Population genetics, a branch of genetics that studies the gene pool of populations and its changes in space and time. Let's take a closer look at this definition. Individuals do not live alone, but form more or less stable groups, jointly mastering their habitat. Such groups, if they self-reproduce over generations and are not supported only by newcomers, are called populations. For example, a school of salmon spawning in one river forms a population because the descendants of each fish tend to return to the same river, to the same spawning grounds, from year to year. In farm animals, a population is usually considered to be a breed: all individuals in it are of the same origin, i.e. have common ancestors, are kept in similar conditions and are supported by uniform selection and breeding work. Among aboriginal peoples, the population consists of members of related camps.
In the presence of migrations, the boundaries of populations are blurred and therefore indefinable. For example, the entire population of Europe are descendants of the Cro-Magnons who settled our continent tens of thousands of years ago. The isolation between the ancient tribes, which increased as each of them developed their own language and culture, led to differences between them. But their isolation is relative. Constant wars and seizures of territory, and in Lately– the gigantic migration led and is leading to a certain genetic rapprochement of peoples.
The examples given show that the word “population” should be understood as a grouping of individuals related by territorial, historical and reproductive community.
The individuals of each population are different from each other, and each of them is unique in some way. Many of these differences are hereditary, or genetic—they are determined by genes and passed from parents to children.
The totality of genes in individuals of a given population is called its gene pool. In order to solve problems of ecology, demography, evolution and selection, it is important to know the characteristics of the gene pool, namely: how large genetic diversity in each population, what are the genetic differences between geographically separated populations of the same species and between various types how the gene pool changes under the influence environment how it is transformed during evolution, how hereditary diseases spread, how effectively the gene pool is used cultivated plants and pets. Population genetics studies these issues.
Basic concepts of population genetics
Frequencies of genotypes and alleles. The most important concept of population genetics is genotype frequency - the proportion of individuals in a population having a given genotype. Consider an autosomal gene with k alleles, A1, A2, ..., Ak. Let the population consist of N individuals, some of which have alleles Ai Aj. Let us denote the number of these individuals as Nij. Then the frequency of this genotype (Pij) is determined as Pij = Nij/N. Let, for example, a gene have three alleles: A1, A2 and A3 - and let the population consist of 10,000 individuals, among which there are 500, 1000 and 2000 homozygotes A1A1, A2A2 and A3A3, and heterozygotes A1A2, A1A3 and A2A3 - 1000, 2500 and 3000 respectively. Then the frequency of A1A1 homozygotes is P11 = 500/10000 = 0.05, or 5%. Thus we obtain the following observed frequencies of homo- and heterozygotes:
P11 = 0.05, P22 = 0.10, P33 = 0.20,
P12 = 0.10, P13 = 0.25, P23 = 0.30.
Another important concept in population genetics is allele frequency—its proportion among those that have alleles. Let us denote the frequency of the Ai allele as pi. Since a heterozygous individual has different alleles, the frequency of the allele is equal to the sum of the frequency of homozygous and half the frequencies of individuals heterozygous for this allele. This is expressed the following formula: pi = Pii + 0.5jPij. In the example given, the frequency of the first allele is p1 = P11 + 0.5(P12 + P13) = 0.225. Accordingly, p2 = 0.300, p3 = 0.475.
Hardy–Weinberg relations. When studying the genetic dynamics of populations, a population with random crossing, having an infinite number and isolated from the influx of migrants, is taken as a theoretical, “zero” reference point; It is also believed that the rate of gene mutation is negligible and there is no selection. It is mathematically proven that in such a population the allele frequencies of the autosomal gene are the same for females and males and do not change from generation to generation, and the frequencies of homo- and heterozygotes are expressed in terms of allele frequencies as follows:
Pii = pi2, Pij = 2pi pj.
This is called the Hardy-Weinberg relationship, or law, after the English mathematician G. Hardy and the German physician and statistician W. Weinberg, who simultaneously and independently discovered them: the first theoretically, the second from data on the inheritance of traits in humans.
Real populations can differ significantly from the ideal one described by the Hardy–Weinberg equations. Therefore, the observed genotype frequencies deviate from the theoretical values calculated using the Hardy–Weinberg relationships. Thus, in the example discussed above, the theoretical frequencies of genotypes differ from the observed ones and are
P11 = 0.0506, P22 = 0.0900, P33 = 0.2256,
P12 = 0.1350, P13 = 0.2138, P23 = 0.2850.
Such deviations can be partially explained by the so-called. sampling error; After all, in reality, the experiment does not study the entire population, but only individual individuals, i.e. sample. But main reason deviations in genotype frequencies are undoubtedly processes that occur in populations and affect their genetic structure. Let us describe them sequentially.
Population genetic processes
Genetic drift. Genetic drift refers to random changes in gene frequencies caused by a finite population size. To understand how genetic drift occurs, let us first consider a population of the smallest possible size N = 2: one male and one female. Let the female in the initial generation have the genotype A1A2, and the male have the genotype A3A4. Thus, in the initial (zero) generation, the frequencies of alleles A1, A2, A3 and A4 are each 0.25. Individuals of the next generation are equally likely to have one of the following genotypes: A1A3, A1A4, A2A3 and A2A4. Let's assume that the female will have the A1A3 genotype, and the male will have the A2A3 genotype. Then in the first generation, the A4 allele is lost, the A1 and A2 alleles retain the same frequencies as in the original generation - 0.25 and 0.25, and the A3 allele increases the frequency to 0.5. In the second generation, the female and male can also have any combination of parental alleles, for example A1A2 and A1A2. In this case, it turns out that the A3 allele, despite higher frequency, disappeared from the population, and alleles A1 and A2 increased their frequency (p1 = 0.5, p2 = 0.5). Fluctuations in their frequencies will eventually result in either the A1 or A2 allele remaining in the population; in other words, both male and female will be homozygous for the same allele: A1 or A2. The situation could have developed in such a way that the A3 or A4 allele would have remained in the population, but in the case considered this did not happen.
The process of genetic drift described by us takes place in any population of finite size, with the only difference that events develop at a much lower speed than with a population of two individuals. Genetic drift has two important consequences. First, each population loses genetic variation at a rate inversely proportional to its size. Over time, some alleles become rare and then disappear altogether. In the end, only one allele remains in the population, which one is a matter of chance. Secondly, if a population divides into two or more new independent populations, then genetic drift leads to an increase in differences between them: some alleles remain in some populations, while others remain. Processes that counteract the loss of variability and genetic divergence of populations are mutations and migrations.
Mutations. During the formation of gametes, random events occur - mutations, when the parent allele, say A1, turns into another allele (A2, A3 or any other), which was or was not previously present in the population. For example, if in the nucleotide sequence “...TCT TGG...”, encoding a section of the polypeptide chain “...serine-tryptophan...”, the third nucleotide, T, as a result of mutation was passed on to the child as C, then in the corresponding section of the amino acid chain of the protein synthesized in the body child, alanine would be located instead of serine, since it is encoded by the TCC triplet. Regularly occurring mutations have formed, in a long series of generations of all species living on Earth, the gigantic genetic diversity that we now observe.
