mutation(redirected from base substitution mutation)
Also found in: Dictionary, Thesaurus, Medical, Legal.
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.
Mutation and Evolution
See W. Gottschalk and G. Wolff, Induced Mutations in Plant Breeding (1983); G. Obe, Mutations in Man (1984).
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).
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
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)
a spontaneous or artificially induced permanent change in structures that are responsible for the storage and transmission of genetic information in living organisms. The capacity for mutation is a universal property of all forms of life, from viruses and microorganisms to the higher plants, animals, and man. Mutation is the basis for heritable variation in nature.
Mutations appearing in the germ cells or spores (gametic mutations) are hereditarily transmitted. The mutations that arise in cells that are not involved in sexual reproduction (somatic mutations) result in genetic mosaicism. This is a condition in which one part of the organism consists of mutant cells, while the remaining part consists of nonmutant cells. In such cases the mutation can be inherited only by vegetative reproduction involving mutant buds, mutant stalks, mutant tubers, or other mutant somatic parts.
Spontaneous hereditary changes were observed by many scientists in the 18th and 19th centuries and were well known to C. Darwin, but the thorough study of mutation was not begun until the emergence of experimental genetics early in the 20th century. The term “mutation” was introduced into genetics by H. de Vries in 1901.
Types. Mutations are termed genomic, chromosomal, or point (gene), depending on the nature of the change occurring in the genetic apparatus. Genomic mutations involve changes in the total number of chromosomes in the cell. One such mutation is polyploidy, an increase in the total number of complete chromosome sets: Instead of two chromosome sets, typical of diploid organisms, there may be three, four, or even more sets. In haploidy, instead of two chromosome sets there is only one. There are several forms in which aneuploidy, a third type of genomic mutation, can occur: in nullisomy, one or more pairs of homologous chromosomes are absent; in monosomy, one member of a pair of chromosomes is absent; trisomies, tetrasomies, and so forth occur when three or more homologous partners are present.
Several types of chromosomal mutations, or aberrations, are distinguished: (1) inversion, in which a segment of the chromosome is rotated 180° so that the normal sequence of the genes becomes reversed; (2) translocation, in which parts of two or more nonhomologous chromosomes are exchanged; (3) deletions, which involve the complete loss of a substantial part of a chromosome; (4) minor deletions, which involve loss of only a small part of a chromosome; (5) duplication, in which doubling of part of a chromosome occurs; and (6) fracture, in which a chromosome is broken into two or more parts.
Point mutations are permanent changes in the chemical structure of individual genes. Such mutations are usually not visible under a microscope. Mutations are known to occur in genes that are situated not only in the chromosomes but also in certain self-reproducing organelles, for example, in the mitochondria and plastids.
Effects on organism. A great variety of biochemical, physiological, and morphological characteristics of an organism can change as a result of mutation. The changes found in mutants, organisms that have undergone mutation, can be indistinct, only consisting of minor deviations from the average appearance of a certain species characteristic. The changes in a mutant can also be quite pronounced. Polyploid mutants are usually recognized by an enlargement of both the individual cells and the organism as a whole. If a polyploid has an even number of chromosome sets (balanced polyploid), fertility is usually preserved or decreased only slightly. But polyploids in which the number of chromosome sets is uneven (unbalanced polyploids) are infertile or only slightly fertile. The chromosomes of unbalanced polyploids are distributed randomly in the mature germ cells. This results in the formation of aneuploid gametes, most of which cannot be fertilized or cannot produce viable zygotes. Haploid mutants have small cells, and the organism as a whole is smaller than the normal diploid form of the species. Infertility is complete, or nearly complete, because only a few gametes contain a full complement of chromosomes. Various characteristics in aneuploids are altered substantially, often severely enough to kill the organism or render it infertile.
The changes are usually less pronounced in the cases of deletion, minor deletion, and duplication; the extent of change in the organism is generally proportional to the length of the part of the chromosome that was lost or doubled. Large deletions can result in the death of the organism.
