What influences gene expression. General principles of medical genetics

Both terms were introduced in 1926. O. Vogt to describe variation in mutant phenotypes.

expressiveness- this degree of manifestation mutant trait in the phenotype. For example, a mutation eyeless in Drosophila causes eye reduction, the degree of which is not the same in different individuals.

Penetrance - this frequency, or probability of manifestation mutant phenotype among all individuals carrying the given mutation. For example, 100% penetrance of a recessive mutation means that in all homozygous individuals it appears in the phenotype. If phenotypically it is found only in half of the individuals, then the mutation penetrance is 50%.

Conditional mutations

These mutations only appear when certain conditions are met.

Temperature sensitive mutations. Mutants of this type live and develop normally under one ( permissive) temperature and detect deviations at another ( restrictive). For example, in Drosophila, cold-sensitive (at 18 ° C) ts - mutations (temperature sensitive) and heat-sensitive (at 29 ° C) ts -mutations. At 25°C, the normal phenotype is maintained.

Stress sensitivity mutations. In this case, the mutants develop and outwardly look normal if they are not subjected to any stressful influences. Yes, mutants. sesB (stress sensitive) Drosophila under normal conditions do not show any abnormalities.

However, if the test tube is shaken abruptly, the flies will convulse and become unable to move.

Auxotrophic mutations in bacteria. They survive only on a complete medium or on a minimal one, but with the addition of one or another substance (amino acid, nucleotide, etc.).

Mutation accounting methods

Peculiarities of Mutation Accounting Methods. Methods for detecting mutations should be different depending on the mode of reproduction of the organism. Visible morphological changes are easily taken into account; it is more difficult to determine the physiological and biochemical changes in multicellular organisms. Easiest to find visible dominant mutations that can be heterozygous in the first generation are more difficult to analyze recessive mutations, they are necessary homozygous.

For genetically well-studied objects (drosophila, corn, a number of microorganisms), it is quite easy to study a new mutation. For example, for Drosophila, special methods have been developed to account for the frequency of mutations.

Method СlВ. Möller created a line of fruit flies СlВ (c el b) which has one of X- chromosomes marked with a dominant gene Bar (B) And inversion, called FROM . This inversion prevents crossing over and has a recessive lethal effect – l. That is why the line is named СlВ .

The females of this analyzer line crossed with males from the study sample. If males are taken from natural population, then we can estimate the frequency of flights in it. Or take males treated with a mutagen. In this case, the frequency of lethal mutations caused by this mutagen is estimated.

IN F1 select females СlВ/+, heterozygous for the mutation bar, and cross individually (each female in a separate tube with a wild-type male). If in the tested chromosome no mutation, then the offspring will have two classes of females and one class of males ( B+), because the males СlВ die due to the presence of lethal l , i.e. the total gender split will be 2:1 (see picture).

If in the experimental chromosome have a lethal mutation l m , then in F 2 will be only females, since males of both classes will die - in one case due to the presence of flying in X-chromosome СlВ, in the other - due to the presence of flying l m in the experimental X-chromosome (see figure). Determining the ratio of a number X-chromosomes (test tubes with individual crosses) in which lethal arose, to the total number of studied X-chromosomes (test tubes), count the frequency of lethal mutations in a certain group.

Møller repeatedly modified his method for detecting lethals in X- Drosophila chromosome, resulting in such lines - analyzers, how Mu-5 , and later lines - balancers Basc, Binsn and etc.

Method Cy L/Pm . To account for lethal mutations in autosomes fruit flies use lines balanced lethals. For the manifestation of a recessive lethal mutation in an autosome, it is also necessary that it be in a homozygous state. To do this, it is necessary to put two crosses, and keep records of descendants in F3. To detect lethal second chromosome use a line Cy L/Pm (SIL PEM) (see figure).