The probability with which a mutation occurs is called the frequency, or rate, of mutation. The rate of mutation of different genes varies from 10–4 to 10–7 per generation. At first glance, these values seem insignificant. However, it should be taken into account that, firstly, the genome contains many genes, and, secondly, that the population can have a significant size. Therefore, some gametes always carry mutant alleles, and in almost every generation one or more individuals with mutations appear. Their fate depends on how strongly these mutations affect fitness and fertility. The mutation process leads to an increase in the genetic variability of populations, counteracting the effect of genetic drift.
Migrations. Populations of the same species are not isolated from each other: there is always an exchange of individuals—migration. Migrating individuals, leaving offspring, pass on to the next generations alleles that might not exist at all in this population or they might be rare; This is how gene flow is formed from one population to another. Migrations, like mutations, lead to an increase in genetic diversity. In addition, gene flow connecting populations leads to their genetic similarity.
Crossing systems. In population genetics, crossing is called random if the genotypes of individuals do not affect the formation of mating pairs. For example, based on blood groups, crossing may be considered random. However, coloring, size, and behavior can greatly influence the choice of a sexual partner. If preference is given to individuals of a similar phenotype (i.e., with similar individual characteristics), then such positive assortative crossing leads to an increase in the proportion of individuals with the parental genotype in the population. If, when selecting a mating pair, preference is given to individuals of the opposite phenotype (negative assortative crossing), then new combinations of alleles will be presented in the genotype of the offspring; Accordingly, individuals of either an intermediate phenotype or a phenotype that is sharply different from the phenotype of the parents will appear in the population.
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MOSCOW STATE HUMANITIES UNIVERSITY NAMED AFTER M.A. SHOLOKHOV
in General and Molecular Genetics on the topic:
"Fundamentals of population genetics"
Completed by a 3rd year student of the first group
Trubnikova Evgenia Dmitrievna
Teacher Avdeenko V.A.
Moscow 2010
1.1 Non-random crossing
1.2 Genetic drift
1.3 Genetic load
1.4 Mutations
1.5 Migrations
1.6 Crossing systems
1.7 Inbreeding
II.Genetic parameters of the population
Bibliography
Introduction. Gene pool, allele frequencies, Hardy-Weinberg equilibrium law
Population genetics is a branch of genetics that studies the gene pool of populations and its changes in space and time. The word “population” should be understood as a grouping of individuals related by territorial, historical and reproductive community. Let's take a closer look at this definition. Individuals do not live alone, but form more or less stable groups, jointly mastering their habitat. Such groups, if they self-reproduce over generations and are not supported only by newcomers, are called populations. For example, a school of salmon spawning in one river forms a population because the descendants of each fish tend to return to the same river, to the same spawning grounds, from year to year. In farm animals, a population is usually considered to be a breed: all individuals in it are of the same origin, i.e. have common ancestors, are kept in similar conditions and are supported by uniform selection and breeding work. Among aboriginal peoples, the population consists of members of related camps.
The individuals of each population are different from each other, and each of them is unique in some way. Many of these differences are hereditary, or genetic—they are determined by genes and passed on from parents to children.
The gene pool is the collection of genes in individuals of a given population called its gene pool. the gene pool consists of the entire diversity of genes and alleles present in a sexually reproducing population; In any given population, the composition of the gene pool can constantly change from generation to generation. New combinations of genes form unique genotypes, which in their physical expression, i.e. in the form of phenotypes, are subject to the pressure of environmental factors that produce continuous selection and determine which genes will be transmitted to the next generation.
A population whose gene pool continuously changes from generation to generation undergoes an evolutionary change. A static gene pool reflects the absence of genetic variation among individuals of a given species and the absence of evolutionary change.
In order to solve problems of ecology, demography, evolution and selection, it is important to know the features of the gene pool, namely, how much genetic diversity is in each population, what are the genetic differences between geographically separated populations of the same species and between different species, how the gene pool changes under the influence of the environment how it is transformed during evolution, how hereditary diseases spread, how effectively the gene pool of cultivated plants and domestic animals is used. Population genetics studies these issues.
Any physical trait, such as fur color in mice, is determined by one or more genes. Each gene can exist in several various forms, which are called alleles. Allele frequency is the ratio of the number of these alleles in all individuals to total number alleles in a population. For example, in humans, the frequency of the dominant allele, which determines normal pigmentation of the skin, hair and eyes, is 99%. A recessive allele that determines the absence of pigmentation - so-called albinism - occurs with a frequency of 1%. The frequency of a dominant allele is usually denoted by the letter p, and the frequency of a recessive allele by the letter q. If a gene is represented by two alleles, then the mathematical equality p + q = 1 is satisfied.
Thus, knowing the frequency of one of the alleles, you can determine the frequency of the other allele. So, if the frequency of the dominant allele is 78%, then the frequency of the recessive allele is q = 1 - p = 1 - 0.78 = 0.22 (or 22%).
The frequencies of individual alleles in the gene pool allow us to calculate genetic changes in a given population and determine the frequency of genotypes. Since the genotype of a given organism is the main factor determining its phenotype, calculating the genotype frequency is used to predict the possible results of certain crosses. This has important practical significance in agriculture and medicine.
The mathematical relationship between the frequencies of alleles and genotypes in populations was established in 1908 independently by the English mathematician J. Hardy and the German physician W. Weinberg. For allele frequencies, there is a Hardy-Weinberg equilibrium condition. The frequencies of dominant and recessive alleles remain unchanged if the following conditions are met in the population:
1) the population size is large;
2) mating occurs randomly;
3) new mutations do not arise;
4) all genotypes are equally fertile, i.e. no selection occurs;
5) generations do not overlap;
6) there is no emigration or immigration, i.e. there is no exchange of genes with other populations.
Failure to meet one or more of these conditions can lead to changes in allele frequency and cause evolutionary changes in a given population.
Thus, during a monohybrid cross, three genotypes appear: AA with a frequency of p2 (homozygous individuals with a dominant allele), Aa with a frequency of 2pq (heterozygous individuals) and aa with a frequency of q2 (homozygous individuals with a recessive allele). The sum of allele frequencies is equal to one:
population genetics crossing mutation selection
p2 + 2pq + q2 = 1.
This relationship is called the Hardy-Weinberg equation.
Using this equation together with the equation
you can calculate the frequency, for example, of individuals homozygous for the dominant allele, knowing the number of carriers of the recessive phenotype (that is, the frequency of individuals homozygous for the recessive phenotype). Let q2 = 0.0004. Then q = 0.02, p = 1 - q = 0.98, p2 = 0.9604, 2pq = 0.0392. A consequence of the Hardy-Weinberg equation is a significant excess (often by orders of magnitude) of the number of individuals whose genotype contains a recessive allele over the number of individuals with a recessive phenotype.
