Genetic variability limited to one species (Homo sapiens in our case) is called genetic polymorphism (GP).

The genomes of all people, with the exception of identical twins, are different.

Pronounced population, ethnic, and, most importantly, individual differences in genomes both in their semantic part (exons) and in their non-coding sequences (intergene gaps, introns, etc.) are due to various mutations leading to HP. The latter is usually defined as a Mendelian trait that occurs in a population in at least 2 variants with a frequency of at least 1% for each. The study of HP is the main objective of the rapidly growing program "Human Genetic Diversity" (see Table 1.1).

HP can be qualitative, when nucleotide substitutions occur, or quantitative, when the number of nucleotide repeats of various lengths varies in DNA. Both types of HP are found both in sense (protein-coding) and in extragene sequences of the DNA molecule.

Qualitative HP is represented mainly by single nucleotide substitutions, the so-called single nucleotide polymorphism (SNP) . This is the most common GP. Already the first comparative study of the genomes of representatives of different races and ethnic groups showed not only the deep genetic relationship of all people (the similarity of genomes is 99.9%), but also made it possible to obtain valuable information about the origin of man, the routes of his settlement around the planet, and the ways of ethnogenesis. The solution of many problems of genogeography, the origin of man, the evolution of the genome in phylogenesis and ethnogenesis - this is the circle of fundamental problems facing this rapidly developing direction.

Quantitative GP - represented by variations in the number of tandem repeats (STR - Short Tandem Repeats) in the form of 1-2 nucleotides (microsatellite DNA) or 3-4 or more nucleotides per core (repeating) unit. This is the so-called minisatellite DNA. Finally, DNA repeats can have a large length and an internal structure variable in nucleotide composition - the so-called VNTR (Variable Number Tandem Repeats).

As a rule, quantitative GP refers to off-sense non-coding (coding) regions of the genome. The only exception is trinucleotide repeats. More often it is CAG (citosine-adenine-guanine) - a triplet encoding glutamic acid. They can also be found in the coding sequences of a number of structural genes. In particular, such GPs are characteristic of genes for "expansion diseases" (see Chapter 3). In these cases, upon reaching a certain copy number of the trinucleotide (polynucleotide) repeat, GPs cease to be functionally neutral and manifest themselves as a special type of so-called "dynamic mutations" . The latter are especially characteristic of a large group of neurodegenerative diseases (Huntington's chorea, Kennedy's disease, spinocerebellar ataxia, etc.). The characteristic clinical features of such diseases are: late manifestation, the effect of anticipation (increasing the severity of the disease in subsequent generations), the lack of effective methods of treatment (see Chapter 3).

All the people who inhabit our planet today are indeed genetically brothers and sisters. Moreover, interindividual variability, even when sequencing the genes of representatives of the white, yellow, and black races, did not exceed 0.1% and was mainly due to single nucleotide substitutions, SNPs (Single Nucleotide Polymorphisms). Such substitutions are very numerous and occur every 250-400 bp. Their total number in the genome is estimated at 10-13 million (Table 1.2). It is assumed that about half of all SNPs (5 million) are in the sense (expressed) part of the genome. These substitutions, as it turned out, are especially important for the molecular diagnosis of hereditary diseases. They play the main role in human HP.

Today it is well known that polymorphism is characteristic of almost all human genes. Moreover, it has been established that it has a pronounced ethnic and population specificity. This feature makes it possible to widely use polymorphic gene markers in ethnic and population studies. Polymorphism affecting the semantic parts of genes often leads to the replacement of amino acids and the appearance of proteins with new functional properties. Substitutions or repetitions of nucleotides in the regulatory (promoter) regions of genes can have a significant effect on the expression activity of genes. Inherited polymorphic changes in genes play a decisive role in determining the unique biochemical profile of each person, in assessing his hereditary predisposition to various frequent multifactorial (multifactorial) diseases. The study of the medical aspects of HP is the conceptual and methodological basis of predictive (predictive) medicine (see 1.2.5).

Recent studies have shown that single nucleotide substitutions (SNPs) and short tandem mono-, di-, and trinucleotide repeats are dominant, but by no means the only polymorphism variants in the human genome. It has recently been reported that about 12% of all human genes are present in more than two copies. Therefore, the real differences between the genomes of different people are likely to significantly exceed the previously postulated 0.1%. Based on this, it is currently believed that the proximity of unrelated genomes is not 99.9%, as previously thought, but approximately equal to about 990%. Particularly surprising was the fact that not only the number of copies of individual genes, but even entire fragments of chromosomes with sizes of 0.65-1.3 Megabases (1 Mgb = 10 6 bp) can vary in the genome. In recent years, using the method of comparative genomic hybridization on chips containing DNA probes corresponding to the entire human genome, amazing data have been obtained proving the polymorphism of individual genomes in large (5–20 Mgb) DNA fragments. This polymorphism is called Copy Number Variation, and its contribution to human pathology is currently being actively investigated.