The flies of this line second chromosome two dominant mutations Cy (Curly - curved wings ) And L (lobe - small lobular eyes ) , each of which in the homozygous state causes a lethal effect. Mutations are extended inversions on different arms of the chromosome. Both of them " lock up» crossing over. The homologous chromosome also has a dominant mutation - inversion Pm (Plum - Brown eyes). The analyzed male is crossed with a female from the line CyL/Pm (not all descendant classes are shown in the figure).

IN F1 select males CyL/Pm+ And individually cross them with females of the original line Cy L/Pm . IN F2 select males and females Cy L in which the homologous chromosome is the test. As a result of crossing them with each other, three classes of descendants are obtained. One of them dies due to homozygosity for mutations Cy And L , another class of descendants are heterozygotes CyL/Pm+, as well as the class of homozygotes for the tested chromosome. The end result is flies. Cy L And Cy+L+ in relation to 2:1 .

If the test chromosome has lethal mutation, in the offspring from the last crossing will be only flies Cy L . Using this method, it is possible to take into account the frequency of recessive lethal mutations on the second chromosome of Drosophila.

Accounting for mutations in other objects. Similar mutation detection methods have been developed for other objects. They are based on the same principles:

1) discover recessive mutation can be translated into homo- or hemizygous condition,

2) it is possible to accurately take into account the frequency of emerging mutations only under the condition lack of crossover in heterozygous individuals.

For mammals(mouse, rabbit, dog, pig, etc.) a method has been developed to account for the frequency of occurrence dominant lethal mutations. The frequency of mutations is judged by the difference between the number corpus luteum in the ovary and developing embryos in an opened pregnant female.

Accounting for the frequency of mutations in humans very difficult, however genealogical analysis , i.e. analysis of pedigrees, allows you to establish the occurrence of new mutations. If a trait has not been found in the pedigree of the spouses for several generations, and it appeared in one of the children and began to be transmitted to the next generations, then the mutation arose in the gamete of one of these spouses.

Accounting for mutations in microorganisms. It is very convenient to study mutations in microorganisms, since all their genes in the singular and mutations show up in the first generation.

Mutants are easy to spot imprint method, or replicas, which was proposed by the spouses E. And J. Lederbergs.

To identify resistance mutations in E. coli to bacteriophage T1, bacteria are plated on nutrient agar to form individual colonies. These colonies are then reprinted using a velvet replica onto plates coated with a suspension of T1 phage particles. Most of the cells of the original sensitive ( Tons ) cultures will not form colonies, since they are lysed by a bacteriophage. Only individual mutant colonies will grow ( TonR ) are resistant to phage. By counting the number of colonies in the control and experimental (for example, after irradiation with ultraviolet light) variants, it is easy to determine the frequency of induced mutations.

These concepts were first introduced in 1926 by N.V. Timofeev Ressovsky and O. Vogt to describe the varying manifestation of traits and the genes that control them. expressiveness there is a degree of expression (variation) of the same trait in different individuals who have a gene that controls this trait. There is low and high expressivity. Consider, for example, the different severity of rhinitis (runny nose) in three different patients (A, B, and C) with the same diagnosis of ORI. In patient A, rhinitis is mild (“sniffing”), which allows one handkerchief to be dispensed with during the day; in patient B, rhinitis is moderately expressed (daily 2-3 handkerchiefs); Patient C has a high degree of rhinitis (5-6 handkerchiefs). When talking about the expressiveness not of a single symptom, but of the disease as a whole, doctors often assess the patient's condition as satisfactory or of moderate severity, or as severe,

those. in this case, the concept of expressivity is similar to the concept of "severity of the course of the disease."

Penetrance- is the probability of manifestation of the same trait in different individuals who have a gene that controls this trait. Penetrance is measured as the percentage of individuals with a particular trait out of the total number of individuals who are carriers of the gene that controls that trait. 0 is incomplete or complete.

An example of a disease with incomplete penetrance is the same rhinitis with 0RVI. So, we can assume that patient A does not have rhinitis (but there are other signs of the disease), while patients B and C have rhinitis. Therefore, in this case, the penetrance of rhinitis is 66.6%.