It follows from the Hardy-Weinberg equation that a significant proportion of the recessive alleles present in a population are found in heterozygous carriers. In fact, heterozygous genotypes serve as an important potential source of genetic variation. This leads to the fact that in each generation only a very small proportion of recessive alleles can be eliminated from the population. Only those recessive alleles that are in a homozygous state will manifest themselves in the phenotype and thereby be subject to the selective influence of environmental factors and can be eliminated. Many recessive alleles are eliminated because they are unfavorable for the phenotype - they cause either the death of the organism even before it has time to leave offspring, or “genetic death,” that is, the inability to reproduce.
However, not all recessive alleles are unfavorable for the population. For example, in humans, of all blood groups, group O is most often found, corresponding to homozygosity for the recessive allele. Another example is sickle cell anemia. This is a hereditary blood disease that is widespread in several areas of Africa and India, in some Mediterranean countries and among the black population of North America. Individuals homozygous for the corresponding recessive allele usually die before reaching puberty, thus eliminating two recessive alleles from the population . As for heterozygotes, they do not die. It has been established that in many parts globe The frequency of the sickle cell allele remains relatively stable. In some African tribes, the frequency of the heterozygous phenotype reaches 40%. Previously, it was thought that this level was maintained due to the emergence of new mutants. However, as a result of further research, it turned out that the situation is different: it turned out that in many parts of Africa, where among the factors threatening health and life, important place malaria occupies, people carrying the sickle cell allele have increased resistance to this disease. In malarial areas of Central America, this selective advantage of the heterozygous genotype maintains the frequency of the sickle cell allele in the population at 10–20%. In North American blacks, who have not experienced the selective effect of malaria for 200-300 years, the frequency of the sickle cell allele has dropped to 5%. This decline can be partly attributed to the exchange of genes resulting from marriages between blacks and whites, but an important factor is the lack of North America malaria, eliminating selective pressure in favor of heterozygotes; as a result, the recessive allele is slowly eliminated from the population.
This example of evolution in action clearly demonstrates the selective influence of the environment on allele frequency, a mechanism that upsets the genetic equilibrium predicted by the Hardy-Weinberg law. It is precisely these kinds of mechanisms that cause shifts in populations that lead to evolutionary change.
I. Population genetic processes
The conditions necessary for the Hardy-Weinberg equilibrium are violated in a number of other cases: when the crossing is non-random; when the population is small, leading to genetic drift; when genotypes have different fertility, which creates genetic load; in the presence of gene exchange between populations
1.1 Non-random crossing
In most natural populations, mating occurs in a non-random manner. In all those cases where the presence of one or more heritable characteristics increases the probability of successful fertilization of gametes, sexual selection takes place. Plants and animals have many structural and behavioral mechanisms that exclude purely random selection of parental individuals. For example, flowers that have larger petals and more nectar than usual are likely to attract more insects, increasing the likelihood of pollination and fertilization. The coloring patterns of insects, fish and birds and the characteristics of their behavior associated with nest building, territory protection and mating ceremonies increase selectivity during crossing.
The effect of non-random crossing on the genotype and on the frequency of alleles is demonstrated, for example, by experiments carried out on Drosophila. In a culture of flies that initially contained equal numbers of red-eyed and white-eyed males and females, after 25 generations all white-eyed individuals disappeared.
As observations have shown, both red-eyed and white-eyed females preferred to mate with red-eyed males. Thus, sexual selection as a mechanism of selective mating provides some individuals with higher reproductive potential, resulting in an increased likelihood of passing on the genes of these individuals to the next generation. The reproductive potential of individuals with less favorable traits is reduced, and the transmission of their alleles to subsequent generations occurs less frequently.
1.2 Genetic drift
Genetic drift is said to occur when changes in gene frequency in populations are random and do not depend on natural selection. Random genetic drift, or the Sewall Wright effect (named for the American geneticist who understood its role in evolution), can serve as an important mechanism for evolutionary change in small or isolated populations. In a small population, not all alleles typical for a given species may be represented.
Random events, for example, the premature death of an individual that was the only owner of an allele, will lead to the disappearance of this allele in the population. If a given allele occurs in a population of a million individuals with a frequency of, say, 1% (that is, q = 0.01), then 10,000 individuals will have it, but in a population of 100 individuals, only one individual will have this allele, so the probability of its accidental loss in a small population is much higher. Just as an allele can disappear from a population, its frequency can and will increase purely by chance. Random genetic drift, as its name suggests, is unpredictable. It can lead to death of a small population, or it can make it even more adapted to a given environment or increase its divergence from the parent population. Over time, it is possible for a new species to form from it under the influence of natural selection. Genetic drift is considered a significant factor in the emergence of new species in island and other reproductively isolated populations. Genetic drift can lead to decreased variation within a population, but it can also increase variation within a species as a whole. In small isolated populations, traits atypical for the main population may arise, which, if the environment changes, can provide a selective advantage. Thus, genetic drift may be involved in the process of speciation.
Genetic drift is associated with a phenomenon known as the founder principle. It consists in the fact that when a small part of it is separated from the parent population, the latter may accidentally turn out to be not quite typical in its allelic composition. Some alleles may be absent, while others will be present at a disproportionately high frequency. Constant crossing within such a pioneer population will lead to the creation of a gene pool that differs in allele frequencies from the gene pool of the original parent population. Genetic drift typically reduces genetic variation in a population, mainly through the loss of alleles that are rare. Long-term crossing of individuals within a small population reduces the proportion of heterozygotes and increases the proportion of homozygotes. Examples of the founder principle have been identified in studies of small populations formed in America by religious sects that emigrated from Germany in the 18th century. In some of these sects, marriages took place almost exclusively between members of that sect. In such cases, the frequency of a number of alleles here is very different from their frequency among the population of both Germany and America.
1.3 Genetic load
The existence of unfavorable alleles in heterozygous genotypes in a population is called genetic load. Some recessive alleles, harmful in the homozygous state, can persist in heterozygous genotypes and, under certain environmental conditions, provide a selective advantage; an example is the sickle cell allele in areas where malaria is common. Genetic load is considered as a measure of the unadaptability of a population to environmental conditions. It is assessed by the difference in fitness of a real population - in relation to the fitness of an imaginary, maximally adapted population. Any increase in the frequency of recessive alleles in a population as a result of deleterious mutations increases its genetic load.
1.4 Mutations
During the formation of gametes, random events occur - mutations, when the parent allele, say A1, turns into another allele (A2, A3 or any other), which was or was not previously present in the population. The probability with which a mutation occurs is called the frequency, or rate, of mutation. Some gametes always carry mutant alleles, and in almost every generation one or more individuals with mutations appear. The rate of mutation of different genes varies from 10-4 to 10-7 per generation. At first glance, these values seem insignificant. However, it should be taken into account that, firstly, the genome contains many genes, and, secondly, that the population can have a significant size. Therefore, some gametes always carry mutant alleles, and in almost every generation one or more individuals with mutations appear. Their fate depends on how strongly these mutations affect fitness and fertility. The mutation process leads to an increase in the genetic variability of populations, counteracting the effect of genetic drift.