According to modern data, quantitative polymorphism in the human genome is much wider than previously thought; the main qualitative variant of polymorphism are single nucleotide substitutions - SNPs.

1.2.З.1. International project "Haploid genome" (NarMar)

The decisive role in the study of genomic polymorphism belongs to the international project for the study of the haploid human genome - "Haploid map" - HapMap.

The project was initiated by the Institute for the Study of the Human Genome (USA) in 2002. The project was implemented by 200 researchers from 6 countries (USA, Great Britain, Canada, Japan, China, Nigeria), who formed a Scientific Consortium. The goal of the project is to obtain a genetic map of the next generation, the basis of which should be the distribution of single nucleotide substitutions (SNPs) in the haploid set of all 23 human chromosomes.

The essence of the project is that when analyzing the distribution of already known SNPs (ONZ) in individuals of several generations, neighboring or closely located SNPs in the DNA of one chromosome are inherited in blocks. Such a SNP block is a haplotype - an allelic set of several loci located on the same chromosome (hence the name of the NarMar project). Each of the mapped SNPs acts as an independent molecular marker. To create a genome-wide map of SNPs, it is important, however, that the genetic linkage between two neighboring SNPs be highly reliable. By linking such SNP markers with the studied trait (disease, symptom), the most probable localization sites of candidate genes, mutations (polymorphism) of which are associated with one or another multifactorial disease, are determined. Usually, several SNPs that are closely linked to an already known Mendelian trait are selected for mapping. Such well-characterized ONZs with a frequency of rare alleles of at least 5% are called marker SNPs (tagSNPs). It is anticipated that only about 500,000 tagSNPs will eventually be selected from the approximately 10 million DHCs present in each individual's genome during the project.

But even this number is quite enough to cover the entire human genome with the ONZ map. Naturally, the gradual saturation of the genome with such point molecular markers, convenient for genome-wide analysis, opens up great prospects for mapping many as yet unknown genes, the allelic variants of which are associated (linked) with various severe diseases.

The first phase of the $138 million NarMar project was completed in October 2005. Genotyping of over a million DHCs (1,007,329) was carried out in 270 representatives of 4 populations (90 European Americans, 90 Nigerians, 45 Chinese and 45 Japanese). The result of the work was a haploid SNP map containing information on the distribution and frequencies of marker SNPs in the studied populations.

As a result of the second stage of the HapMap project, which ended in December 2006, the same sample of individuals (269 people) was genotyped for another 4,600,000 SNPs. To date, the Next Generation Genetic Map (NarMar) already contains information on more than 5.5 million NHCs. In its final version, which, given the ever-increasing speed of SNP mapping, will become available in the near future, there will be information on 9,000,000 SNPs of the haploid set. Thanks to NarMar, which includes not only SNPs of already mapped genes with known phenotypes, but also SNPs of genes not yet identified, scientists get a powerful universal navigator necessary for in-depth analysis of the genome of each individual, for fast and efficient mapping of genes whose allelic variants predispose to various multifactorial diseases, to conduct large-scale studies on human population genetics, pharmacogenetics and individual medicine.

According to Francis Collins, director of the National Institute for the Study of the Human Genome (USA): “Even when discussing the Human Genome Program 20 years ago, I dreamed of a time when the genomic approach would become a tool for diagnosing, treating and preventing severe common diseases that suffer from sick people fill our hospitals, clinics and doctors' offices. successes

The NarMar project allows us to take a serious step towards this dream today” (http://www.the-scientist.com/2006/2/1/46/1/).

Indeed, using the NarMar technique, it was possible to quickly map the gene responsible for macular degeneration, identify the main gene and several gene markers of heart disease, determine chromosome regions and find genes associated with osteoporosis, bronchial asthma, type 1 and type 2 diabetes. and also with prostate cancer. Using the NarMar technology, it is possible not only to carry out genome-wide screening, but also to study individual parts of the genome (chromosome fragments) and even candidate genes. The combination of Nar-Mar technology with the capabilities of high-resolution hybridization DNA chips and a special computer program made available genome-wide association screening and made a real revolution in predictive medicine in terms of the effective identification of genes predisposing to various MDs (see Chapters 8 and 9).

Considering that genetic polymorphism is by no means limited to ONZ, and molecular variations of the genome are much more diverse, scientists and publishers of the scientific journal Human Mutation Richard Cotton (Australia) and Haig Kazazian (USA) initiated the Human Variom Project, the purpose of which is to create a universal bank data, which includes information not only on mutations leading to various monogenic diseases, but also on polymorphisms predisposing to multifactorial diseases - http://www.humanvariomeproject.org/index.php?p = News . Given the rather arbitrary boundaries between "polymorphism" and "mutations", the creation of such a universal library of genome variations can only be welcomed.

