Mutation (redirected from Loss-of-function)

mutation, in biology, a sudden, random change in a gene, or unit of hereditary material, that can alter an inheritable characteristic. Most mutations are not beneficial, since any change in the delicate balance of an organism having a high level of adaptation to its environment tends to be disruptive. As the environment changes, however, mutations can prove advantageous and thus contribute to evolutionary change in the species. In higher animals and many higher plants a mutation may be transmitted to future generations only if it occurs in germ, or sex cell, tissue; somatic, or body cell, mutations cannot be inherited except in plants that propagate asexually (see reproduction). Sometimes the word mutation is used broadly to include variations resulting from aberrations of chromosomes; in chromosomal mutations the number of chromosomes may be altered, or segments of chromosomes may be lost or rearranged. Changes within single genes, called point mutations, are actual chemical changes to the structure of the constituent DNA.

Point Mutations

Each gene is made up of a long sequence of substances called nucleotides; these nucleotides, taken in series of three at a time, specify each amino acid subunit of a protein (see nucleic acid). In a frameshift mutation, a nucleotide is added or deleted to the sequence and the decoding of the entire gene sequence will be radically altered and the amino acid sequence of the protein produced will also be very different. Often the resulting protein is totally ineffective. If one nucleotide substitutes for another in the sequence only one amino acid of the protein will be different, but the effect can be quite dramatic. For example, the inherited sickle cell disease is the result of a mutation that results in the substitution of the amino acid valine for glutamic acid in hemoglobin.

Because proteins called enzymes control most cell activities, a mutation affecting an enzyme can result in alteration of other cell components. A single gene mutation may have many effects if the enzyme it controls is involved in several metabolic processes. Occasionally a mutation can be offset by either another mutation on the same gene or on another gene that suppresses the effect of the first. Certain genes are responsible for producing enzymes that can repair some mutations. While this process is not fully understood, it is believed that if these genes themselves mutate, the result can be a higher mutation rate of all genes in an organism.

Induced Mutations

Mutations may be induced by exposure to ultraviolet rays and alpha, beta, gamma, and X radiation, by extreme changes in temperature, and by certain mutagenic chemicals such as nitrous acid, nitrogen mustard, and chemical substitutes for portions of the nucleotide subunits of genes. H. J. Muller, an American geneticist, pioneered in inducing mutations by X-ray radiation (using the fruit fly, Drosophila) and developed a method of detecting mutations that are lethal.

Mutation and Evolution

In 1901 the observation of mutants, or sports, among evening primrose plants led the Dutch botanist Hugo de Vries to present his theory that new characteristics may appear suddenly and that these characteristics are inheritable; before this time the sources of evolutionary variation were not known and some still believed that evolution resulted from a gradual selection of favorable acquired characteristics. The work of de Vries and of subsequent investigators who demonstrated the distinction between mutation and environmental variations has shown the importance of mutation in the mechanism of evolution.

Bibliography

See W. Gottschalk and G. Wolff, Induced Mutations in Plant Breeding (1983); G. Obe, Mutations in Man (1984).

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mutation

Alteration in the genetic material of a cell that is transmitted to the cell's offspring. Mutations may be spontaneous or induced by outside factors (mutagens). They take place in the genes, occurring when one base is substituted for another in the sequence of bases that determines the genetic code, or when one or more bases are inserted or deleted from a gene. Many mutations are harmless, often masked by the presence of a dominant normal gene (see dominance). Some have serious consequences; for example, a particular mutation inherited from both parents results in sickle-cell anemia. Only mutations that occur in the sex cells (eggs or sperm) can be transmitted to the individual's offspring. Alterations caused by these mutations are usually harmful. In the rare instances in which a mutation produces a beneficial change, the percentage of organisms with this gene will tend to increase until the mutated gene becomes the norm in the population. In this way, beneficial mutations serve as the raw material of evolution.

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Mutation

Any alteration capable of being replicated in the genetic material of an organism. When the alteration is in the nucleotide sequence of a single gene, it is referred to as gene mutation; when it involves the structures or number of the chromosomes, it is referred to as chromosome mutation, or rearrangement. Mutations may be recognizable by their effects on the phenotype of the organism (mutant).

Gene mutations

Two classes of gene mutations are recognized: point mutations and intragenic deletions. Two different types of point mutation have been described. In the first of these, one nucleic acid base is substituted for another. The second type of change results from the insertion of a base into, or its deletion from, the polynucleotide sequence. These mutations are all called sign mutations or frame-shift mutations because of their effect on the translation of the information of the gene. See Nucleic acid

More extensive deletions can occur within the gene which are sometimes difficult to distinguish from mutants which involve only one or two bases. In the most extreme case, all the informational material of the gene is lost.