An example of a disease with complete penetrance is autosomal dominant chorea of Huntington(4r16). 0na manifests itself mainly in persons aged 31-55 years (77% of cases), in other patients - at a different age: both in the first years of life, and at 65, 75 years and more. It is important to emphasize that if the gene for this disease is passed on to a descendant from one of the parents, then the disease will definitely manifest itself, which is complete penetrance. True, the patient does not always survive to the manifestation of Huntington's chorea, dying from another cause.

Genecopying and its causes
Genocopies (lat. genocopia) are similar phenotypes formed under the influence of different non-allelic genes.
A number of signs similar in external manifestation, including hereditary diseases, can be caused by various non-allelic genes. This phenomenon is called genocopy. The biological nature of genocopies lies in the fact that the synthesis of the same substances in the cell in some cases is achieved in different ways.

Phenocopies - modification changes - also play an important role in human hereditary pathology. They are due to the fact that in the process of development, under the influence of external factors, a trait that depends on a particular genotype may change; at the same time, traits characteristic of another genotype are copied.

That is, these are the same changes in the phenotype, caused by alleles of different genes, as well as occurring as a result of various gene interactions or violations of various stages of one biochemical process with the cessation of synthesis. It manifests itself as the effect of certain mutations that copy the action of genes or their interaction.

One and the same trait (group of traits) may be due to different genetic causes (or heterogeneity). Such an effect, at the suggestion of the German geneticist H. Nachtheim, was obtained in the mid-40s of the XX century. title gencopying. Three groups of causes of genocopy are known.

Causes of the first group combines heterogeneity due to polylocus, or the action of different genes located at different loci on different chromosomes. For example, 19 types (subtypes) of mucopolysaccharidoses have been identified among hereditary diseases of the metabolism of complex sugars - glucoseaminoglycans. All types of character

teriziruyutsya defects of different enzymes, but are manifested by the same (or similar) symptoms gargoylic dysmorphism or the phenotype of the ringer Quasimodo - the main character of the novel "Notre Dame Cathedral" by the classic of French literature Victor Hugo. A similar phenotype is often observed in mucolipidoses (lipid metabolism disorders).

Another example of polylocus is phenylketonuria. Now, not only its classical type, due to a deficiency of phenylalanine-4-hydroxylase (12q24.2), but also three atypical forms have been identified: one is caused by a deficiency of dihydropteridine reductase (4p15.1), and two more are caused by a deficiency of pyruvoiltetrahydropterin synthetase and tetrahydrobiopterin enzymes (corresponding to genes have not yet been identified).

Additional examples of polylocus: glycogenoses (10 genocopies), Ellers-Danlos syndrome (8), Recklinghausen neurofibramatosis (6), congenital hypothyroidism (5), hemolytic anemia (5), Alzheimer's disease (5), Bardet-Biedl syndrome (3), breast cancer (2).

Causes of the second group unites intralocus heterogeneity. It is due either to multiple allelism (see Chapter 2) or to the presence genetic compounds, or double heterozygotes having two identical pathological alleles in identical loci of homologous chromosomes. An example of the latter is heterozygous beta-thalassemia (11p15.5), resulting from deletions of two genes encoding beta-chains of globins, which lead to an increased content of hemoglobin HbA 2 and an increased (or normal) level of hemoglobin HbF.

Causes of the third group combines heterogeneity due to mutations at different points in the same gene. An example is cystic fibrosis (7q31-q32), which develops due to the presence of almost 1000 point mutations in the gene responsible for the disease. With a total length of the cystic fibrosis gene (250 thousand bp), it is expected to detect up to 5000 such mutations in it. This gene encodes a protein responsible for the transmembrane transport of chloride ions, which leads to an increase in the viscosity of the secretion of exocrine glands (sweat, salivary, sublingual, etc.) and blockage of their ducts.