Inversions and translocations do not themselves alter the characteristics of the organism (unless a change occurs in the gene’s phenotypic manifestation because of the gene’s proximity to a new set of neighboring genes). However, translocations and inversions do have significant genetic consequences. In the case of inversion in heterozygotes, the exchange of genetic information between the normal chromosome and the chromosome bearing the inversion is complicated. When translocation occurs in heterozygotes, partially aneuploid germ cells and mostly nonviable germ cells result. This also occurs in the case of fractures, because the chromosome fragment that is left without a centromere after breakage is lost.
Point mutations, which make up the majority of all mutations, give rise to a great variety of changes. A modification of one gene usually causes changes in several phenotypic characteristics. Point mutations can be dominant, semidominant, or recessive. Mutation of a gene can produce a variant, or allele, of that gene. The phenotypic expressions of allelic genes differ from each other. The expression of a mutant allele can differ from the expression of the corresponding normal allele in the following ways: (1) the product (usually an enzyme) that is coded for at that particular gene site is not formed at all, (2) the product is formed in abnormally low or high quantities, (3) a substance that inactivates or inhibits the product of a nonmutant gene is synthesized, and (4) instead of the normal product being formed, a nonreactive product, absent in nonmutant individuals, is evolved. A gene that has mutated is usually as stable as the nonmutant gene from which it originated, and it may return to its original state following a new mutation. Such an occurrence is known as a reversible mutation. Point mutations are usually injurious, because they interfere with vital processes and diminish the body’s viability and fertility. A mutant gene often kills a developing organism. Such mutations are called lethal. Point mutations that have comparatively little effect on viability and fertility are not as common as lethal mutations, and those that improve various properties of the body are even less frequent. Despite their relatively rare occurrence, favorable point mutations are very important in that they provide the basic material for both natural and artificial selection, crucial processes in evolution and breeding.
Causes and artificial induction. Polyploidy generally arises at the start of mitotic cell divisions (cell division of somatic cells) in which the chromosomes do separate successfully but in which cell division for some reason does not proceed past that point of separation. Polyploidy can be artificially induced by treating the cell, once mitosis has begun, with substances that interfere with cell division. Less frequently, polyploidy results from the fusion of two somatic cells or from the participation of two spermatozoa in the fertilization of a single egg cell. Haploidy usually results from parthenogenesis, the development of an embryo without fertilization of the egg. Parthenogenesis is artificially induced by using dead pollen or pollen from a distant species to pollinate the plant. The main cause of aneuploidy is the accidental nondisjunction during meiosis (cellular division of germ cells) of a pair of homologous chromosomes. Nondisjunction either causes both chromosomes of a homologous pair to enter a single germ cell or completely prevents both chromosomes from entering the germ cell. Less commonly, aneuploids originate from a few nonviable germ cells formed in unbalanced polyploids.
The causes of chromosomal aberrations and of the most important category of mutations, point mutations, remained unknown a long time. Thus, the erroneous concept known as autogenesis was developed, whereby spontaneous gene mutations arise in nature seemingly without the participation of environmental factors. It was not until methods for quantitatively evaluating gene mutations were developed that mutations could be induced by a variety of chemical and physical factors. Such factors are called mutagens.
The earliest data regarding the effect of radium on heritable variation in lower fungi was obtained in the USSR by G. A. Nadson and G. S. Filippov in 1925. Convincing proof that mutations can be artificially induced was given in 1927 by G. Muller, who in experiments on Drosophila discovered the powerful mutagenic property of X rays. Subsequent research on the genetic effects of radiation on different organisms revealed the universal capacity of all ionizing radiation to induce not only gene mutations but also chromosomal aberrations.
