Mutation

MUTATION (from Latin mutatio—change, alteration). In genetics, this term is currently understood to mean any newly arising hereditary change in an organism. However, various researchers give this word a somewhat different meaning. Mutation as a genetic concept should be distinguished from the paleontological one introduced by Waagen in 1869. In 1901, the Dutch botanist de Vries published a book titled The Mutation Theory. In it, he clearly demarcated modifications or fluctuations (see), which represent minor deviations from the average value that are non-hereditary in nature and arise due to diverse influences of environmental conditions, from mutations—abrupt deviations from the norm that are transmitted by inheritance. At present, the criterion for distinguishing between modifications and mutations is only the non-hereditary character of the former and the hereditary nature of the latter, rather than the degree of change. De Vries pointed out the significance of mutation as material for the evolutionary process and, based mainly on the study of mutation in the plant Oenothera lamarckiana, set forth a number (8) of tenets of his mutation theory: concerning the suddenness of the appearance of new elementary species, their constancy and character, the periodicity of mutation, etc. De Vries's observations were not absolutely new. Animal and plant breeders knew that sometimes in completely pure breeds, individual specimens appear with extremely deviating properties and that such new traits are hereditary from the very beginning. Darwin, in his book The Variation of Animals and Plants Under Domestication, gathered a significant number of such reliably established cases of saltatory variability (Ancon and Moशan sheep, black-shouldered peacocks, etc.). In 1894, Bateson wrote about discontinuous variability. De Vries's immediate predecessor, however, was the Russian botanist Korzhinsky (Heterogenesis and Evolution, 1899). Based on a large number of facts from the plant world, he established the existence of so-called "heterogeneous" variations—variations appearing in an abrupt form in a single unique specimen due to some internal changes in sex cells and subsequently proving to be hereditary. Korzhinsky's views are a typical example of the autogenetic standpoint, since the author emphasizes the complete independence of the origin of hereditary changes from the external environment. "To explain the origin of higher forms from lower ones, it is necessary to assume the presence of a special tendency toward progress in organisms," writes Korzhinsky, revealing an idealistic stance on the question of the factors of evolution. Although the evening primrose (Oenothera), the study of which allowed de Vries to develop the mutation theory, turned out to possess very complex and entangled phenomena that gave rise and still give rise to a rich literature (the so-called "enothera dispute"), the existence of mutations was subsequently absolutely proven, and a multitude of mutations are now known in a vast number of animal and plant species. After 1901, works on mutations in plants appeared by Baur (snapdragon—Antirrhinum majus), Correns (four o'clock—Mirabilis jalapa), East, Jones, Emerson (corn), Blakeslee (jimson weed), Nilsson-Ehle (oats), and many others. It was also fundamentally important that Johannsen discovered mutations in pure lines of beans. Mutations were also discovered in animals, and the palm for the number of found and studied mutations belongs to the now unusually popular genetic object—the fruit fly Drosophila melanogaster. From 1911, the study of Drosophila genetics began in the laboratory of the American scientist Morgan, and since then many hundreds of mutations have been obtained, including in the USSR. Their analysis made it possible to establish the concept of mutation more precisely, to classify them, and to approach to a certain degree an understanding of the regularities in their appearance. The customary term "mutation," used by Morgan in a broad sense to denote any newly arising hereditary change, actually unites very different types of phenomena occurring in hereditary elements. Hereditary changes in the genotype can, firstly, be caused by changes in the number of chromosomes and various regroupings of their individual parts. This group of mutations can be called chromosomal aberrations (deviations from the usual type). The second category of mutations encompasses changes in individual, single hereditary factors or genes located along the length of the chromosome. These are local mutations (locus is usually understood as the place where the mutated gene is located), or otherwise "point" mutations or transgenations (Americans use different terminology—point mutations, gene mutations, etc.). Chromosomal abnormalities can also be very diverse: multiple multiplications of the number of chromosomes of the haploid set—polyploidy (triploidy, tetraploidy, etc.); addition to the normal set or loss of one, two, three, etc. chromosomes—polysomy (monosomy, disomy, etc.) and heteroploidy; translocations of individual segments from one chromosome to another—translocations; duplication of individual segments—duplications; losses or inactivations of segments of different sizes—deletions and deficiencies; inversion of chromosomes—inversions, etc. If initially the term mutation referred primarily to the appearance of new hereditary traits, now the name mutation denotes changes in gene or chromosomal structure. Therefore, the term proposed by Chetverikov—genovariation = mutation in Morgan's sense—is entirely legitimate and is beginning to spread. According to the site of origin, mutations can be classified into gametic, if they occur in the germline or gamete, and somatic, if any of the cells of the developing organism mutate (this is how, for example, mosaics in animals and bud mutations in plants are obtained). A change appearing as a result of mutation will be inherited differently depending on where and what mutation occurred (sex-linked and autosomal, dominant and recessive, etc.). Mutations are very diverse both in the number and degree of external traits they affect and in viability. Here