Another example is classical phenylketonuria, caused by the presence of 50 point mutations in the gene encoding phenylalanine-4-hydroxylase (12q24.2); in total, more than 500 point mutations of the gene are expected to be detected in this disease. Most of them arise from restriction fragment length polymorphism (RFLP) or tandem repeat number polymorphism (VNTP). Found: the main mutation of the phenylketonuria gene in Slavic populations is R408 W/

Pleiotropy effect

The aforementioned ambiguity in the nature of the relationships between genes and traits is also expressed in pleiotropy effect or pleiotropic action, when one gene causes the formation of a number of traits.

For example, the gene for autosomal recessive ataxia-telangiectasia, or Louis Bar syndrome(11q23.2) is responsible for the simultaneous damage to at least six body systems (nervous and immune systems, skin, mucous membranes of the respiratory and gastrointestinal tract, as well as the conjunctiva of the eyes).

Other examples: gene Bardet-Biedl syndrome(16q21) causes dementia, polydactyly, obesity, retinitis pigmentosa; the anemia gene Fanconi (20q13.2-13.3), which controls the activity of topoisomerase I, causes anemia, thrombocytopenia, leukopenia, microcephaly, aplasia of the radius, hypoplasia of the metacarpal bone of the first finger, malformations of the heart and kidneys, hypospadias, pigment spots of the skin, increased fragility of chromosomes .

Distinguish between primary and secondary pleiotropy. Primary pleiotropy due to biochemical mechanisms of action of the mutant enzyme protein (for example, lack of phenylalanine-4-hydroxylase in phenylketonuria).

Secondary pleiotropy due to complications of the pathological process that developed as a result of primary pleiotropy. For example, due to increased hematopoiesis and hemosiderosis of parenchymal organs, a patient with thalassemia develops thickening of the skull bones and hepatolienal syndrome.

Genes? What is her role? How does the mechanism of gene expression work? What prospects does it open for us? How is gene expression regulated in eukaryotes and prokaryotes? Here is a short list of issues that will be discussed in this article.

general information

Gene expression is the name given to the process of transfer from DNA via RNA to proteins and polypeptides. Let's make a small digression for understanding. What are genes? These are linear DNA polymers that are connected in a long chain. They help form chromosomes. If we talk about a person, then we have forty-six of them. They contain approximately 50,000-10,000 genes and 3.1 billion base pairs. How are they guided here? The length of the sections with which work is being carried out is indicated in thousands and millions of nucleotides. One chromosome contains about 2000-5000 genes. In a slightly different expression - about 130 million base pairs. But this is only a very rough estimate, which is more or less true for significant sequences. If you work on short sections, then the ratio will be violated. It can also be affected by the sex of the organism, the material of which is being worked on.

About genes

They have the most varied length. For example, globin is 1500 nucleotides. And dystrophin is already as much as 2 million! Their regulatory cis-elements can be removed from the gene at a considerable distance. So, in globin, they are located at a distance of 50 and 30 thousand nucleotides in the 5 "- and 3" direction, respectively. The presence of such an organization makes it much more difficult for us to define the boundaries between them. Also, genes contain a significant number of highly repetitive sequences, the functional responsibilities of which are not yet clear to us.

To understand their structure, one can imagine that 46 chromosomes are separate volumes in which information is located. They are grouped into 23 pairs. One of the two elements is inherited from the parent. The "text" that is in the "volumes" was repeatedly "re-read" by thousands of generations, which introduced many errors and changes (called mutations) into it. And all of them are inherited by offspring. Now there is enough theoretical information to start understanding what gene expression is. This is, after all, the main topic of this article.

Operon theory

It is based on genetic studies of the induction of β-galactosidase, which is involved in the hydrolytic breakdown of lactose. It was formulated by Jacques Monod and Francois Jacob. This theory explains the mechanism of control over protein synthesis in prokaryotes. Transcription also plays an important role. The theory is that genes for proteins that are functionally closely related in metabolic processes often cluster together. They create structural units called operons. Their importance is that all the genes that are included in it are expressed in concert. In other words, they can all be transcribed, or none of them can be "read". In such cases, the operon is considered active or passive. The level of gene expression can change only if there is a set of individual elements.