Unfortunately, we have to state that while in the case of the Human Genome project in Russia some attempts were still made to participate in joint research, in the implementation of the international NarMar project, domestic scientists were practically not involved. Accordingly, it is very problematic to use the technology of genome-wide screening of SNPs in Russia in the absence of the necessary hardware and software. Meanwhile, given the population characteristics of genetic polymorphism, the introduction of GWAS technology in Russia is absolutely necessary (see Chapter 9).

It is with deep regret that we have to state that the already existing colossal gap between domestic and advanced world science in the field of studying the human genome after the completion of the NarMar program will only rapidly increase.

1.2.З.2. New projects for the study of the human genome

The NarMar project is by no means the only one, although it is the most advanced in the study of the structural and functional organization of the human genome in our time. Another international project - ENCODE "Encyclopedia of DNA elements", initiated by the National Institute of Human Genome Research, USA (NIHGR) (National Institute of Human Genome Research - NIHGR). Its goal is the accurate identification and mapping of all protein-synthesizing genes and functionally significant elements of the human genome. As a pilot study, the project involves repeatedly sequencing and studying in detail a fragment of the genome up to 1% of the total DNA length. The most likely candidate is a genome region of about 30 Megabases (million bp) in the short arm of chromosome 6. It is there that the HLA locus, which is very complex in structural and functional terms, is responsible for the synthesis of histocompatibility antigens. It is planned to sequence the HLA region in 100 patients with autoimmune diseases (systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, bronchial asthma, etc.) and in 100 somatically healthy donors in order to understand the molecular nature of gene features in these pathologies. Similarly, it is proposed to identify candidate genes in loci that show a non-random association with frequent severe diseases of a multifactorial nature. The results of the ENCODE project have already been partly published, however, the HLA locus is not included in it.

Another project - NIHGR "Chemical Genomics" - aims to create a public library of chemicals, mainly organic compounds, convenient for studying the main metabolic pathways of the body, directly interacting with the genome and promising for the creation of new drugs.

The Genome to Life project "Genome for Life" focuses on the peculiarities of metabolism and organization of the genomes of unicellular organisms pathogenic to humans. It is assumed that the result of its implementation will be computerized models of the reaction of microbes to external influences. Research will focus on four main areas: bacterial proteins, regulatory mechanisms of genes, microbial associations (symbiosis), interaction with the human body (www.genomestolife.org).

Finally, the Wellcome Trust, the main organization for funding scientific projects in the UK, has created the Structural Genomic Consortium. Its goal is to increase the efficiency of the search and synthesis of new targeted drugs based on data from the study of the human genome.

Directly related to predictive medicine and pharmacogenetics is the Environmental Genome Project being developed in the USA and Western Europe. Some details of this project will be discussed in the next chapter.

Genetic polymorphism is understood as a state of long-term diversity of genotypes, when the frequency of even the most rare genotypes in populations exceeds 1%. Genetic polymorphism is maintained by mutations and recombinations of genetic material. As shown by numerous studies, genetic polymorphism is widespread. So, according to theoretical calculations, in the offspring from crossing two individuals that differ only in ten loci, each of which is represented by 4 possible alleles, there will be about 10 billion individuals with different genotypes.

The greater the stock of genetic polymorphism in a given population, the easier it is for it to adapt to a new environment and the faster evolution proceeds. However, it is practically impossible to estimate the number of polymorphic alleles using traditional genetic methods, since the very fact of the presence of a gene in the genotype is established by crossing individuals with different forms of the phenotype determined by this gene. Knowing the proportion of individuals with different phenotypes in the population, it is possible to find out how many alleles are involved in the formation of a given trait.

Since the 1960s, the method of protein gel electrophoresis (including enzymes) has been widely used to determine genetic polymorphism. Using this method, it is possible to cause the movement of proteins in an electric field, depending on their size, configuration, and total charge, to different sections of the gel, and then, by the location and number of spots that appear in this case, identify the substance under study. To assess the degree of polymorphism of certain proteins in populations, about 20 or more loci are usually examined, and then the number of allelic genes, the ratio of homo- and heterozygotes are determined mathematically. Studies show that some genes tend to be monomorphic, while others are extremely polymorphic.

Distinguish between transitional and balanced polymorphism, which depends on the selective value of genes and the pressure of natural selection.

