. However, the alignment of Mendelian genetics and natural selection began as early as 1902 with a paper by Udny Yule, and built up with theoretical and experimental work in Europe and America. Despite the controversy, the early mutationists had by 1918 already accepted natural selection and explained continuous variation as the result of multiple genes acting on the same characteristic, such as height.
Mutationism, along with other alternatives to Darwinism like Lamarckism and orthogenesis, was discarded by most biologists as they came to see that Mendelian genetics and natural selection could readily work together; mutation took its place as a source of the genetic variation essential for natural selection to work on. However, mutationism did not entirely vanish. In 1940, Richard Goldschmidt again argued for single-step speciation by macromutation, describing the organisms thus produced as "hopeful monsters", earning widespread ridicule. In 1987, Masatoshi Nei argued controversially that evolution was often mutation-limited. Modern biologists such as Douglas J. Futuyma conclude that essentially all claims of evolution driven by large mutations can be explained by Darwinian evolution.
Main article: Mutagenesis
Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of naturally occurring DNA damage (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens. Scientists may also deliberately introduce mutant sequences through DNA manipulation for the sake of scientific experimentation.
One 2017 study claimed that 66% of cancer-causing mutations are random, 29% are due to the environment (the studied population spanned 69 countries), and 5% are inherited.
Spontaneous mutations occur with non-zero probability even given a healthy, uncontaminated cell. They can be characterized by the specific change:
- Tautomerism — A base is changed by the repositioning of a hydrogen atom, altering the hydrogen bonding pattern of that base, resulting in incorrect base pairing during replication.
- Depurination — Loss of a purine base (A or G) to form an apurinic site (AP site).
- Deamination — Hydrolysis changes a normal base to an atypical base containing a keto group in place of the original amine group. Examples include C → U and A → HX (hypoxanthine), which can be corrected by DNA repair mechanisms; and 5MeC (5-methylcytosine) → T, which is less likely to be detected as a mutation because thymine is a normal DNA base.
- Slipped strand mispairing — Denaturation of the new strand from the template during replication, followed by renaturation in a different spot ("slipping"). This can lead to insertions or deletions.
Error-prone replication bypass
There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (translesion synthesis) past DNA damage in the template strand. Naturally occurring oxidative DNA damages arise at least 10,000 times per cell per day in humans and 50,000 times or more per cell per day in rats. In mice, the majority of mutations are caused by translesion synthesis. Likewise, in yeast, Kunz et al. found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translesion synthesis.
Errors introduced during DNA repair
See also: DNA damage (naturally occurring) and DNA repair
Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation. Non-homologous end joining (NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few nucleotides to allow somewhat inaccurate alignment of the two ends for rejoining followed by addition of nucleotides to fill in gaps. As a consequence, NHEJ often introduces mutations.
Induced mutations are alterations in the gene after it has come in contact with mutagens and environmental causes.
Induced mutations on the molecular level can be caused by:
- Base analogs (e.g., Bromodeoxyuridine (BrdU))
- 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 mutate the DNA only 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.
- Agents that form DNA adducts (e.g., ochratoxin A)
- DNA intercalating agents (e.g., ethidium bromide)
- DNA crosslinkers
- Oxidative damageThis figure depicts the following processes of transcription, splicing, and translation of a eukaryotic gene.
- Nitrous acid converts amine groups on A and C to diazo groups, altering their hydrogen bonding patterns, which leads to incorrect base pairing during replication.
Classification of types
See also: Chromosome abnormality
By effect on structure
The 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. Mutations in the structure of genes can be classified into several types.
Small-scale mutations, affecting a gene in one or a few nucleotides, include:
- Substitution mutations, often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another. These changes are classified as transitions or transversions. 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 mis-pairing, or mutagenic base analogs such as BrdU. Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is the conversion of adenine (A) into a cytosine (C). A point mutation are modifications of single base pairs of DNA or other small base pairs within a gene. 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).
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:
- Insertions add one or more extra nucleotides into the DNA. They are usually caused by transposable elements, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter splicing of the mRNA (splice site mutation), or cause a shift in the reading frame (frameshift), both of which can significantly alter the gene product. Insertions can be reversed by excision of the transposable element.
- (Point) deletions remove one or more nucleotides from the DNA. Like insertions, these mutations can alter the reading frame of the gene. In general, they are irreversible: Though exactly the same sequence might in theory be restored by an insertion, transposable elements able to revert a very short deletion (say 1–2 bases) in any location either are highly unlikely to exist or do not exist at all.