Induction of protein synthesis

Let's imagine that we have a cell that uses carbon glucose as a source of its growth. If it is changed to the disaccharide lactose, then in a few minutes it will be possible to fix that it has adapted to the conditions that have been changed. There is such an explanation for this: a cell can work with both sources of growth, but one of them is more suitable. Therefore, there is a “target” for a more easily processed chemical compound. But if it disappears and lactose appears to replace it, then the responsible RNA polymerase is activated and begins to exert its influence on the production of the necessary protein. This is more of a theory, but now let's talk about how gene expression actually occurs. This is very exciting.

Organization of chromatin

The material from this paragraph is a model of a differentiated cell of a multicellular organism. In nuclei, chromatin is arranged in such a way that only a small part of the genome (about 1%) is available for transcription. But, despite this, due to the diversity of cells and the complexity of the processes going on in them, we can influence them. At the moment, the following influence on the organization of chromatin is available to a person:

Change the number of structural genes.
Efficiently transcribe different parts of the code.
rearrange genes on chromosomes.
Make modifications and synthesize polypeptide chains.

But effective expression of the target gene is achieved as a result of strict adherence to technology. It doesn’t matter what the work is being done with, even if the experiment is on a small virus. The main thing is to stick to the planned intervention plan.

Change the number of genes

How can this be implemented? Imagine that we are interested in the effect on gene expression. We took eukaryotic material as a prototype. It has high plasticity, so we can make the following changes:

Increase the number of genes. It is used in cases where it is necessary for the body to increase the synthesis of a certain product. Many useful elements of the human genome (for example, rRNA, tRNA, histones, and so on) are in this amplified state. Such regions can have a tandem arrangement within the chromosome and even go beyond them in an amount from 100 thousand to 1 million base pairs. Let's look at the practical application. Of interest to us is the metallothionein gene. Its protein product can bind heavy metals like zinc, cadmium, mercury and copper and, accordingly, protect the body from poisoning by them. Its activation can be useful for people who work in unsafe conditions. If a person has an increased concentration of the previously mentioned heavy metals, then the activation of the gene occurs gradually automatically.
Reduce the number of genes. This is a rather rare method of regulation. But here, too, examples can be given. One of the most famous is red blood cells. When they mature, the nucleus is destroyed and the carrier loses its genome. Lymphocytes, as well as plasma cells of various clones, undergo a similar process in the process of maturation, which synthesize secreted forms of immunoglobulins.

Gene rearrangement

Important is the ability to move and combine the material, in which it will be able to transcription and replication. This process is called genetic recombination. By what mechanisms is it possible? Let's look at the answer to this question using the example of antibodies. They are created by B-lymphocytes that belong to a particular clone. And if an antigen enters the body, for which there is an antibody with a complementary active center, they will attach with subsequent cell proliferation. Why does the human body have the ability to create such a variety of proteins? This possibility is provided by recombination and But this may also be a consequence of artificial changes in the structure of DNA.

RNA change

Gene expression is a process in which mRNA plays a significant role. If we consider mRNA, it should be noted that after transcription, the primary structure can change. The sequence of nucleotides in genes is the same. But in different tissues, mRNA may appear substitutions, insertions, or simply fall out of pairs. A natural example is apoprotein B, which is produced in the cells of the small intestine and liver. What is the difference in editing? The gut-made version has 2152 amino acids. Whereas the liver variant boasts 4563 residues! And despite this difference, we have apoprotein B.

Change in mRNA stability

We have almost come to the point where we can deal with proteins and polypeptides. But before that, let's look at how mRNA stability can be fixed. To do this, it must first leave the nucleus and exit the cytoplasm. This is done thanks to the existing pores. A large amount of mRNA will be cleaved by nucleases. Those that escape this fate organize complexes with proteins. The lifetime of eukaryotic mRNA varies over a wide range (up to several days). If the mRNA is stabilized, then at a fixed rate it will be possible to observe that the amount of the newly formed protein product increases. The level of gene expression will not change, but, more importantly, the body will operate with greater efficiency. With help, you can encode the final product, which will have a significant lifespan. So, for example, it is possible to create a β-globin that functions for about ten hours (this is a lot for him).