Transitional polymorphism occurs in a population when an allele that was once common is replaced by other alleles that give their carriers higher fitness (multiple allelism). With transitional polymorphism, a directed shift is observed in the percentage of genotype forms. Transitional polymorphism is the main path of evolution, its dynamics. An example of transitional polymorphism can be the phenomenon of the industrial mechanism. So, as a result of atmospheric pollution in the industrial cities of England over the past hundred years, more than 80 species of butterflies have developed dark forms. For example, if before 1848 the birch moths had a pale cream color with black dots and separate dark spots, then in 1848 the first dark forms appeared in Manchester, and by 1895 already 98% of the moths had become dark. This was due to the sooting of tree trunks and the selective eating of light-bodied moths by thrushes and robins. Later, it was found that the dark coloration of the body in moths is carried out by a mutant melanistic allele.

Balanced polymorphism is characterized by the absence of a shift in the numerical ratios of various forms, genotypes in populations under stable environmental conditions. At the same time, the percentage of forms either remains the same from generation to generation, or fluctuates around some constant value. In contrast to transitional, balanced polymorphism is the static of evolution. I.I. Schmalhausen (1940) called it an equilibrium heteromorphism.

An example of balanced polymorphism is the presence of two sexes in monogamous animals, since they have equivalent selective advantages. Their ratio in populations is 1:1. With polygamy, the selective value for representatives of different sexes may differ, and then representatives of one sex are either destroyed, or, to a greater extent than individuals of the other sex, are removed from reproduction. Another example is human blood groups according to the ABO system. Here, the frequency of different genotypes in different populations may vary, however, in each specific population it remains constant from generation to generation. This is because no one genotype has a selective advantage over others. So, although men with the first blood type, as statistics show, have a higher life expectancy than men with other blood types, they are more likely than others to develop a duodenal ulcer, which, if perforated, can lead to death.

Genetic balance in populations can be disturbed by the pressure of spontaneous mutations that occur at a certain frequency in each generation. The persistence or elimination of these mutations depends on whether natural selection favors or opposes them. Tracing the fate of mutations in a given population, one can speak of its adaptive value. The latter is equal to 1 if selection does not exclude it and does not counteract the spread. In most cases, the indicator of the adaptive value of mutant genes is less than 1, and if the mutants are completely unable to reproduce, then it is equal to zero. Such mutations are swept aside by natural selection. However, the same gene can mutate repeatedly, which compensates for its elimination by selection. In such cases, an equilibrium can be reached where the appearance and disappearance of mutated genes becomes balanced. An example is sickle cell anemia, when a dominant mutant gene in a homozygote leads to early death of the organism, however, heterozygotes for this gene are resistant to malaria. In areas where malaria is common, there is a balanced polymorphism in the gene for sickle cell anemia, since along with the elimination of homozygotes, there is counter-selection in favor of heterozygotes. As a result of multi-vector selection in the gene pool of populations, genotypes are maintained in each generation, ensuring the adaptability of organisms, taking into account local conditions. In addition to the sickle cell gene, there are a number of other polymorphic genes in human populations that are thought to cause the phenomenon of heterosis.

Recessive mutations (including deleterious ones) that do not manifest themselves phenotypically in heterozygotes can accumulate in populations to a higher level than deleterious dominant mutations.

Genetic polymorphism is a prerequisite for continuous evolution. Thanks to him, in a changing environment, there can always be genetic variants pre-adapted to these conditions. In a population of diploid dioecious organisms, a huge reserve of genetic variability can be stored in a heterozygous state, without manifesting phenotypically. The level of the latter, obviously, can be even higher in polyploid organisms, in which not one, but several mutant alleles can be hidden behind the phenotypically manifested normal allele.

Each person is unique, and this uniqueness is possible due to the individual combination of genes (genotype). The general set of genes in all people is the same, it determines the characteristic features from the point of view of the whole species. The unique differences of each organism arise due to different combinations of DNA elements.

DNA cells located on the same parts of the chromosome (loci) and providing for different states of the same trait are polymorphic (polys - many and morphe - appearance, shape, image). Their dual nature is due to different alleles, or, in other words, forms.

Different alleles arise as a result of mutation, that is, spontaneous or directed changes in the structure of DNA under the influence of provoking factors. Gene polymorphism determines individual differences in the development of physical or mental characteristics of a person, but in addition, it causes a predisposition to certain diseases.

In cases where mutations determine not the presence of the pathology itself, but only a predisposition to it, it can develop only under the influence of certain external or internal factors. In particular, genetic thrombophilia can begin to develop due to pregnancy or exposure to diseases of the cardiovascular system - atrial fibrillation, hypertension, varicose veins, etc.

Even under the influence of provoking factors, thrombophilia does not develop in all people prone to this, it all depends on the individual characteristics of the organism.

In most patients with a predisposition to the formation of blood clots, this feature is precisely congenital, that is, acquired during fetal development. In this case, there are two options for the occurrence of polymorphism. Firstly, it can result from combining different alleles of the father and mother in one gene, and secondly, a polymorphic gene can be completely inherited from one of the parents.