Large-scale mutations in chromosomal structure include:
- Amplifications (or gene duplications) leading to multiple copies of all 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: an intra-chromosomal deletion that removes a segment of DNA from a single chromosome, thereby apposing previously distant genes. For example, cells isolated from a human astrocytoma, a type of brain tumor, were found to have a chromosomal deletion removing sequences between the Fused in Glioblastoma (FIG) gene and the receptor tyrosine kinase (ROS), producing a fusion protein (FIG-ROS). The abnormal FIG-ROS fusion protein has constitutively active kinase activity that causes oncogenic transformation (a transformation from normal cells to cancer cells).
- Chromosomal inversions: reversing the orientation of a chromosomal segment.
- Loss of heterozygosity: loss of one allele, either by a deletion or a genetic recombination event, in an organism that previously had two different alleles.
By effect on function
- Loss-of-function mutations, also called inactivating mutations, result in the gene product having less or no function (being partially or wholly inactivated). When the allele has a complete loss of function (null allele), it is often called an amorph or amorphic mutation in the Muller's morphs schema. Phenotypes associated with such mutations are most often recessive. Exceptions are when the organism is haploid, or when the reduced dosage of a normal gene product is not enough for a normal phenotype (this is called haploinsufficiency).
- Gain-of-function mutations, also called activating mutations, change the gene product such that its effect gets stronger (enhanced activation) or even is superseded by a different and abnormal function. When the new allele is created, a heterozygote containing the newly created allele as well as the original will express the new allele; genetically this defines the mutations as dominant phenotypes. Several of Muller's morphs correspond to gain of function, including hypermorph and neomorph. In December 2017, the U.S. government lifted a temporary ban implemented in 2014 that banned federal funding for any new "gain-of-function" experiments that enhance pathogens "such as Avian influenza, SARS and the Middle East Respiratory Syndrome or MERS viruses."
- 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 characterized by a dominant or semi-dominant phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes p53,ATM,CEBPA and PPARgamma). Marfan syndrome is caused by mutations in the FBN1 gene, located on chromosome 15, which encodes fibrillin-1, a glycoprotein component of the extracellular matrix. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.
- Hypomorphs, after Mullerian classification, are characterized by altered gene products that acts with decreased gene expression compared to the wild type allele.
- Neomorphs are characterized by the control of new protein product synthesis.
- Lethal mutations are mutations that lead to the death of the organisms that carry the mutations.
- A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype.
By effect on fitness
See also: Fitness (biology)
In applied genetics, it is usual to speak of mutations as either harmful or beneficial.
- A harmful, or deleterious, mutation decreases the fitness of the organism.
- A beneficial, or advantageous mutation increases the fitness of the organism. Mutations that promotes traits that are desirable, are also called beneficial. In theoretical population genetics, it is more usual to speak of mutations as deleterious or advantageous than harmful or beneficial.
- A neutral mutation has no harmful or beneficial effect on the organism. Such mutations occur at a steady rate, forming the basis for the molecular clock. In the neutral theory of molecular evolution, neutral mutations provide genetic drift as the basis for most variation at the molecular level.
- A nearly neutral mutation is a mutation that may be slightly deleterious or advantageous, although most nearly neutral mutations are slightly deleterious.
Distribution of fitness effects
Attempts have been made to infer the distribution of fitness effects (DFE) using mutagenesis experiments and theoretical models applied to molecular sequence data. DFE, as used to determine the relative abundance of different types of mutations (i.e., strongly deleterious, nearly neutral or advantageous), is relevant to many evolutionary questions, such as the maintenance of genetic variation, the rate of genomic decay, the maintenance of outcrossing sexual reproduction as opposed to inbreeding and the evolution of sex and genetic recombination. In summary, the DFE plays an important role in predicting evolutionary dynamics. A variety of approaches have been used to study the DFE, including theoretical, experimental and analytical methods.
- Mutagenesis experiment: The direct method to investigate the DFE is to induce mutations and then measure the mutational fitness effects, which has already been done in viruses, bacteria, yeast, and Drosophila. For example, most studies of the DFE in viruses used site-directed mutagenesis to create point mutations and measure relative fitness of each mutant. In Escherichia coli, one study used transposon mutagenesis to directly measure the fitness of a random insertion of a derivative of Tn10. In yeast, a combined mutagenesis and deep sequencing approach has been developed to generate high-quality systematic mutant libraries and measure fitness in high throughput. However, given that many mutations have effects too small to be detected and that mutagenesis experiments can detect only mutations of moderately large effect; DNA sequence data analysis can provide valuable information about these mutations.
- Molecular sequence analysis: With rapid development of DNA sequencing technology, an enormous amount of DNA sequence data is available and even more is forthcoming in the future. Various methods have been developed to infer the DFE from DNA sequence data. By examining DNA sequence differences within and between species, we are able to infer various characteristics of the DFE for neutral, deleterious and advantageous mutations. To be specific, the DNA sequence analysis approach allows us to estimate the effects of mutations with very small effects, which are hardly detectable through mutagenesis experiments.