Process speed

So, in general, the system of gene expression is considered. Now it remains only to supplement the existing knowledge with information about how fast the processes occur, as well as how long proteins live. Let's just say we control gene expression. It should be noted that the influence on the rate is not considered the main way to regulate the diversity and quantity of the protein product. Although its change to achieve this goal was still used. An example is the synthesis of a protein product in reticulocytes. Hematopoietic cells at the level of differentiation lack a nucleus (and hence DNA). The levels of regulation of gene expression are generally built depending on the ability of some compound to actively influence the ongoing processes.

Duration of existence

When a protein is synthesized, the time during which it will live depends on the proteases. It is impossible to give exact terms here, since the range in this case is from several hours to a couple of years. The rate at which a protein is broken down varies widely depending on which cell it is in. Enzymes that can catalyze processes tend to be "used up" quickly. Because of this, they are also created by the body in large quantities. Also, the physiological state of the body can affect the life of the protein. Also, if a defective product was created, it will be quickly eliminated by the protective system. Thus, we can confidently say that the only thing we can judge is the standard lifetime obtained in the laboratory.

Conclusion

This direction is very promising. For example, the expression of foreign genes can help cure hereditary diseases, as well as eliminate negative mutations. Despite the presence of extensive knowledge on this topic, we can confidently say that humanity is still at the very beginning of its journey. Genetic engineering has recently learned how to isolate the necessary sections of nucleotides. 20 years ago, one of the biggest events in this science took place - Dolly the sheep was created. Research is currently underway with human embryos. It is safe to say that we are already on the threshold of a future where there is no disease and physiological suffering. But before we get there, it will be necessary to work very hard for prosperity.

A gene that is present in the genotype in the amount necessary for manifestation (1 allele for dominant traits and 2 alleles for recessive traits) can manifest itself as a trait to varying degrees in different organisms (expressivity) or not manifest itself at all (penetrance).

Modification variability (exposure to environmental conditions)

Combinative variability (influence of other genes of the genotype).

expressiveness- the degree of phenotypic manifestation of the allele. For example, alleles of blood groups AB0 in humans have constant expressivity (always appear at 100%), and alleles that determine eye color have variable expressivity. A recessive mutation that reduces the number of eye facets in Drosophila reduces the number of facets differently in different individuals, up to their complete absence.

Expressivity reflects the nature and severity of symptoms, as well as the age of onset of the disease.

If a person suffering from a dominant disease wants to know how severe the disease will be in his child who has inherited a mutation, then he raises the question of expressivity. With the help of gene diagnostics, it is possible to identify a mutation that does not even manifest itself, but it is impossible to predict the range of expression of a mutation in a given family.

Variable expressivity, up to the complete absence of gene expression, may be due to:

The influence of genes located in the same or in other loci;

The impact of external and random factors.

Penetrance is the probability of a phenotypic manifestation of a trait in the presence of the corresponding gene. For example, the penetrance of congenital hip dislocation in humans is 25%, i.e. only 1/4 of recessive homozygotes suffer from the disease. Medico-genetic significance of penetrance: a healthy person, in which one of the parents suffers from a disease with incomplete penetrance, can have an unexpressed mutant gene and pass it on to children.

It is determined by the percentage of individuals in the population from among those carrying the gene in which it manifested itself. With complete penetrance, the dominant or homozygous-recessive allele appears in each individual, and with incomplete penetrance, in some individuals.

Penetrance may be important in genetic counseling for autosomal dominant disorders. A healthy person, one of whose parents suffers from a similar disease, from the point of view of classical inheritance, cannot be a carrier of a mutant gene. However, if we take into account the possibility of incomplete penetrance, then the picture is completely different: an outwardly healthy person can have an unmanifested mutant gene and pass it on to children.

Gene diagnostic methods can determine whether a person has a mutant gene and distinguish a normal gene from a non-manifesting mutant gene.