Each person can have many polymorphic genes, but not all of them can lead to thrombophilia. Some of them cause completely harmless differences between a particular person and others, others give rise to genetic diseases. Only a few genes related to the blood coagulation system can affect the occurrence of thrombophilia.

Prothrombin polymorphism

Prothrombin (coagulation factor II or F2) is one of the main components of the coagulation system. This is a complex protein structure that precedes thrombin, the main enzyme of hemostasis (clotting), which is directly involved in the formation of blood clots. When analyzing prothrombin polymorphism, the following results can be obtained:

1. prothrombin time. This value, expressed in seconds, corresponds to the clotting time. Normally, the predicted time should be in the range of 9-12.6 seconds.
2. prothrombin index. This is an indicator calculated as the ratio of the patient's prothrombin time to the normative value for a particular age and gender in percent. A prothrombin index ranging from 77 to 120% is considered normal.
3. Prothrombin according to Quick. This is the most modern and accurate analysis for prothrombin polymorphism. The result of the study is calculated as the ratio of the activity of the patient's plasma and the normative value of the control plasma in percent. A normal indicator is 78-142%.

The occurrence of a predisposition to thrombosis is affected by an increased prothrombin index, which can exceed the norm by 1.5-2 times. The resulting mutation is inherited in an autosomal dominant manner, that is, even if the gene of the second parent is normal, the child will inherit a polymorphism that may or may not lead to thrombophilia.

Mutation Leiden

Polymorphism of the Leiden factor (factor V) of the coagulation system is one of the most dangerous in terms of the risk of thrombosis. This component of the clotting process, or, in other words, proaccelerin, is a protein synthesized in the liver. It is a cofactor, that is, an auxiliary element that is involved in the conversion of prothrombin to thrombin.

The Leiden mutation occurs in 5% of the total population of the planet, and specifically in patients suffering from thrombosis, this feature occurs in 20-40%. Moreover, if both parents had a polymorphic proaccelerin gene, then the risk of developing thrombophilia in a child is 80%, but if the phenomenon occurred only in the father or mother, the probability is 7%.

The risk of developing thrombophilia with mutation of the Leiden factor increases in the presence of the following provoking factors:

• surgical interventions, especially on the pelvic organs;
• the period after surgery or injury, suggesting a long static position;
• malignant tumors;
• overweight;
• chronic diseases of the cardiovascular system;
• taking drugs from certain pharmacological groups;
• taking oral contraceptives (birth control pills) and other hormonal drugs;
• pregnancy, childbirth and the postpartum period;
• frequent long journeys and flights;
• frequent venous catheterization;
• dehydration.

Most people with only one mutated proaccelerin gene with a normal second allele do not have a single case of thrombosis in their entire life. If a polymorphic gene is represented by two altered alleles at once, then it is almost impossible to prevent the influence of thrombophilia without regular preventive measures.

Factor VII polymorphism

Factor VII or F7 (proconvertin) is an element of the blood coagulation system that is involved in the early stage of thrombus formation. Together with some other factors of hemostasis, it contributes to the activation of factor X, which, in turn, converts prothrombin from a passive state to an active one and promotes the formation of thrombin.

Proconvertin is synthesized in the liver under the influence of vitamin K.

In contrast to other gene polymorphisms, factor VII mutation in thrombophilia has a beneficial effect. A change in the primary structure of proconvertin contributes to a decrease in its enzymatic activity, that is, it will have a lesser effect on the activation of the conversion of prothrombin to thrombin.

The polymorphism of the factor VII hemostasis gene affects not only the reduction in the risk of thrombosis, but also the reduction in the likelihood of miscarriage, that is, miscarriage. Also, under the influence of the mutation, the risk of myocardial infarction is reduced, and if it does happen, then the probability of death also decreases. However, it also increases the risk of bleeding.

Fibrinogen polymorphism

Fibrinogen (factor I, F1) is a specific protein that is found in the blood in a dissolved form and during bleeding is the basis for the formation of a blood clot. Under the influence of thrombin, this component is converted into fibrin, which, under the influence of enzymes, is converted directly into a thrombus.

Fibrinogen is called F1 because it was the first to be discovered by scientists.

Fibrinogen polymorphism significantly increases the likelihood of thrombus formation, but in most cases this occurs under the influence of external negative factors. These include inflammatory, infectious and autoimmune pathologies. The following provocateurs may also influence:

• diabetes;
• overweight;
• malignant neoplasms;
• acute myocardial infarction;
• skin injury;
• smoking;
• hepatitis;
• tuberculosis.

It should also be borne in mind that when taking tests, an increase in fibrinogen levels can be affected by stress, previous intense physical activity, elevated cholesterol levels, taking oral contraceptives, etc. It is not recommended to conduct a study for colds.