1.5 Migrations
Populations of the same species are not isolated from each other: there is always an exchange of individuals - migration. Migrating individuals, leaving offspring, pass on to the next generations alleles that might not exist at all in this population or they might be rare; This is how gene flow is formed from one population to another. Migrations, like mutations, lead to an increase in genetic diversity. In addition, gene flow connecting populations leads to their genetic similarity.
1.6 Crossing systems
In population genetics, crossing is called random if the genotypes of individuals do not affect the formation of mating pairs. For example, based on blood groups, crossing may be considered random. However, coloring, size, and behavior can greatly influence the choice of a sexual partner. If preference is given to individuals of a similar phenotype (i.e., with similar individual characteristics), then such positive assortative crossing leads to an increase in the proportion of individuals with the parental genotype in the population. If, when selecting a mating pair, preference is given to individuals of the opposite phenotype (negative assortative crossing), then new combinations of alleles will be presented in the genotype of the offspring; Accordingly, individuals of either an intermediate phenotype or a phenotype that is sharply different from the phenotype of the parents will appear in the population.
1.7 Inbreeding
The formation of marriage pairs based on kinship is called inbreeding. Inbreeding increases the proportion of homozygous individuals in a population because it is more likely that the parents have similar alleles. As the number of homozygotes increases, the number of patients with recessive hereditary diseases also increases. But inbreeding also promotes a higher concentration of certain genes, which can provide better adaptation of a given population.
Differences in fertility, survival, sexual activity, etc. lead to the fact that some individuals leave more sexually mature offspring than others - with a different set of genes. The different contributions of individuals with different genotypes to the reproduction of a population are called selection. From a genetic perspective, selection is the process that determines which alleles will be passed on to offspring, giving them an advantage in life. competition. Changes in allele frequencies can lead to evolutionary changes, the main reason for which is the appearance of mutant alleles. A recessive mutant allele can spread especially quickly in a population, being linked to some dominant allele that has important for the life of the body. Mutant alleles associated with small changes in phenotype can accumulate and produce evolutionary changes.
Selection is divided into three main types.
Stabilizing selection. Occurs in the absence of external changes and relatively weak competition. Suppresses genotypes of individuals with extreme trait deviations (for example, too big or too small). Maintains population stability and does not promote evolution.
Directional selection. Occurs in response to changes in living conditions. Shifts the phenotype in one direction or another; When a new state of equilibrium is reached, it stops. Leads to evolutionary changes.
Disruptive selection. It begins to act when there is not one, but two or more favorable phenotypes in the population. Divides the population into two groups; When gene flow between groups stops, the population may split into two species, which will compete with each other less strongly.
II. Genetic parameters of the population
When describing populations or comparing them with each other, a number of genetic characteristics are used:
Polymorphism. A population is called polymorphic at a given locus if two or more alleles occur in it. If a locus is represented by a single allele, we speak of monomorphism. By examining many loci, it is possible to determine the proportion of polymorphic ones among them, i.e. assess the degree of polymorphism, which is an indicator of the genetic diversity of the population.
The difference in one nucleotide pair (nucleotides - building blocks DNA).
Heterozygosity. An important genetic characteristic of a population is heterozygosity - the frequency of heterozygous individuals in the population. It also reflects genetic diversity.
Inbreeding coefficient. This coefficient is used to estimate the prevalence of inbreeding in a population.
Gene association. Allele frequencies of different genes can depend on each other, which is characterized by association coefficients.
5. Genetic distances. Different populations differ from each other in allele frequencies. For quantification of these differences, indicators called genetic distances have been proposed.
Various population genetic processes have different effects on these parameters: inbreeding leads to a decrease in the proportion of heterozygous individuals; mutations and migrations increase, and drift decreases, the genetic diversity of populations; selection changes the frequencies of genes and genotypes; genetic drift increases, and migration decreases genetic distances, etc. Knowing these patterns, it is possible to quantitatively study the genetic structure of populations and predict its possible changes. This is facilitated by solid theoretical basis population genetics - population genetic processes are mathematically formalized and described by dynamic equations. Statistical models and criteria have been developed to test various hypotheses about genetic processes in populations.
By applying these approaches and methods to the study of populations of humans, animals, plants and microorganisms, many problems of evolution, ecology, medicine, selection, etc. can be solved.
Bibliography:
Green N., Stout W., Taylor D. Biology (in three volumes, volume 3) Ed. R. Soper. Per. from English - M.: “Mir”, 1993.
Zhimulev I.F. “General and molecular genetics”, Siberian University Publishing House, 2007, 480 p.
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Population genetics
Population genetics studies patterns of distribution of genes and genotypes in populations. The establishment of these patterns has both scientific and practical significance in various branches of biology, such as ecology and environmental genetics, biogeography, selection, etc. In medical practice, there is also often a need to establish quantitative relationships between people with different genotypes for a gene that includes a pathological allele, or the frequency of occurrence of this gene among the population.
Populations can be in a state of genetic equilibrium or be genetically disequilibrium. In 1908, G. Hardy and V. Weinberg proposed a formula reflecting the distribution of genotype frequencies in populations with free crossing, i.e. panmictic. If the frequency of the dominant allele R, and recessive – q, and
p + q = 1, Then r*r (A.A.
) + 2pq (Aa
) + q*q (aa
) = 0
, where p*p is the frequency of the dominant homozygous genotype, 2pq is the frequency of heterozygotes, and q*q is the frequency of recessive homozygotes.
In a genetically equilibrium population, the frequencies of genes and genotypes do not change from generation to generation. This, in addition to panmixia, i.e. The absence of special selection of pairs based on any individual characteristics contributes to:
Large population size;
The absence of outflow or influx of genes into it due to the migration of individuals;
Absence of mutation pressure that changes the frequency of any allele of a given gene or leads to the appearance of new alleles;
The absence of natural selection, which may result in unequal viability or unequal fertility of individuals with different genotypes.
The action of any of these factors may cause a violation of the genetic balance in a given population, i.e. the dynamics of its genetic structure or its change in time (from generation to generation) or in space. Such a population may be evolving.
Using the Hardy-Weinberg formula, you can perform a number of calculations. For example, based on the known frequencies of phenotypes whose genotypes are known, it is possible to calculate the allele frequencies of the corresponding genes. Knowing the frequency of a dominant or recessive homozygous genotype in a given population, it is possible to calculate the parameters of the genetic structure of this population, namely, the frequencies of genes and genotypes. In addition, based on the Hardy-Weinberg formula, it is possible to determine whether a given population with a certain ratio of genotype frequencies is genetically equilibrium. Thus, analysis of populations from the standpoint of the main provisions of the Hardy-Weinberg law allows us to assess the state and direction of variability of a particular population.
The Hardy-Weinberg law also applies to genes represented by multiple alleles. If a gene is known in three allelic forms, the frequencies of these alleles are expressed, respectively, as p, q and r, and the Hardy-Weinberg formula, reflecting the ratio of the frequencies of the genotypes formed by these alleles, takes the form:
p*p + q*q + r*r + 2pq + 2pr + 2qr = 1
1. In one isolated human population, approximately 16% of people have Rh negative blood (a recessive trait). Determine the number of heterozygous carriers of the Rh-negative blood gene.