In practice, the determination of penetrance often depends on the quality of the research methods, for example, with the help of MRI, symptoms of the disease can be detected that were not previously detected.

From the point of view of medicine, the gene is considered manifested even with an asymptomatic disease, if functional deviations from the norm are detected. From the point of view of biology, a gene is considered manifested if it disrupts the functions of the organism.

Polygenic inheritance

Polygenic inheritance- inheritance, in which several genes determine the manifestation of one trait.

complementarity- such an interaction of genes in which 2 or more genes cause the development of a trait. For example, in humans, the genes responsible for the synthesis of interferon are located on chromosomes 2 and 5. In order for the human body to be able to produce interferon, it is necessary that at least one dominant allele be present simultaneously on chromosomes 2 and 5. Let us denote the genes associated with the synthesis of interferon and located on the 2nd chromosome - A (a), and on the 5th chromosome - B (c). Options AABB, AaBB, AAVv, AaBv will correspond to the ability of the body to produce interferon, and options aavb, AAvv, aaBB, Aavv, aaBv - inability.

The type of inheritance of traits due to the action of many genes, each of which has only a weak effect. Phenotypically, the manifestation of a polygenically determined trait depends on environmental conditions. In descendants, there is a continuous series of variations in the quantitative manifestation of such a trait, and not the appearance of classes that clearly differ in phenotype. In a number of cases, when a single gene is blocked, the trait does not appear at all, despite its polygenic conditionality. This indicates a threshold manifestation of the trait.

Since the development of polygenic traits is greatly influenced by environmental factors, it is difficult to identify the role of genes in these cases.

Polymerism Several genes act on the same trait in the same way. At the same time, when forming a trait, it does not matter which pair of dominant alleles belong, it is their number that matters.

For example, the color of a person's skin is affected by a special substance - melanin, the content of which provides a color palette from white to black (except for red). The presence of melanin depends on 4-5 pairs of genes. To simplify the problem, we will conditionally assume that there are two such genes. Then the Negro genotype can be written - AAAA, the white genotype - aaaa. Light-skinned blacks will have the AAAa genotype, mulattoes - AAaa, light mulattos - Aaaa.

Pleiotropy- the influence of one gene on the appearance of several traits. An example is an autosomal dominant disease from the group of hereditary connective tissue pathologies. In classic cases, individuals with Marfan syndrome are tall (dolichostenomelia), have elongated limbs, extended fingers (arachnodactyly), and underdevelopment of fatty tissue. In addition to the characteristic changes in the organs of the musculoskeletal system (elongated tubular bones of the skeleton, hypermobility of the joints), pathology is observed in the organs of vision and the cardiovascular system, which in the classical variants constitutes the Marfan triad.

Without treatment, people with Marfan syndrome often have a life expectancy of 30–40 years and death occurs due to a dissecting aortic aneurysm or congestive heart failure. In countries with developed health care, patients are successfully treated and live to an advanced age. Among famous historical figures, this syndrome manifested itself in A. Lincoln, N. Paganini, K.I. Chukovsky (Fig. 3.4, 3.5).

epistasis- suppression by one gene of another, non-allelic. An example of epistasis is the "Bombay phenomenon". In India, families are described in which parents had the second (AO) and first (00) blood groups, and their children had the fourth (AB) and first (00). In order for a child in such a family to have an AB blood type, the mother must have a B blood type, but not O. It was found that in the ABO blood group system there are recessive modifier genes that suppress the expression of antigens on the surface of red blood cells, and phenotypically a person manifests blood type O.

Another example of epistasis is the appearance of white albinos in a black family. In this case, the recessive gene suppresses the production of melanin, and if a person is homozygous for this gene, then no matter how many dominant genes responsible for the synthesis of melanin he has, his skin color will be albiotic (Fig. 3.6).

Morris syndrome- androgen insensitivity syndrome (testicular feminization syndrome) is manifested by disorders of sexual development that develop as a result of a weak response to male sex hormones in individuals with a male set of chromosomes (XY). The term "testicular feminization syndrome" was first introduced by the American gynecologist John Morris in 1953.