Gene polymorphism tests

Gene polymorphism is diagnosed using a specific blood test taken from a vein in the morning on an empty stomach. You can undergo such an examination in clinical diagnostic centers or private hospitals, since such a service is not provided in public clinics. It is worth preparing for the fact that each analysis can cost from 1.5 to 4 thousand rubles, and several of them may be needed.

An appointment for each analysis is given by the attending physician based on the results of a general blood test. Any specialist can send for examination - a therapist, surgeon, phlebologist, etc., but only a hematologist should decipher the results. Do not try to draw a conclusion on your own.

Often, an analysis for gene polymorphism is prescribed during pregnancy, since thrombophilia during the period of bearing a child can lead to irreparable consequences. These include intrauterine growth retardation, pregnancy failure, miscarriage and premature birth. Despite this, every woman with such a diagnosis can give birth to a healthy child without the use of a caesarean section, if she fully adheres to the doctor's recommendations.



Polymorphism of human populations. genetic cargo.

Classification of polymorphism.

Genetic polymorphism of human populations.

genetic load.

Genetic aspects of predisposition to diseases.

Natural selection can:

Stabilize the view;

Lead to new formation of species;

Promote diversity.

Polymorphism- the existence in a single panmix population of two or more sharply different phenotypes. They may be normal or abnormal. Polymorphism is an intrapopulation phenomenon.

Polymorphism happens:

Chromosomal;

Transition;

Balanced.

Genetic polymorphism occurs when a gene is represented by more than one allele. An example is blood group systems.

Chromosomal polymorphism - between individuals there are differences in individual chromosomes. This is the result of chromosomal aberrations. There are differences in heterochromatic regions. If the changes do not have pathological consequences - chromosomal polymorphism, the nature of the mutations is neutral.

Transitional polymorphism is the replacement in a population of one old allele with a new one that is more useful under given conditions. A person has a haptoglobin gene - Hp1f, Hp 2fs. The old allele is Hp1f, the new one is Hp2fs. Hp forms a complex with hemoglobin and causes aggregation of erythrocytes in the acute phase of diseases.

Balanced polymorphism - occurs when none of the genotypes benefits, and natural selection favors diversity.

All forms of polymorphism are very widespread in nature in populations of all organisms. In populations of sexually reproducing organisms, there is always polymorphism.

The root "morphism" involves consideration of the structure.

Now the term "polymorphism" is understood as any trait that is determined genetically and is not a consequence of phenocopy. Very often there are 2 alternative signs, then they talk about dimorphism. For example, sexual dimorphism.

Until the mid-1960s (more precisely, 1966), mutations with a morphological trait were used to study polymorphism. They happen with a small frequency, lead to serious changes, and therefore, are very noticeable.

Timofeev - Risovsky "on the flower morphs of the Berlin ladybug population ...". 8 types of coloring. 3 more common (black spots on a red background) - red morphs, if vice versa - black morphs. I determined that reds are dominant and blacks are recessive. There are more reds in winter, blacks in summer. The presence of polymorphism in a population is adaptive.

Studying the color of the garden snail in Europe.

In 1960, Hubby and Lewontin proposed the use of electrophoresis to determine the morphs of human and animal proteins. There is a distribution of proteins in layers due to the charge. The method is very accurate. An example is isoenzymes. Organisms of the same species have several forms of enzymes that catalyze the same chemical reaction, but differ in structure. Their activity also varies. Their physicochemical properties are also excellent. 16% of structural gene loci are polymorphic. Glucose-6-phosphatase has 30 forms. Often there is adhesion to the floor. In the clinic, lactate dehydrogenases (LDH) have long been distinguished, of which there are 5 forms. This enzyme converts glucose into pyruvate, the concentration of one or another isoenzyme in different organs differs on what the laboratory diagnosis of diseases is based.

Invertebrates are more polymorphic than vertebrates. The more polymorphic the population, the more evolutionarily plastic it is. In a population, large stocks of alleles do not have maximum fitness in a given place at a given time. These stocks occur in small numbers and are heterozygous. After changes in the conditions of existence, they can become useful and begin to accumulate - transitional polymorphism. Large genetic stocks help populations respond to their environment. One of the mechanisms that maintain diversity is the superiority of heterozygotes. With complete dominance, there is no manifestation; with incomplete dominance, heterosis is observed. In a population, selection maintains a genetically unstable heterozygous structure, and such a population contains 3 types of individuals (AA, Aa, aa). As a result of natural selection, genetic death occurs, which reduces the reproductive potential of the population. The population is falling. Therefore, genetic death is a burden for the population. It is also called genetic cargo.

genetic cargo- part of the hereditary variability of the population, which determines the appearance of less adapted individuals that undergo selective death as a result of natural selection.