One of the earliest theoretical studies of the distribution of fitness effects was done by Motoo Kimura, an influential theoretical population geneticist. His neutral theory of molecular evolution proposes that most novel mutations will be highly deleterious, with a small fraction being neutral. Hiroshi Akashi more recently proposed a bimodal model for the DFE, with modes centered around highly deleterious and neutral mutations. Both theories agree that the vast majority of novel mutations are neutral or deleterious and that advantageous mutations are rare, which has been supported by experimental results. One example is a study done on the DFE of random mutations in vesicular stomatitis virus. Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral. Another example comes from a high throughput mutagenesis experiment with yeast. In this experiment it was shown that the overall DFE is bimodal, with a cluster of neutral mutations, and a broad distribution of deleterious mutations.
Though relatively few mutations are advantageous, those that are play an important role in evolutionary changes. Like neutral mutations, weakly selected advantageous mutations can be lost due to random genetic drift, but strongly selected advantageous mutations are more likely to be fixed. Knowing the DFE of advantageous mutations may lead to increased ability to predict the evolutionary dynamics. Theoretical work on the DFE for advantageous mutations has been done by John H. Gillespie and H. Allen Orr. They proposed that the distribution for advantageous mutations should be exponential under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations.
In general, it is accepted that the majority of mutations are neutral or deleterious, with rare mutations being advantageous; however, the proportion of types of mutations varies between species. This indicates two important points: first, the proportion of effectively neutral mutations is likely to vary between species, resulting from dependence on effective population size; second, the average effect of deleterious mutations varies dramatically between species. In addition, the DFE also differs between coding regions and noncoding regions, with the DFE of noncoding DNA containing more weakly selected mutations.
By impact on protein sequence
- A frameshift mutation is a mutation caused by insertion or deletion of a number of nucleotides that is not evenly divisible by three from a DNA sequence. Due to the triplet nature of gene expression by codons, the insertion or deletion can disrupt the reading frame, or the grouping of the codons, resulting in a completely different translation from the original. The earlier in the sequence the deletion or insertion occurs, the more altered the protein produced is.
- For example, the code CCU GAC UAC CUA codes for the amino acids proline, aspartic acid, tyrosine, and leucine. If the U in CCU was deleted, the resulting sequence would be CCG ACU ACC UAx, which would instead code for proline, threonine, threonine, and part of another amino acid or perhaps a stop codon (where the x stands for the following nucleotide).
- In contrast, any insertion or deletion that is evenly divisible by three is termed an in-frame mutation.
- A nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product. This sort of mutation has been linked to different mutations, such as congenital adrenal hyperplasia. (See Stop codon.)
- Missense mutations or nonsynonymous mutations are types of point mutations where a single nucleotide is changed to cause substitution of a different amino acid. This in turn can render the resulting protein nonfunctional. Such mutations are responsible for diseases such as Epidermolysis bullosa, sickle-cell disease, and SOD1-mediated ALS.
- A neutral mutation is a mutation that occurs in an amino acid codon that results in the use of a different, but chemically similar, amino acid. The similarity between the two is enough that little or no change is often rendered in the protein. For example, a change from AAA to AGA will encode arginine, a chemically similar molecule to the intended lysine.
- Silent mutations are mutations that do not result in a change to the amino acid sequence of a protein but do change the nucleotide sequence, unless the changed amino acid is sufficiently similar to the original. They may occur in a region that does not code for a protein, or they may occur within a codon in a manner that does not alter the final amino acid sequence. Silent mutations are also called silent substitutions, since they are not palpable changes as the changes in phenotype. The phrase silent mutation is often used interchangeably with the phrase synonymous mutation; however, synonymous mutations are a subcategory of the former, occurring only within exons (and necessarily exactly preserving the amino acid sequence of the protein). Synonymous mutations occur due to the degenerate nature of the genetic code. There can also be silent mutations in nucleotides outside of the coding regions, such as the introns, because the exact nucleotide sequence is not as crucial as it is in the coding regions.
In multicellular organisms with dedicated reproductive cells, mutations can be subdivided into germline mutations, which can be passed on to descendants through their reproductive cells, and somatic mutations (also called acquired mutations), which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.
A germline mutation gives rise to a constitutional mutation in the offspring, that is, a mutation that is present in every cell. A constitutional mutation can also occur very soon after fertilisation, or continue from a previous constitutional mutation in a parent.
The distinction between germline and somatic mutations is important in animals that have a dedicated germline to produce reproductive cells. However, it is of little value in understanding the effects of mutations in plants, which lack dedicated germline. The distinction is also blurred in those animals that reproduce asexually through mechanisms such as budding, because the cells that give rise to the daughter organisms also give rise to that organism's germline. A new germline mutation not inherited from either parent is called a de novo mutation.