2. Does the following ratio of homozygotes and heterozygotes in the population correspond to the Hardy-Weinberg formula: 239 AA:79 Ahh: 6 ahh?
3. Gout occurs in 2% of people and is caused by an autosomal dominant gene. In women, the gout gene does not manifest itself; in men, its penetrance is 20% (V.P. Efroimson, 1968). Determine the genetic structure of the population based on the analyzed trait based on these data.
4. The frequency of blood group genes according to the AB0 system among the European population is given below (N.P. Bochkov, 1979).
Population Gene Frequencies
Russians 0.249 0.189 0.562
Buryats 0.165 0.277 0.558
English 0.251 0.050 0.699
Determine the percentage of people with I, II, III and IY blood groups among Russians, Buryats and English.
Homework:
1. In one of the panmictic populations, the allele frequency b is equal to 0.1, and in the other – 0.9. Which population has more heterozygotes?
2. In European populations, there is 1 albino per 20,000 people. Determine the genetic structure of the population.
3. The island's population descended from several individuals from a population characterized by the frequency of occurrence of the dominant allele B(brown eyes) equal to 0.2, and a recessive allele b(blue eyes) equal to 0.8. For this island population, determine the percentage of people with brown and blue eyes in the first generation. Will this ratio of individuals by phenotype and the gene pool of the population change after changes of several generations, provided that the population is panmictic in nature, and there were practically no mutations in eye color in it.
4. In the United States, about 30% of the population perceives the bitter taste of phenylthiourea (PTC); 70% of people do not distinguish its taste. The ability to taste FTC is determined by a recessive gene A. Determine allele frequency A And A and genotypes AA, Ahh And ahh in this population.
5. There are three genotypes for the albinism gene in the population: A in ratio: 9/16 A.A., 6/16 Aa and 1/16 ahh. Is this population in a state of genetic equilibrium?
6. Congenital hip dislocation is inherited dominantly, the average penetrance is 25%. The disease occurs with a frequency of 6: 10,000 (V.P. Efroimson, 1968). Determine the number of homozygous individuals for the recessive gene.
7. Find the percentage of heterozygous individuals in the population:
8. See task 4 - Buryats and British. Compare.
Population is the elementary unit of evolution. This term is understood as a collection of individuals of the same species who are connected by a common origin, common territory, the ability to freely interbreed and a common gene pool. As a result of natural selection, the population is dominated by organisms that have certain phenotypes, and also, as follows from this, certain genotypes. Such genotypes, individual genes or their combinations are widely distributed in the population.
Subject studying genetics populations are not the genotypes of individual individuals, but frequency of genes (alleles) And genotype frequencies . When analyzing the processes occurring in a population, we consider not individual individuals and crosses between these individuals, but inheritance in large populations of organisms, which can often be heterogeneous in their genotypic composition. The entire set of genes of individuals included in a population forms it gene pool . In this area of genetics, it is extremely important to trace the dynamics of the frequencies of genes, alleles, and genotypes in a population over time.
In population genetics, the concept is important ideal population , by it we mean a population that will be infinitely large in size, in which free crossings can take place ( panmixia ) in all possible combinations of organisms and genotypes and in this case no external factors(for example, there is no mutation process, no migration of individuals from one population to another, no selection, no random genetic drift, no selective crossbreeding and no isolation). Naturally, such populations do not exist in nature; however, the introduction of the concept of such a model system allows us to understand the patterns operating at the microevolutionary (i.e., population) level. Saying that no external factors act in an ideal population actually implies the existence of equilibrium in opposite directions of processes. Thus, the frequency of direct mutations (for example A x a) should be equal to the frequency of occurrence of reverse mutations ( a x A). In this case, the overall result will look like the absence of a mutation process.
The situation is similar with migrations. Share (or frequency) of emigrants of a certain genotype (individuals leaving a population) (e.g. AA ) should be equal to the share of immigrants (individuals entering a given population). At the level of allele and genotype frequencies, such an equalization of frequencies looks like the absence of migration.
Changes in the frequencies of genes (alleles) or genotypes in ideal, or Mendelian, populations are described by the basic law of population genetics - Hardy-Weinberg law . According to this law, in such a population allele frequencies do not change in successive generations and remain constant. This state of the population is often called equilibrium .
If we denote the allele frequency A through pA, a allele frequency A How qa, That pA + qa = 1.
The ratio of genotypes in the population in this case will be calculated as (pA+qa) 2 =p 2 aa+2pAqa+q 2 a=1, which can be easily verified if we consider the Punnett lattice:
|
Male gametes ⇒ Gametes females ⇓ |
pA | qa |
| pA | p 2 A.A. | pqAa |
| qa | pqAa | q 2 aa |
This ratio of genes, alleles and genotypes will be maintained in the population for an indefinitely long time. In other words, a population can be in equilibrium for an unlimited number of generations, starting with the first. If you know the frequencies of genotypes, you can calculate the frequencies of alleles and vice versa, and therefore you can predict the ratio of phenotypes.
The main consequence of the Hardy-Weinberg law is the existence of recessive alleles predominantly in the heterozygous state. The Hardy-Weinberg Law considers microevolutionary processes that operate at the species or population level.
Factors that influence the frequencies of genotypes, genes and alleles are called factors in the dynamics of gene (allele) frequencies in populations . Acting in a population, they change the corresponding frequencies.
- Natural selection.
It affects different groups of organisms differently. It leads to the selective elimination of a certain phenotype (and, consequently, the genotype that determines it), and, accordingly, to the establishment of a new equilibrium state in the population.
Depending on the influence of selection on traits, three types of selection are distinguished: a) stabilizing selection preserves the average value of the trait; b) disruptive leads to the consolidation of extreme values of the attribute; c) directed, or driving, ensures a gradual change in a characteristic in a certain direction. - Migration . If individuals of a certain phenotype emigrate (or immigrate into it) from a population with a noticeable frequency, this will lead to a change in the ratio of genotypes in the population, and, as a consequence, to the establishment of a new equilibrium value. If all genotypes are involved in migration evenly, no visible consequences are observed.
- Population limitation and panmixia . If, as a result of the action of natural or artificial factors, the number of individuals decreases significantly, the ratio of different genotypes in such a population may be disrupted. This will lead to the establishment of new allele frequencies. This is evidenced by cases known as “ genetic drift ", or genetic-automatic processes.
They are implemented in conditions of population decline as a result of the action of “ waves of life " The fact is that in different years, depending on the specific conditions of existence, the number of individuals in the population experiences rises (maximum) and declines (minimum). In addition, individuals in a population tend to be unevenly distributed, which limits panmixia. As a result of these events, the gene pool of each subsequent generation is formed from the genotypes of a fairly limited number of individuals. The ratio of different genotypes in them may not be the same as in the entire population, and, therefore, in subsequent generations, the balance will be different. However, if the number of breeding individuals reaches a certain value, then the frequencies of alleles and genotypes in it behave as in a panmictic ideal population. This effective strength , or population size . This is seen even more clearly in the example of the so-called “ principle (or effect) of the founder " When an existing old population resettles into a new territory, only a small part of it (sometimes just a few individuals) can penetrate into a new territory, whose gene pool turns out to be depleted compared to the original one. Naturally, the ratio of genotypes in the new daughter population that arose as a result of colonization will be completely different. Quite often, both in “genetic drift” and in the case of the “founder effect,” some alleles completely disappear, being replaced by others. Moreover, new alleles can cause even less fitness than disappeared ones.