A single-base alteration, whether a transition or a transversion, affects only the codon or triplet in which it occurs. Because of code redundancy, the altered triplet may still insert the same amino acid as before into the polypeptide chain, which in many cases is the product specified by the gene. Such DNA changes pass undetected. However, many base substitutions do lead to the insertion of a different amino acid, and the effect of this on the function of the gene product depends upon the amino acid and its importance in controlling the folding and shape of the enzyme molecule. Some substitutions have little or no effect, while others destroy the function of the molecule completely.

Single-base substitutions may sometimes lead not to a triplet which codes for a different amino acid but to the creation of a chain termination signal. Premature termination of translation at this point will lead to an incomplete and generally inactive polypeptide.

Sign mutations (adding or subtracting one or two bases to the nucleic acid base sequence of the gene) have a uniformly drastic effect on gene function. Because the bases of each triplet encode the information for each amino acid in the polypeptide product, and because they are read in sequence from one end of the gene to the other without any punctuation between triplets, insertion of an extra base or two bases will lead to translation out of register of the whole sequence distal to the insertion or deletion point. The polypeptide formed is at best drastically modified and usually fails to function at all. This sometimes is hard to distinguish from the effects of intragenic deletions. However, whereas extensive intragenic deletions cannot revert, the deletion of a single base can be compensated for by the insertion of another base at, or near, the site of the original change. See Gene, Genetic code

Chromosomal changes

Some chromosomal changes involve alterations in the quantity of genetic material in the cell nuclei, while others simply lead to the rearrangement of chromosomal material without altering its total amount. See Chromosome

Origins of mutations

Mutations can be induced by various physical and chemical agents or can occur spontaneously without any artificial treatment with known mutagenic agents.

Until the discovery of x-rays as mutagens, all the mutants studied were spontaneous in origin; that is, they were obtained without the deliberate application of any mutagen. Spontaneous mutations occur unpredictably, and among the possible factors responsible for them are tautomeric changes occurring in the DNA bases which alter their pairing characteristics, ionizing radiation from various natural sources, naturally occurring chemical mutagens, and errors in the action of the DNA-polymerizing and correcting enzymes.

Spontaneous chromosomal aberrations are also found infrequently. One way in which deficiencies and duplications may be generated is by way of the breakage-fusion-bridge cycle. During a cell division one divided chromosome suffers a break near its tip, and the sticky ends of the daughter chromatids fuse. When the centromere divides and the halves begin to move to opposite poles, a chromosome bridge is formed, and breakage may occur again along this strand. Since new broken ends are produced, this sequence of events can be repeated. Unequal crossing over is sometimes cited as a source of duplications and deficiencies, but it is probably less important than often suggested.

In the absence of mutagenic treatment, mutations are very rare. In 1927 H. J. Muller discovered that x-rays significantly increased the frequency of mutation in Drosophila. Subsequently, other forms of ionizing radiation, for example, gamma rays, beta particles, fast and thermal neutrons, and alpha particles, were also found to be effective. Ultraviolet light is also an effective mutagen. The wavelength most employed experimentally is 253.7 nm, which corresponds to the peak of absorption of nucleic acids.

Some of the chemicals which have been found to be effective as mutagens are the alkylating agents which attack guanine principally although not exclusively. The N7 portion appears to be a major target in the guanine molecule, although the O⁶ alkylation product is probably more important mutagenically. Base analogs are incorporated into DNA in place of normal bases and produce mutations probably because there is a higher chance that they will mispair at replication. Nitrous acid, on the other hand, alters DNA bases in place. Adenine becomes hypoxanthine and cytosine becomes uracil. In both cases the deaminated base pairs differently from the parent base. A third deamination product, xanthine, produced by the deamination of guanine, appears to be lethal in its effect and not mutagenic. Chemicals which react with DNA to generate mutations produce a range of chemical reaction products not all of which have significance for mutagenesis.

Significance of mutations

Mutations are the source of genetic variability, upon which natural selection has worked to produce organisms adapted to their present environments. It is likely, therefore, that most new mutations will now be disadvantageous, reducing the degree of adaptation. Harmful mutations will be eliminated after being made homozygous or because the heterozygous effects reduce the fitness of carriers. This may take some generations, depending on the severity of their effects. Chromosome alterations may also have great significance in evolutionary advance. Duplications are, for example, believed to permit the accumulation of new mutational changes, some of which may prove useful at a later stage in an altered environment.

Rarely, mutations may occur which are beneficial: Drug yields may be enhanced in microorganisms; the characteristics of cereals can be improved. However, for the few mutations which are beneficial, many deleterious mutations must be discarded. Evidence suggests that the metabolic conditions in the treated cell and the specific activities of repair enzymes may sometimes promote the expression of some types of mutation rather than others. See Deoxyribonucleic acid (DNA)