one encounters all transitions from changes that are little specific, very diverse in their external expression, to highly specific, from those possessing fully normal viability to almost or completely lethal ones. The same mutations, both transgenations and chromosomal aberrations, can repeat many times. Morgan in his 1925 review (Genetics of Drosophila) points out, for example, that in the locus occupied by the "white" gene, about 25 changes appeared, 11 of them different, and all of them affected eye color; the "Notch" mutation (notches on the wings) arose just as many times, and so on. In reality, all these numbers can be significantly increased, especially after the application of X-rays, with the help of which it is possible to obtain both chromosomal disturbances and local mutations in an almost unlimited quantity. It is characteristic that along with points mutating repeatedly, there are also those in which mutations were observed only 1–2 times. This seems to indicate a different degree of stability and ability to change of individual chromosome points, but other explanations of these facts are also possible. On average, under normal laboratory breeding conditions in Drosophila, one mutation arises per 8–10 thousand individuals examined. But if we take into account that in terms of external expression, mutations can be very diverse—from strong and well-noticeable to extremely minor, the appearance of which can sometimes be judged only indirectly (e.g., Zeleny's data on the selection of the number of facets, proving the appearance of minor mutations affecting the number of facets)—the actual frequency of mutations is significantly higher. Calculations by Altenburg and Muller showed that a lethal mutation arises in approximately 1% of the X-chromosomes of Drosophila. A local mutation (transgenation) of the same gene can occur in different directions, i.e., a mutation of a certain gene that has arisen can mutate back to the initial position (reverse mutations) according to the scheme A -> A1 -> A. In this sense, the mutation process is reversible. Data on certain Drosophila genes also make it possible to judge the comparative rate of "forward" and "reverse" mutation (Timofeeff-Ressovsky). When we speak of the repeated appearance of the same mutations, it must be kept in mind that the criterion of mutation identity is very conditional. The white mutation in Drosophila has appeared many times, but we do not have sufficient grounds to consider all white genes identical. Analysis of many allelomorphs of the scute gene (Dubinin and others) showed that all of them differ to one degree or another in their action. The same applies to reverse mutations. A reverse mutation is not always (and perhaps even never) an exact return of the gene to the initial normal state. The vast majority of mutations, in particular in Drosophila, arose under conditions of laboratory breeding, which previously provided a reason to point to laboratory housing conditions as the cause of mutation phenomena in Drosophila. However, even in nature within an outwardly homogeneous species, mutations constantly arise that remain in a hidden (heterozygous) state for a long time and saturate a given species (Chetverikov).

For a long time it was impossible either to induce mutations through artificial influences or even to increase the frequency of their occurrence. Old materials of the Lamarckians had to be discarded as methodically unsatisfactory and built on incorrect foundational principles (see Lamarckism, Heredity, etc.), while precise experiments on Drosophila gave negative results. In 1927, Muller reported that he had succeeded in obtaining mutations of various types in Drosophila by exposure to X-rays, and the frequency of mutation appearance in the experiment turned out to be 150 times greater than under ordinary conditions. From this moment, the mutation problem entered a new phase. Subsequent years brought complete confirmation and deepening of Muller's data on various animal and plant objects. As for chromosomal aberrations, many influences are already known, the physical and chemical application of which causes the appearance of many chromosomal irregularities. But what other factors besides such a specific type of radiant energy as X-rays are capable of causing transgenations is difficult to say, although they are entirely possible. There were only attempts to show the role of the earth's radioactive radiation, cosmic radiation, and finally high temperature (Goldschmidt, Jollos). Directly connected with this is the fundamental question of the causes of mutations. Geneticists on this issue are divided into two directions: autogeneticists, who recognize that the cause of mutation appearance lies within the mutating genes themselves, and ectogeneticists, who believe that mutations are the result of the action of some environmental factors on the genes. One of the prominent representatives of the autogenetic direction is Korzhinsky; similar views were developed until recently by Morgan and a number of other American geneticists; in the USSR, Filipchenko spoke in favor of autogenesis ("The Evolutionary Idea in Biology"). Ectogenesis was clearly formulated by Geoffroy Saint-Hilaire, partly by Haeckel and Spencer. A number of Soviet geneticists who worked on the artificial production of mutations by the action of X-rays (Agol, Levit, Serebrovsky) remain essentially on the idealistic position of autogeneticists, arguing that external conditions cause only the acceleration of that process of mutation origin which proceeds even without experimental exposure. "Mutations naturally arise in any environment, largely autonomously from the latter. The environment surrounding the organism, naturally transforming within the organism and its germ cells, can only accelerate, intensify (or, conversely, slow down) the spontaneously proceeding process" (S. G. Levit). When studying the essence of the mutational process, it is necessary to take into account both the properties of the germ cells themselves and their constituent parts (chromosomes, genes) and the specific (as well as nonspecific) influences of the external environment.