POPULATION GENETICS Population genetics is a branch of genetics that studies the genetic structure of populations, their gene pool, factors and patterns during generational change. Genetic analysis of a population begins with studying the prevalence of a particular trait of interest to the researcher, for example, hereditary diseases. Further, knowing the frequency of a trait, it is possible to establish the genetic structure and gene pool of a population for this trait. The population structure is characterized by the frequency of genotypes that control alternative variations of a trait, and the gene pool is characterized by the frequency of alleles of a given locus. The frequency of a certain genotype in a population is the relative number of individuals possessing a given genotype. Frequency can be expressed as a percentage of the total number of individuals in the population, which is taken as 100%. However, more often in population genetics the total number of individuals is taken as one - 1.
Let's look at ways to calculate the frequency of genotypes using a specific example. According to the MN blood group system, each population consists of three genotypes: LMLM; LNLN; LMLN. Membership in each group can be determined by serological methods. The LMLM genotype is manifested by the presence of the M antigen, the LNLN genotype is manifested by the presence of the N antigen, and the LMLN genotype by the presence of both antigens. Suppose, when determining MN blood groups in a population, it is established that out of 4200 examined, 1218 people have only the M antigen (LMLM genotype), 882 people have only the N antigen (LNLN genotype) and 2100 people have both antigens (LMLN genotype). It is necessary to determine the frequency of all three antigens in the population. To solve the problem, let’s take the total number of people examined (4200) as 100% and calculate what percentage are people with the LMLM genotype. 1218/4200 x 100% = 29% Therefore, the frequency of the LMLM genotype is 29%. The frequency of the other two genotypes can be calculated in the same way. For the LNLN genotype it is 21%, and for the LMLN genotype it is 50%. Expressing genotype frequencies in fractions of unity, we obtain 0.29, 0.21, 0.5, respectively.
In population genetics, other methods of expressing frequency are also used, mainly for rare genotypes. Suppose that in maternity hospitals, when examined for phenylketonuria, 7 patients out of 69,862 newborns were identified. The disease is caused by the recessive gene f and patients are homozygous for this gene (ff). Determine the frequency of the ff genotype among newborns. Let's write the frequency using the usual method and get: 7/69862=0.0001. This recording method shows that at a given frequency in the population there is 1 sick child per 10 thousand newborns.
HARDY-WEINBERG LAW The basic pattern that makes it possible to study the genetic structure of populations was established in 1908 independently by the English mathematician G. Hardy and the German physician W. Weinberg. The Hardy-Weinberg law states that under the condition of hereditary continuity and in the absence of mutational pressure and selection pressure, an equilibrium of genotype frequencies is established, which is maintained from generation to generation. From the point of view of population genetic analysis, it is important that the Hardy-Weinberg law establishes a mathematical relationship between the frequencies of genes and genotypes. This dependence is based on mathematical calculation. If the gene pool of a population is determined by a pair of allelic genes, for example A and A/, and gene A occurs with frequency p, and gene A/ with frequency g, then the ratio of the frequencies of these alleles in the population will be equal to: p. A+g. A/ = 1
By squaring both sides of the equality, we get (p. A + g. A/) = 12, after opening the brackets we get a formula reflecting the frequencies of genotypes: p 2 AA + 2 pg. AA/ + g 2 A/A/ =1 The unit on the right side of the equations shows that the total number of individuals in the population is taken as 1, and the frequencies of alleles and genotypes are expressed in fractions of unity. In this case, the symbols p and g in both equalities express the frequencies of genes A and A/, and the coefficients for genotypes in equality 2 express the frequencies of genotypes. Consequently, the AA genotype occurs in the population under consideration with a frequency of p 2, the A/A/ genotype with a frequency of g 2, and heterozygotes with a frequency of 2 pg. Thus, knowing the frequency of alleles, one can establish the frequency of all genotypes, and, conversely, knowing the frequency of genotypes, one can establish the frequency of alleles.
They allow, for example, to calculate the frequency of heterozygous carriers of pathological alleles, even in cases where they are not phenotypically different from homozygotes. In a similar way, you can study the genetic structure of a population using the ABO blood group system. Before you take it apart practical use These formulas, let us dwell on the conditions for the emergence of equilibrium of genotypes in populations.
These conditions include: 1. The presence of panmixia, i.e. random selection of married couples, without a tendency to marry partners similar or opposite in genotype. 2. No influx of alleles caused by mutation pressure. 3. Absence of allele flow caused by selection. 4. Equal fertility of heterozygotes and homozygotes. 5. Generations should not overlap in time. 6. The population size must be large enough. Well-known geneticists Niel and Schell note that in no particular population this set of conditions can be met; in most cases, calculations according to the Hardy-Weinberg law are so close to reality that the law turns out to be quite suitable for analyzing the genetic structure of populations.
Well-known geneticists Niel and Schell note that in no particular population this set of conditions can be met; in most cases, calculations according to the Hardy-Weinberg law are so close to reality that the law turns out to be quite suitable for analyzing the genetic structure of populations. For medical genetics, it is important that this law can be used to analyze populations and pathological genes that reduce the viability and fertility of individuals. This is due to the fact that in human populations, the outflow of pathological alleles caused by natural selection (with the elimination of individuals with reduced viability) is balanced by the influx of the same alleles as a result of mutational pressure.
The Hardy-Weinberg law explains the tendency for genetic structure to persist across successive generations of a population. However, there are a number of factors that disrupt this trend. These include, firstly, natural selection. Selection is the only evolutionary factor that causes a directed change in the gene pool by removing less fit individuals from the population or reducing their fertility. The second important factor ensuring the influx of alleles into a population is the mutation process. The question arises. How often do mutations occur in populations under natural conditions? Such mutations are called spontaneous.
An important factor influencing the frequency of alleles in small populations is genetic-automatic processes - Genetic drift. Random genetic drift (genetic drift) is a change in allele frequencies over a series of generations caused by random reasons, for example, a small population. As a result of genetic drift, some adaptive alleles can be removed from the population, and less adaptive and even pathological ones, due to random reasons, can reach relatively high concentrations. These processes occur especially intensively during uneven reproduction. The ruler of Persia in the 18th century, Fecht-Alishah, had 66 sons, 124 eldest grandchildren, 53 married daughters, and 135 sons. By the age of 80, he had 935 direct descendants. Under these conditions, any mutation, not only beneficial, but also harmful, was bound to multiply enormously among the aristocratic families of Persia.