Diploid organisms (e.g., humans) contain two copies of each gene—a paternal and a maternal allele. Based on the occurrence of mutation on each chromosome, we may classify mutations into three types.
- A heterozygous mutation is a mutation of only one allele.
- A homozygous mutation is an identical mutation of both the paternal and maternal alleles.
- Compound heterozygous mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles.
A wild type or homozygous non-mutated organism is one in which neither allele is mutated.
- Conditional mutation is a mutation that has wild-type (or less severe) phenotype under certain "permissive" environmental conditions and a mutant phenotype under certain "restrictive" conditions. For example, a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deleterious consequences at a lower temperature (permissive condition). These mutations are non-autonomous, as their manifestation depends upon presence of certain conditions, as opposed to other mutations which appear autonomously. The permissive conditions may be temperature, certain chemicals, light or mutations in other parts of the genome.Invivo mechanisms like transcriptional switches can create conditional mutations. For instance, association of Steroid Binding Domain can create a transcriptional switch that can change the expression of a gene based on the presence of a steroid ligand. Conditional mutations have applications in research as they allow control over gene expression. This is especially useful studying diseases in adults by allowing expression after a certain period of growth, thus eliminating the deleterious effect of gene expression seen during stages of development in model organisms. DNA Recombinase systems like Cre-Lox Recombination used in association with promoters that are activated under certain conditions can generate conditional mutations. Dual Recombinase technology can be used to induce multiple conditional mutations to study the diseases which manifest as a result of simultaneous mutations in multiple genes. Certain inteins have been identified which splice only at certain permissive temperatures, leading to improper protein synthesis and thus, loss of function mutations at other temperatures. Conditional mutations may also be used in genetic studies associated with ageing, as the expression can be changed after a certain time period in the organism's lifespan.
- Replication timing quantitative trait loci affects DNA replication.
In order to categorize a mutation as such, the "normal" sequence must be obtained from the DNA of a "normal" or "healthy" organism (as opposed to a "mutant" or "sick" one), it should be identified and reported; ideally, it should be made publicly available for a straightforward nucleotide-by-nucleotide comparison, and agreed upon by the scientific community or by a group of expert geneticists and biologists, who have the responsibility of establishing the standard or so-called "consensus" sequence. This step requires a tremendous scientific effort. Once the consensus sequence is known, the mutations in a genome can be pinpointed, described, and classified. The committee of the Human Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature, which should be used by researchers and DNA diagnostic centers to generate unambiguous mutation descriptions. In principle, this nomenclature can also be used to describe mutations in other organisms. The nomenclature specifies the type of mutation and base or amino acid changes.
- Nucleotide substitution (e.g., 76A>T) — The number is the position of the nucleotide from the 5' end; the first letter represents the wild-type nucleotide, and the second letter represents the nucleotide that replaced the wild type. In the given example, the adenine at the 76th position was replaced by a thymine.
A gene is a long sequence of nucleotides on a DNA molecule. A mutation is a change in the amount of an organism’s genetic material and when a change in genotype produces a change in phenotype, the individual affected is said to be a mutant. A gene mutation involves a change in one or more of the nucleotides in a strand of DNA. The sequence of nucleotides in a gene controls the order in which amino acids are made into a protein, therefore if the sequence of nucleotides in a gene is altered by a mutation, then the order in which amino acids are made into a protein will be changed.
THE OCCURANCE OF MUTANT ALLELES & THE EFFECT OF MUTAGENIC AGENTS
Most gene mutations produce an inferior version of the phenotype, i.e. the majority of mutant alleles are recessive. If this results in death, then the altered allele is said to be lethal. In the absence of outside influences gene mutations occur spontaneously and at random. Gene mutations also occur very rarely, i.e. they have a low frequency. Mutation rate can be artificially increased by mutagenic agents. These include certain chemicals such as mustard gas, x-rays and ultraviolet light. The resultant mutations are said to be induced.
TYPES OF GENE MUTATION & HOW THEY ALTER AMINO ACID SEQUENCE
There are four types of gene mutation which can occur in an organism; Substitution, Inversion, Deletion and Insertion. These four types of mutation can be categorised into point and frameshift mutations. Substitution, where an incorrect nucleotide is substituted for the correct one and Inversion, where two or more nucleotides are reversed, are examples of point mutations. On the other hand Deletion, where a nucleotide is deleted or lost from the sequence and Insertion, where an extra nucleotide is inserted into the sequence of nucleotides, are frameshift mutations. Point mutations only bring about a minor change and sometimes the organism is only affected slightly or not at all, however if a substituted amino acid occurs in a critical position in the protein then a major defect may arise. Frameshift mutations lead to a major change since it causes a large portion of the gene’s DNA to be misread. The protein produced differs from the normal protein by many amino acids and is usually non-disfunctional.