* In mutations of the chromosomal aberration type, in the overwhelming majority of cases, it can be said with certainty what happened in the chromosome or chromosomal complex. Additions or losses of whole chromosomes are usually immediately proven cytologically. But even such changes as the transfer of pieces from one chromosome to another or the loss of chromosome segments, proven by genetic analysis, were often brilliantly confirmed by cytological pictures (Painter, Muller). Not so with transgenations. The viewpoint based on Bateson's "presence-absence" theory, that a loss of a chromosome segment occurs during transgenation, cannot be considered proven to any degree, although its acceptance is tempting, since it allows outlining a unified mutation scheme covering such seemingly different types as the loss of entire chromosomes or pieces of them, on the one hand, and local mutations, on the other (Serebrovsky). Believing that genes are parts (perhaps radicals) of a giant protein molecule (Koltsov), one must think that the slightest chemical changes in them, the detachment of some atoms, and their replacement by others, must be the sources of new mutations. It is not surprising that until now we reliably have X-rays and temperature influences as a source of mutational changes, since all crude chemical or mechanical influences irrevocably disrupt the complex protein structure of the chromosome. Mutations, unlike modifications, are an important link in the evolutionary process, creating new traits that serve as material for artificial and natural selection. The doctrine of hereditary variability (mutations) together with the Darwinian idea of selection basically exhausts the content of evolutionary theory. The next task in studying mutations is to elucidate the regularities of the mutational process under experimental conditions and to solve the question of the factors causing mutations in nature. At present, work is underway to study the effect of temperature, ultraviolet rays, and other factors on the mutational process. Serious attention is also required by the nature of the system reacting to external influences, which is the germ cell, the carrier of hereditary rudiments. Mutations in humans. Although it is undoubted that numerous hereditary diseases or malformations known to us appeared thanks to mutations, the number of such cases where the appearance of mutation was actually tracked is numbered in units. The main explanation, of course, is that the researcher manages to trace only a very small number of generations. Most often (and practically this is extremely rare) one can trace the appearance of a dominant mutation. If for one or more generations not a single family member had the corresponding change and if in subsequent generations it appears and behaves as a dominant, we are unquestionably dealing with a mutation that has occurred. Such is the case of heterohemophilia in one family described by S. G. Levit. Rokitsky considers it indisputable; if so, this is perhaps one of the few accurately registered cases of mutation. Koltsov described a case of dominant hexadactyly, and Patlis of claw-shaped limb, where also the first generation did not have this trait. But even in the case of dominance of the change, errors are possible in determining the moment of mutation, since 1) dominance may be incomplete, and due to any reasons affecting the degree of dominance, the feature will "skip" a generation; 2) if the trait or disease is such that according to domestic conditions efforts were made to hide it, the children may remain unaware of its presence in the paternal or grandparental generation. This circumstance will tell more and more the further up the pedigree one has to climb. A recessive, but sex-linked mutation is detected not much more difficult than a dominant one. If a mutation arose in the mother's germ cells, then her sons will already manifest the new feature. Upon the appearance of a mutation in the father, his daughters will be "carriers" of the new gene, but only their sons will manifest it, i.e., the feature will not appear for only one generation. The possibility of tracking a recessive autosomal mutation is significantly less. A recessive change, once arisen, can remain in a hidden state for an indefinitely long time until a marriage occurs between two heterozygotes. Therefore, observing the visible appearance of some recessive trait, in the overwhelming majority of cases we must look for the mutation of which it is the result in the depths of centuries. A clear example of the duration of the recessive gene remaining in the heterozygous state can serve the case of Friedreich's ataxia in 20 patients of one Swiss village described by Rütimeyer and Frey. It turned out that their common ancestor lived in the 16th century and is separated from the examined families by 11-12 generations. But with all the difficulties of finding mutations in humans, their search is unquestionably necessary and is of great importance in the study of human heredity (see also Somatic mutation).