The mutagenic action of certain chemical agents was first discovered in the USSR by M. N. Meisel’ (1928), V. V. Sakharov (1933), and M. E. Lobashev (1934). Heterologus DNA, the first powerful chemical mutagen, was discovered in 1939 by S. M. Gershenzon and his co-workers. In 1946 the powerful mutagenic action of formaldehyde and ethylenimine was discovered by the Soviet geneticist I. A. Rapoport. That same year the British geneticists C. Auerbach and D. Robson discovered the powerful mutagen mustard gas. Hundreds of other chemical mutagens have been found since then. Powerful physical and chemical mutagens increase the frequency of gene mutations and chromosomal aberrations by many factors often: the most powerful chemical mutagens, the supermutagens, many of which were discovered and studied by the Soviet geneticist Rapoport and co-workers, increase the mutation and aberration rates by a factor of 100 or more over the base level frequency of spontaneous mutation.
Experiments using cell cultures and laboratory animals revealed that many viruses can induce mutations. In viruses, it is the indigenous nucleic acids that appear to act as the mutagen. Thus, viruses not only are the causative agents of many diseases in animals, man, plants, and microorganisms but also serve as one of the sources of heritable variation. All mutagens cause point mutations by directly or indirectly altering the molecular structure of the nucleic acids in which the genetic information is coded.
Mutations have been studied most in corn, in Drosophila, and in some microorganisms. Experimental studies on spontaneous and induced mutations have revealed a number of important characteristics of the mutation of genes. The frequency with which spontaneous mutation occurs varies from gene to gene and from organism to organism, ranging for an individual gene from one mutation per 105 genes to one mutation per 107 genes in a generation. A few genes, called mutable genes, may mutate much more frequently. The frequency of forward mutation and that of backward mutation in the same gene are often different. Mutagens increase the mutation frequency for all the genes at approximately the same rate, so that the mutation spectrum—the ratio of the number of more commonly mutating genes to the number of less commonly mutating genes—remains about the same for both the spontaneous and the induced mutation processes. Chemical mutagens may effect slightly different mutation spectra from other mutagens.
It is only in microorganisms that some chemical mutagens can significantly increase the mutation rate of certain genes over the mutation rate of the other genes. Sites on the chromosome that are susceptible to mutation are called hot spots. A similar phenomenon occurs during the mutagenic action of viral nucleic acids on multicellular organisms. The ratio of the number of point mutations to the number of chromosomal aberrations depends on whether the mutagens are chemical or physical. Chemical mutagens are responsible for a greater number of point mutations than are physical mutagens. There are also other differences in the ways in which chemical and physical mutagens function.
Not all the changes induced by mutagens in DNA are expressed as mutations. A damaged portion of DNA is often removed, or excised, in the course of recombination by the repair enzymes in the cell, which restore the structure of DNA. During the subsequent replication of the DNA, the damaged portion is replaced by a corresponding normal fragment.
The frequency with which any mutation appears depends on many external and internal factors, for example, temperature, partial pressure of oxygen, age of the organism, and phase of development and physiological condition of the cell. The characteristics of the genotype are very important, because even within a single species genetically different strains may differ with respect to their mutabilities. Mutator genes, which sharply increase the frequency of mutations, have been described in several organisms. Because of its dependence on genetic factors, mutability can be increased or decreased through artificial selection. The differences in mutability among the various species are a consequence of the effect of natural selection on the course of the species’ evolution.
Significance in evolution, plant breeding, and medicine. The basis for understanding the role of mutation in evolution was established in the 1920’s by the Soviet geneticist S. S. Chetverikov, the British scientists J. Haldane and R. Fisher, and the American scientist S. Wright, pioneers in the field of evolutionary genetics. All the hereditary changes that serve as the raw material for natural selection were shown to have arisen through mutation. Recombinant variation, resulting from the formation of new combinations of genes through crossing over, is ultimately also the consequence of those mutations that were responsible for the genetic differences of the parent individuals.