There are 3 types of genetic cargo.

Mutational.

Segregation.

Substitutional.

Each type of genetic cargo correlates with a certain type of natural selection.

mutational genetic cargo- a side effect of the mutation process. Stabilizing natural selection removes harmful mutations from a population.

Segregation genetic cargo- characteristic of populations that use the advantage of heterozygotes. Weaker adapted homozygous individuals are removed. If both homozygotes are lethal, half of the offspring die.

Substitutional genetic cargo- the old allele is replaced by a new one. Corresponds to the driving form of natural selection and transitional polymorphism.

Genetic polymorphism creates all the conditions for ongoing evolution. When a new factor appears in the environment, the population is able to adapt to new conditions. For example, insect resistance to various types of insecticides.

For the first time, the genetic load in the human population was determined in 1956 in the Northern Hemisphere and amounted to 4%. Those. 4% of children were born with a hereditary pathology. Over the following years, more than a million compounds were introduced into the biosphere (more than 6000 annually). Daily - 63,000 chemical compounds. The influence of sources of radioactive radiation is growing. The DNA structure is broken.

3% of children in the US suffer from congenital mental retardation (not even in high school).

At present, the number of congenital abnormalities has increased by 1.5 - 2 times (10%), and medical geneticists speak of a figure of 12-15%.

Conclusion: protect the environment.

Polymorphism in blood groups.

Blood group antigens are becoming increasingly important in medicine. In some cases, agglutination occurs during blood transfusion - the result of the interaction of the donor antigen and the recipient's antibodies.

There are 4 blood groups in the ABO system. Each person belongs to only one group.

3 alleles -A, B, O.

JªJª, JªJ° - A

JªJв, Jв J° - В

All human populations are polymorphic in blood types, but each population will have different frequencies of occurrence. In Sweden, the O group is frequent. Among the Indians, the B group is completely absent. Parallel polymorphism in blood groups according to the ABO system was also found in great apes. Conclusion: polymorphism arose before the emergence of the human species, which means that already the human ancestor had different blood types.

There is an association between blood types and diseases.

Oh group. Rheumatism is rare, but gastric and duodenal ulcers are more common in populations if they have been in isolation for a long time. For example - Aborigines, Indians, the indigenous population of Australia. They had a natural selection, its cause - infectious diseases - cholera, tuberculosis, syphilis.

Alcoholism is an important phenotypic trait. There are acute and chronic. More often seen in men. For a long time it was believed that alcoholism develops in environmental conditions, the contribution of heredity was not taken into account. However, it turned out that the genotype is important.

For example, in the case of taking a child from an orphanage to a family, the following results were obtained:

True and adoptive parents are alcoholics - 46% of children are alcoholics, and not alcoholics - 8%.

The true parent is an alcoholic, the adoptive parent is not - 50% are alcoholics.

True - not an alcoholic, an adopted alcoholic - 14%.

In humans, there are 2 isoenzymes that break down ethyl alcohol - alcohol dehydrogenases. There are ADN1 and ADN2. The faster the breakdown of alcohol, the worse a person tolerates alcohol, because. as a result of the reaction, an aldehyde is formed, which has toxic properties. ADH1 is less active than ADH2, so people with ADH2 cannot tolerate alcohol.

However, there is another enzyme that breaks down the aldehyde, and its activity also determines a person's tolerance for alcohol.

Genetic polymorphism is widespread and underlies the hereditary predisposition to diseases. However, diseases of hereditary predispositions are manifested only in the interaction of genes and the environment. Environmental conditions - lack or excess of nutrients, the presence of psychogenic factors, toxic substances, etc. The clinical course of diseases can be varied. The greater the impact of environmental factors, the more patients with a predisposition to this disease. Diseases are more severe (hypertension, rheumatism, diabetes mellitus and others),

There are monogenic and polygenic diseases.

Monogenic diseases of hereditary predisposition - hereditary diseases that manifest themselves due to a mutation of one gene or manifest themselves under the action of a certain environmental factor (autosomal recessive or linked to the X chromosome).

Manifested under the influence of factors:

physical;

Chemical;

food;

Environmental pollution.

Paramyotomy - in wet weather, tonic muscle spasms occur when cold, under the influence of heat - they disappear. The disease is associated with a thermosensitive protein. The reaction manifests itself in infancy and does not change throughout a person's life.

Pigmentary xeroderma is a special type of freckled skin. Appears at 4-6 years of age. Children do not tolerate UV light, malignant tumors occur, such children die from metastases before the age of 15. They also cannot tolerate gamma rays.

Bloom Syndrome. Pigmented "butterfly" on the face, short stature, elongated head. Jews, Poles, Belarusians, Austrians. They die before the age of 18. They do not tolerate UV radiation, gamma rays.