If the population is not too small, then changes in allele frequencies caused by genetic drift that occur in one generation are also small, however, accumulating over a number of generations, they can become very significant. In the case where allele frequencies at a given locus are not influenced by any other processes (mutation or selection), evolution will lead to the fact that one of the alleles will be fixed, and all alternative alleles will be eliminated. If only genetic drift occurs in a population, then the probability that a given allele will eventually become fixed is exactly equal to its original frequency.
The limiting case of genetic drift is the process of the emergence of a new population consisting of only a few individuals, such a process was called by Ernst Mayr - the Founder Effect. Populations of many species that live on oceanic islands, numbering millions of individuals, are descended from one or more individuals that migrated there a long time ago. A similar situation occurs in lakes and isolated forests. Due to sampling errors, the gene frequencies at various loci in the few individuals founding a new population may be very different from the gene frequencies in the population from which they originate, which can leave a strong imprint on the evolution of newly founded populations.
CYTOGENETICS Cytogenetics is a branch of genetics that studies the structural and functional organization of genetic material at the cell level, mainly chromosomes. For a comprehensive understanding of the organization of chromosomes of higher organisms (including humans), knowledge of the general patterns of DNA packaging in all variants provided by living nature is necessary - the genomes of viruses, prokaryotes, mitochondria, protists.
Chromosomes and karyotype Each cell of any organism contains a certain set of chromosomes. Total Karyotype. The chromosomes of a cell are called. In the karyotype of somatic cells, pairs of identical (in structure, shape and genetic composition) chromosomes are distinguished - the so-called Homologous chromosomes (1st - maternal, 2nd - paternal). A set of chromosomes containing pairs of homologs is called Diploid (denoted 2 n).
Sex cells - Gametes - contain half of the diploid set, one chromosome from each pair of homologues. Such a set is called haploid (denoted 2n). A human has a diploid set of 46 chromosomes, a chimpanzee - 48, a rat - 42, a dog - 78, a cow - 60, a fruit fly - 8, a silkworm - 56, a potato - 48
The karyotype is usually examined at the metaphase stage of mitosis, when each chromosome consists of two identical chromatids and is maximally spiralized. The chromatids are connected in the region of the centromere (primary constriction). In this area there is a fibrillar body - the Kinetochore, to which the spindle filaments are attached during mitosis. The ends of chromosomes are called Telomeres. They prevent chromosomes from sticking together, that is, they are responsible for their “individuality”.
The section of chromatid between the centromere and telomere is called the arm. The shoulders have their own designations: short - p and long - q. Depending on the location of the centromere, the following morphological types of chromosomes are distinguished: metacentric (p = q), submetacentric (q>p), acrocentric (one-armed - q).
Some karyotype chromosomes have a secondary constriction, where the nucleolar organizer is usually located - the region of nucleolus formation. The synthesis of r-RNA and the formation of ribosomal subunits occurs in the nucleolus. The nuclei of different organisms have from 1 to 10 nucleoli, some have none at all.
For cytogenetic analysis, all chromosomes included in the karyotype must be identified. The main method for identifying chromosomes on cytological preparations is various ways differential staining (Q-, G-, R-, C-, etc.), which are based on the use of certain dyes that specifically bind to DNA sections of different structures.
Differential staining methods were developed in the late 1960s and early 1970s, and they opened a new page in cytogenetics. Each differentially colored chromosome has its own specific striation pattern, which allows it to be identified. A karyotype can be represented as a diagram in which chromosomes are arranged in a certain order (usually in groups that unite chromosomes of the same morphological type), under certain numbers. Such a diagram is called an idiogram. Homologous chromosomes have the same number, but only one of them is depicted in the diagram.
The term genome (German Genom) was proposed by the German botanist Hans Winkler in 1920 to denote the minimum set of chromosomes. Therefore, at present, in molecular genetics, the term genome increasingly refers to the minimally ordered DNA molecules in a cell. totality
Let us consider the organization of the human genome at the cytogenetic level. The number of chromosomes in a haploid set (basic number) is 23. All chromosomes are numbered and divided into classes.
All chromosomes are numbered and divided into classes. and Of these, class A includes chromosomes 1, 2, 3; to class B – chromosomes 4, 5; to class C – chromosomes 6, 7, 8, 9, 10, 11, 12; to class D – chromosomes 13, 14, 15; to class E – chromosomes 16, 17, 18; to class F – chromosomes 19, 20; to class G - chromosomes 21, 22. The listed chromosomes are called autosomes, they are present in both men and women.
Chromosome structure Each chromatid contains one DNA molecule associated with histone and non-histone proteins. The nucleosomal model of eukaryotic chromatin organization is currently accepted. According to this model, histone proteins (they are almost the same in all eukaryotes) form special globules, 8 molecules in each globule (2 molecules of histones H 2 a, H 2 b, IZ, H 4). The DNA strand makes 2 turns around each globule. A structure consisting of a histone octamer wrapped around a piece of DNA (140-160 bp in size) is called a nucleosome. This DNA folding reduces its length by 7 times. The nucleosomal model is called “beads on a string”. Positively charged histones and negatively charged DNA form a reliable DNA
The DNA region between the nucleosomes has histone HI. It plays an important role in the spiralization of the nucleosomal thread and the formation of the second level of chromosome organization - the helical structure of the solenoid. The subsequent multi-stage folding of the DNA-histone strand determines the compact packaging of genetic material in the chromosome, the so-called chromatin compaction process. In total, there are 4-5 levels of packaging, starting with the nucleosome. The degree of chromatin compaction varies in different regions of chromosomes and depends on the period of the cell cycle. A variety of non-histone proteins play a specific role in this process. play Thanks to the process of compaction, very long DNA molecules are packed into a small volume in the cell.
There are 2 types of chromatin: euchromatin (packed less tightly) and heterochromatin (packed more tightly). In turn, heterochromatin is divided into two classes: structural (or constitutive) heterochromatin (constantly detectable areas) and facultative heterochromatin (areas of reversible compaction of euchromatic regions). Structural heterochromatin is localized in the pericentromeric regions and some other regions of chromosomes; it is clearly detected by Sokraska. In interphase, areas of structural heterochromatin often aggregate with each other
It is believed that heterochromatin is genetically inactive due to a high degree of condensation, while euchromatin is active. But, on the other hand, only a small part of euchromatin genes is active, i.e., being in euchromatin is an insufficient condition for gene expression. Even more questions arise when studying the functioning of heterochromatin.
Giant chromosomes In nature, cases of atypical chromosome structure are observed. Since such atypical chromosomes are large, they serve as a convenient model for studying the genome. Lampbrush chromosomes are a stretched and untwisted version of normal oocyte chromosomes during prolonged meiosis. They are best studied in amphibians, due to their particularly large size. The length of such chromosomes is 30 times greater than their normal length. Lampbrush chromosomes get their name from the presence of loops. Loops are regions of the chromosomal strand that protrude from more compact material and are the site of active transcription. At the end of meiosis, the lampbrush chromosomes return to their normal state.