In contrast to the case of modification, in mutation a single mutagenic factor gives rise to a variety of mutations that affect several characteristics in different ways. Thus, mutations are not in themselves adaptive. Nevertheless, the mutations that constantly appear in any species—many of them persisting latently for a long time within the population in the form of recessive mutations—serve as a reservoir for heritable variation that enables natural selection to restructure the hereditary characteristics of a species and adapt the species to changing environmental conditions, such as changes in climate, biocenosis, or migration. Thus, the adaptive value of evolutionary change is a consequence of preservation by natural selection of the carriers of those mutations and combinations of mutations that turn out to be useful in a particular situation. The mutations that were injurious or neutral under some conditions may prove to be useful under different conditions.
Point mutations are the most valuable in terms of their role in evolution. Despite the relatively infrequent mutation of each gene, the overall frequency of spontaneous point mutation is great because there are tens of thousands of genes in the genotype of multicellular organisms. As a result, a large percentage (about 5 to 30 percent in higher plants and animals) of the gametes or spores formed by an organism carries various gene mutations, thereby creating the prerequisite for effective natural selection. The chromosomal aberrations that make recombination difficult —inversions and translocations—contribute to the reproductive isolation and to the subsequent divergence of groups of organisms. Duplications lead to an increase in the number and variety of genes in the genotype, owing to later differentiation of the genes in the duplicated portions of the chromosomes. Polyploidy plays a major role in plant evolution: in conjunction with reproductive isolation, it sometimes can restore fertility to infertile interspecies hybrids.
The development of methods of artificial mutagenesis considerably facilitated the study of plant breeding. Much more starting material became available to plant breeders than when using rare spontaneous mutations. In 1930 the Soviet scientists A. A. Sapegin and L. N. Delone were the first to use ionizing radiation to breed wheat. The method of radiation selection was later used to breed new high-yielding varieties of such plants as wheat, barley, rice, and lupine. Radiation selection is also used to obtain valuable strains of microorganisms used in industry. Chemical mutagens can also produce good results in plant breeding.
Genomic mutations, chromosomal aberrations, and point mutations cause many hereditary diseases and congenital abnormalities in man. Therefore, protecting human beings from mutagens is a highly important task. Of great value in this respect was the initiative taken by the Soviet Union to ban atmospheric nuclear testing, which contaminates the environment with radioactive substances. It is very important for workers in the atomic industry, for those who handle radioactive isotopes, and for those who use X rays to scrupulously protect themselves against radiation. It is necessary to study the possible mutagenic action of new drugs, pesticides, and industrial chemicals and to prohibit the production of substances that prove to be mutagenic. The prevention of viral infections is also important in order to protect offspring against the mutagenic action of viruses.
REFERENCESSupermutageny; sb. st. Moscow, 1966.
Lobashev, M. E. Genetika, 2nd ed. Leningrad, 1967. Chapters 11, 14.
Herskowitz, I. Genetika. Moscow, 1968. Chapters 11–14, 30, 31. (Translated from English.)
Soifer, V. N. Molekuliarnye mekhanizmy mutageneza. Moscow, 1969.
Dubinin, N. P. Obshchaia genetika. Moscow, 1970. Chapters 17, 20.
Ratner, V. A. Printsipy organizatsii i mekhanizmy molekuliarno-geneti-cheskikh protsessov. Novosibirsk, 1972. Chapter 3.
Serra, J. A. Modern Genetics, vol. 3. London-New York, 1968. Chapters 20–22.
Auerbach, C, and B. J. Kilbey. “Mutation in Eukaryotes.” Annual Review of Genetics, 1971, vol. 5, p. 163.
Banks, G. R. “Mutagenesis: A Review of Some Molecular Aspects.” Science Progress, 1971, vol. 59, no. 236.
S. M. GERSHENZON
the alternation of vowels within the same root to produce various grammatical forms. Mutation is seen in the imperfective Russian verb ubirat’ (“to adorn”) and the noun ubor (“attire,” “gear”) and in the English “sing,” “sang,” “sung,” and “song.”