Alpha-1 antitrypsin in air pollution, tobacco smoke is manifested by acute blockage of the bronchi or cirrhosis of the liver.

Among Caucasians, people who cannot tolerate milk make up 10-20%, in Africa - 70-80%.

Influence of drugs: sulfa drugs provoke blood diseases.

There are polygenic diseases of hereditary origin - such diseases that occur under the action of many factors (multifactorial) and as a result of the interaction of many genes. It is very difficult to establish a diagnosis in this case, because. many factors act, and a new quality appears when the factors interact.

Wide polymorphism helps the population adapt to environmental conditions. In healthy people, there is no contradiction between the environment and the genotype, if this contradiction arises, diseases of hereditary predisposition appear. Any classification of diseases includes a group of similar diseases.

Mutations are the main source of genetic polymorphism, i.e. the presence of several alleles of the same locus in a population. The polymorphic nature of DNA has made it possible to develop systems of methods for genetic and psychogenetic analysis that allow one to identify and map a number of genes involved in the formation of individual differences in the studied behavioral traits. For example, the use of polymorphic DNA markers made it possible to map the gene on the short arm of chromosome 4 responsible for the development of Huntington's chorea.

As an example, consider two types of DNA markers: restriction fragment length polymorphism (L / X / "-polymorphism) and polymorphism of repeated nucleotide combinations (STR-no-lymorphism). To study polymorphism (this process is also called DNA typing), DNA is isolated from cells blood or any other body cells containing DNA (for example, a scraping is taken from the inside of the cheek).When using RFLP technology, DNA, under the influence of enzymes that recognize specific nucleotide sequences in DNA and selectively destroy its chain in certain places, is cut into pieces - Fragments Such enzymes were first found in bacteria, which produce them to protect against viral infection.

There are hundreds of these "restriction" enzymes, each of which cuts DNA at a specific location, recognizing a specific base sequence; this process is called restriction. For example, one of the commonly used enzymes, EcoRI, recognizes the GAA TTC sequence and cuts the DNA molecule between bases Cu A. The GAATTC sequence can be represented in the genome several thousand times. If at a certain locus this sequence is different in different people, then in those of them who are carriers of the altered sequence, the enzyme at this locus will not cut it. As a result, the DNA of genomes carrying non-standard sequences will not be cut at this locus and, therefore, will form a longer fragment. In this way, the difference in the structure of DNA is recognized. As a result of cutting with "restricting" enzymes, two types of fragments corresponding to a given locus can be obtained - long and short. They are also called alleles. By analogy with "ordinary" genes, polymorphisms can be homozygous for the short fragment, homozygous for the long fragment, or heterozygous for the long and short fragments.

Although there are hundreds of "restriction enzymes" that recognize different DNA sequences, they have been found to be able to find only about 20% of DNA polymorphisms. Several other types of DNA markers have been developed that recognize other types of polymorphisms. Widely used, for example, polymorphism of repeated combinations of nucleotides (/5TD-polymorphism). As already mentioned, for an as yet unknown reason, repeating sequences consisting of 2, 3 or more nucleotides are present in DNA. The number of such repeats varies from genotype to genotype, and in this sense they also exhibit polymorphism. For example, one genotype can be a carrier of two alleles containing 5 repeats, the other is a carrier of two alleles containing 7 repeats. It is estimated that the human genome contains approximately 50,000 loci containing similar repetitive sequences. Chromosomal coordinates of many loci displaying NGL polymorphism have been established and are now used to map structural genes, serving as coordinates on chromosome maps.

Thus, genetic polymorphism associated with the presence of so-called neutral (not changing the synthesized protein) mutations is fruitfully used in molecular genetic, including psychogenetic, studies, since genetic variability detected by molecular methods can be compared with phenotype variability. So far, this promising path has been used in the vast majority of cases to study various forms of pathology that give clearly defined phenotypes. However, there is every reason to hope that it will also be included in the study of the variability of normal mental functions. ...

One of the most remarkable biological discoveries of the 20th century was the determination of the structure of DNA. The deciphering of the genetic code, the discovery of the mechanisms of transcription, translation and some other processes at the DNA level are the foundation of the building of psychogenetics under construction - a science, one of the tasks of which is to reveal the secrets of the relationship between genes and the psyche. Modern ideas about the structure and functions of DNA have fundamentally changed our understanding of the structure and functioning of genes. Today, genes are defined not as abstract "factors of heredity" but as functional stretches of DNA that control protein synthesis and regulate the activity of other genes. One of the main sources of variability is gene mutations. Modern molecular genetics owes its success to the discovery and use of DNA mutation patterns with the goal of discovering and mapping genetic markers. It is they who will allow psychogenetics to move from population characteristics to individual ones.