This syndrome is the most well-known cause of the development of a man as a girl or the presence of manifestations of feminization in boys who were born with a male set of chromosomes and normal levels of sex hormones. There are two forms of androgen insensitivity: total or partial insensitivity. Children with complete insensitivity have an unambiguously feminine appearance and development, while those with partial form may have a combination of female and male external sex characteristics, depending on the degree of androgen insensitivity. The incidence rate is approximately 1-5 per 100,000 newborns. The syndrome of partial androgen insensitivity is more common. Complete insensitivity to male sex hormones is a very rare disease.

The disease is caused by a mutation in the LA gene on the X chromosome. This gene determines the function of androgen receptors, a protein that responds to signals from male sex hormones and triggers a cellular response. In the absence of androgen receptor activity, the development of male genital organs will not occur. Androgen receptors are necessary for the development of pubic and axillary hair, regulate beard growth and sweat gland activity. With complete androgen insensitivity, there is no androgen receptor activity. If some cells have a normal number of active receptors, then this is partial androgen insensitivity syndrome.

The syndrome is inherited with the X chromosome as a recessive trait. This means that the mutation that causes the syndrome is located on the X chromosome. According to some information, in particular, the study of the reasons for the genius of V.P. Efroimson, Joan of Arc had Morris syndrome.

Pleiotropic action of genes

Pleiotropic action of genes- this is the dependence of several traits on one gene, that is, the multiple action of one gene.

In Drosophila, the gene for white eyes simultaneously affects the color of the body, length, wings, structure of the reproductive apparatus, reduces fertility, and reduces life expectancy. A person has a known hereditary disease - arachnodactyly ("spider fingers" - very thin and long fingers), or Marfan's disease. The gene responsible for this disease causes a violation of the development of connective tissue and simultaneously affects the development of several signs: a violation of the structure of the lens of the eye, anomalies in the cardiovascular system.

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Penetrance is the frequency of gene expression. It is determined by the percentage of individuals in the population from among those carrying the gene in which it manifested itself. With complete penetrance, the dominant or homozygous-recessive allele appears in each individual, and with incomplete penetrance, in some individuals.

Expressivity is the degree of phenotypic manifestation of a gene as a measure of the strength of its action, determined by the degree of development of the trait. Expressivity can be influenced by genes - modifiers and environmental factors. In mutants with incomplete penetrance, expressivity often also changes. Penetrance is a qualitative phenomenon, expressiveness is a quantitative one.

In medicine, penetrance is the proportion of people with a given genotype who have at least one symptom of a disease (in other words, penetrance determines the likelihood of a disease, but not its severity). Some believe that penetrance changes with age, such as in Huntington's disease, but differences in age of onset are usually attributed to variable expressivity. Sometimes penetrance depends on environmental factors, for example, in G-6-PD deficiency.

Genetic diagnostic methods can determine whether a person has a mutant gene and distinguish a normal gene from a non-manifesting mutant gene.

Although penetrance and expressiveness of autosomal dominant diseases are commonly referred to, the same principles apply to chromosomal, autosomal recessive, X-linked, and polygenic diseases.

The development of the embryo proceeds with the continuous interaction of hereditary and external factors. In the process of such relationships, a phenotype is formed, which actually reflects the result of the implementation of the hereditary program in specific environmental conditions. Despite the fact that the intrauterine development of the embryo in mammals takes place in a relatively constant environment under optimal conditions, the influence of external unfavorable factors during this period is not at all excluded, especially with their increasing accumulation in the environment due to technical progress. Currently, a person in all periods of his life is exposed to chemical, physical, biological and psychological factors.

An experimental study of the development of animals led to the idea of the so-called critical periods in the development of organisms. This term is understood as the periods when the embryo is most sensitive to the damaging effect of various factors that can disrupt normal development, i.e. these are the periods of the least resistance of the embryo to environmental factors.