Polytene chromosomes are formed in some cells as a result of maximum despiralization and multiple replication without subsequent chromosome divergence. This phenomenon is called endomitosis. Before endomitosis, homologous chromosomes are joined in pairs - conjugated. Such conjugation is not typical for other somatic cells. All polytene chromosomes of the karyotype are united by centromeres into a common chromocenter. Polytene chromosomes have been best studied in dipteran insects (including the classic object, Drosophila), although they are also found in some other organisms. Since polytene chromosomes contain more than 1000 strands, they are 1000 times thicker than ordinary chromosomes and they have clearly visible areas of denser spiralization - disks.
Molecular mechanisms and biological role of DNA repair The resistance of living organisms to various damaging agents of a physical, chemical and biological nature is determined by their ability to restore damaged structures. A special role belongs to the process of DNA repair at the molecular level, leading to the restoration of the normal structure of nucleic acids altered during interaction with these agents. This is how repair systems emerged, aimed at correcting damage in the DNA molecule. Currently, post-replicative repair is distinguished. pre-replicative and pre-replicative repair: photoreactivation, excision or dark repair.
Photoreactivation The phenomenon of photoreactivation was discovered in 1949 by Kelner. Photoreactivation is a one-step process and is carried out with the help of a photoreactivating enzyme (PRF) - photolyase. The essence of this phenomenon is that visible light with a wavelength of 300 -400 nm excites a photoreactivating enzyme, which breaks down pyrimidine dimers. This mechanism has the property of eliminating only one type of damage (thymine dimers), carried out by one enzyme, in one stage. In the dark, an enzyme (photolyase) attaches to the dimer and, under the influence of visible light, cleaves the dimer to form the original intact bases, and the photolyase is released. In 1971, FGF was discovered in all types of living organisms. Photoreactivation was detected in human leukocytes and fibroblasts.
Returning to the mechanism of action of FGF, it should be noted that the binding of the enzyme to DNA containing dimers is reversible, and if this complex is not exposed to photoreactivating light, then its dissociation occurs and DNA that carries altered fragments can become a substrate for the action of dark repair enzymes. The biological role of photoreactivation is to protect cell DNA from the inactivating effects of UV radiation.
Excision repair (dark repair, unscheduled DNA synthesis). Most in a general way correction of structural DNA damage caused by chemical mutagens, UV and ionizing radiation, is an excision repair. The mechanism of excision repair was discovered in 1964 in microbial cells irradiated with UV light. Characteristic feature there was excision of pyrimidine dimers from UV-irradiated DNA. (cut) Later it turned out that this mechanism is not limited to the elimination of UV damage in DNA, but has the universal significance of a system that eliminates any chemical damage to the primary structure of DNA. Another feature of excision repair is that it does not require visible or near-UV light energy.
Excision repair is a multi-stage process, occurs in 4 stages using a multienzyme system and eliminates dimers, pyrimidine bases, and radiolysis products. The first stage of the cycle is incision (cutting). This is an enzymatic process that involves breaking the DNA strand near the damage by endonucleases. It is believed that this stage is preceded by the stage of recognition of a defect in DNA. The second stage is excision, during which the dimer is released and standing nearby nucleotides. The enzyme involved is exonuclease. Excision begins with an exonuclease attack on damaged DNA. In this case, the pyrimidine dimer is cleaved off and further sequential cleavage of adjacent nucleotides occurs. The other end of the break, containing a phosphate group at the 3rd end, cannot serve as a primer for the exonuclease activity of DNA polymerase-1, since the activity of the enzyme attached to this end is inhibited, therefore the cleavage of the phosphate from the 3rd end along with the nucleotide occurs under the action of the enzyme type exonuclease-3.
As a result, the 5-P end is formed, which is necessary for completing the repair stage - the DNA polymerase reaction (reparative synthesis). A complementary, undamaged DNA strand is used as a template for reparative DNA synthesis, providing an accurate reproduction of the primary DNA structure that existed before exposure to the damaging agent. the stage of excision repair is a repair synthesis in which the resulting gaps are filled in short sections using DNA polymerase. The third and fourth stage of repair is the cross-linking of the 5 phosphate and 3 OH ends of the repaired DNA, the enzyme ligase is involved. Under the influence of radiation, when a direct DNA strand break occurs, the ligase can act as an independent repair enzyme, carrying out “ultra-fast” repair.
Thus, both photoreactivation and excision repair occur before damaged cells enter the DNA synthesis phase. In contrast, postreplicative repair begins after the cell begins replication. In this case, DNA synthesis bypasses the damage, but against them, gaps are formed in the daughter strands, which are then repaired either by recombination or by de novo DNA synthesis. The latter can be of two kinds - syntheses similar to normal replication, in which nitrogenous bases are incorporated into DNA in full accordance with the rules of complementarity (an error-free repair pathway), or template-free synthesis, when bases are inserted at random. This is an error-prone recovery path.
All three types of repair are widespread in nature. They are found in representatives of different groups. In different groups of organisms, one or another repair pathway may be more or less active or even completely absent, but then this is compensated by the activity of other repair systems. The combined action of various repair systems eliminates many DNA damages. Their diversity suggests that any stable changes in the structure of nucleic acids can be repaired.
Reparation consequences in some hereditary human diseases. Currently, a number of hereditary human diseases are being studied in connection with reparation processes. Five of them are autosomal recessive diseases, different in clinical picture, but their common feature are chromosomal instability, immunological deficiency and an increased risk of cancer. Xeroderma pigmentosum. This clinical name unites a group of diseases in which there is increased sensitivity of the skin to sunlight. Clinically, this manifests itself in skin redness, pigmentation, and the appearance of malignant neoplasms. Signs of skin aging are also characteristic. Neurological abnormalities may also be associated with skin disorders.
Xeroderma pigmentosum is the first human disease for which a connection with the state of repair processes has been shown. Skin fibroblasts from patients with PC turned out to be more sensitive to UV irradiation than fibroblasts from healthy donors. This is due to the fact that they have a reduced ability to release thymine dimers after UV irradiation. Since single breaks, characteristic of the first step of excision repair, do not form in the DNA of fibroblasts from patients with PC after irradiation, it was concluded that in this disease there is a mutation in the gene encoding the synthesis of a UV-specific endonuclease. The addition of this enzyme to the medium completely restored the reparative ability. Subsequently, forms of the disease were discovered in which other enzymes of the excision pathway were also impaired, and the cells of patients turned out to be sensitive to both UV and ionizing radiation.
Pancytopenia or Fanconi anemia. This disease is characterized by hematological abnormalities. All bone marrow sprouts are affected. Leukopenia, thrombocytopenia, anemia, intense brown pigmentation of the skin, developmental defects of the skeleton, heart, kidneys, and gonads are observed. The primary molecular defect in AF is a violation of the synthesis of exonuclease, the enzyme that completes the cutting of the damaged DNA section. Initially, this was shown in UV-irradiated fibroblasts from patients. In cells from patients with FA, cross-link excision is impaired due to the absence of exonuclease. Cells exhibit premature condensation of chromatin when entering mitosis, and chromosomal aberrations appear. A study of chromosomal aberrations in lymphocytes showed that both types of cells (T and B lymphocytes) are affected. It is believed that both lymphocytes may be involved in the development of leukemia in AF.
