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HEREDITY,the inherent property of all living things to be like their parents. However, individuals of each species, being generally similar, are still different and have their own, individual characteristics ( signs). But even these traits are inherited - they are passed from parents to children. The genetic basis of heredity is the subject of this article.

Carriers of DNA heredity.

Multicellular organisms, like buildings, are composed of millions of bricks - cells. Proteins are the main building blocks of cells. Each type of protein has its own function: some are part of the cell membrane, others create a protective “sheath” for DNA, others convey “instructions” on how to produce proteins, some regulate the functioning of cells and organs, and so on. Each protein molecule is a chain of many tens, even hundreds of links - amino acids; such a chain is called polypeptide... Complex proteins can be composed of multiple polypeptide chains.

In the process of vital activity, proteins are consumed, and therefore they are regularly reproduced in the cell. Their polypeptide chains are built sequentially - link by link, and this sequence coded in DNA. DNA is a long double-stranded molecule; consists of separate links - nucleotides... There are four types of nucleotides, designated as A (adenine), G (guanine), T (thymine), C (cytosine). Three nucleotides ( triplet) encodes one amino acid according to the so-called. genetic code... DNA is stored in the nucleus of the cell in several "packages" - chromosomes.

Genes.

The section of DNA in which a specific polypeptide chain is encoded is called genome... Let's say, its fragment "TCT TGG" encodes an amino acid link: "serine-tryptophan". The main function of genes is to maintain the vital activity of the body by producing proteins in the cell, coordinating cell division and interaction with each other.

Genes in different individuals, even of the same species, can differ - within limits that do not violate their function. Each gene can be represented by one or more forms, called alleles... All cells of the body, except for germ cells, contain two alleles of each gene; such cells are called diploid... If two alleles are identical, then the organism is called homozygous for this gene; if the alleles are different, then - heterozygous.

Alleles evolved and arise as mutations - failures in the transfer of DNA from parents to children. For example, if in the above nucleotide sequence "TCT THG" the third nucleotide, T, would be mistakenly transmitted to the child as C, then instead of the parent "serine-tryptophan" he would have a fragment of the protein "alanine-tryptophan", since the TCC triplet encodes the amino acid alanine ... Alleles that have passed approbation by selection ( cm... POPULATION GENETICS), and form the hereditary diversity that we now observe - from the color of the skin, eyes and hair to physiological and emotional reactions.

Chromosomes.

DNA is protected from external influences by the "packaging" of proteins and is organized in chromosomeslocated in the cell nucleus. The chromosome regulates the activity of genes, their restoration during radiation, chemical or other types of damage, as well as their replication (copying) during cell division - mitosis and meiosis ( cm... CELL). Each species of plants and animals has a certain number of chromosomes. In diploid organisms, it is paired, two chromosomes of each pair are called homologous... Among them there are genital (see below) and nonsex chromosomes, or autosomes... A person has 46 chromosomes: 22 pairs of autosomes and one pair of sex chromosomes; in this case, one of the chromosomes of each pair comes from the mother, and the other from the father. The number of chromosomes in different species is not the same. For example, the classical genetic object - the fruit fly Drosophila - has four pairs. In some species, chromosome sets are composed of hundreds of pairs of chromosomes; however, the number of chromosomes in a set has no direct relationship either with the complexity of the structure of the organism, or with its evolutionary position.

In addition to the nucleus, DNA is found in mitochondria, and in plants, also in chloroplasts. Therefore, those genes that are in nuclear DNA are called nuclear, and extra-nuclear, respectively, mitochondrial and chloroplast... Extra-nuclear genes control part of the energy system of cells: mitochondrial genes are mainly responsible for the synthesis of enzymes for oxidation reactions, and chloroplast genes - for photosynthesis. All the other numerous functions and characteristics of the body are determined by genes located in the chromosomes.

Transfer of genes to offspring.

Species support their existence by replacing one generation with another. At the same time, various forms of reproduction are possible: simple division, as in unicellular organisms, vegetative reproduction, as in many plants, sexual reproduction, characteristic of higher animals and plants ( cm... REPRODUCTION). Sexual reproduction is carried out using germ cells - gametes(sperm and eggs). Each gamete carries a single, or haploid, a set of chromosomes containing only one homologue; in humans, these are 23 chromosomes. Accordingly, each gamete contains only one allele of each gene. Half of the gametes produced by an individual carry one allele, and half the other. When the egg and sperm merge - fertilization - one diploid cell is formed, called zygote... A new organism is formed from the cells resulting from mitotic divisions of the zygote in the process of individual development (ontogenesis). Depending on which alleles a given individual carries, it develops certain characteristics. Note that the equiprobable distribution of alleles across gametes was discovered by Gregor Mendel in 1865 and is known as Mendel's First Rule.

INHERITANCE OF AUTOSOMIC CHARACTERISTICS

Consider a sign such as a blood type. There are a number of types, or systems, of blood groups. The most famous system is AB0, according to which four main groups are distinguished: I, II, III and IV; these groups are also designated as 0, A, B and AB, since the difference between them is determined by which protein (antigen) is present in human erythrocytes: A or B. Genetically, the AB0 blood group system is controlled by three alleles: one allele, designated A, controls the synthesis of antigen A, another allele, B, Is the synthesis of antigen B, and the third allele 0 , Is inactive and does not induce antigen formation. According to the synthesized antigens, four blood groups are distinguished, but they correspond to six genetic variants (genotypes):

Allele 0 manifests itself phenotypically, i.e. as a sign of an organism, only when it is in a homozygous state ( 00 ); this corresponds to the first blood group, characterized by the absence of group antigens. In a heterozygous state (genotypes A0and B0) it has no effect on the formed phenotype, which is entirely determined by the alternative allele ( Aor B). Therefore, phenotypically genotypes A0and AA are identical: they are characterized by the presence of antigen A and determine the second blood group. Similarly, genotypes are identical B0 and BBdefining the third group, i.e. antigen B.

In the case when only one allele is phenotypically manifested in a heterozygous individual, they say that this allele dominant; while the other allele is called recessive... For the AB0 blood group system, alleles Aand B dominate the allele 0 ; the latter is recessive towards them. If both alleles appear in the phenotype of a heterozygous individual, then they are said to be codominant... So, alleles Aand B codominant in relation to each other: in a heterozygous state ( AB) they determine the presence of both antigens, A and B, i.e. fourth blood group.

Mechanisms of recessiveness and dominance.

"Defective" alleles that are unable to produce the corresponding product (protein) are often recessive. Therefore, many hereditary diseases caused by a lack or absence of any protein or enzyme are transmitted as a recessive trait: only persons homozygous for the defective allele suffer from them. Dominant diseases are most often caused by alleles encoding altered polypeptide chains. The latter, being part of the protein, violate its spatial structure and functional activity. Persons heterozygous for the defective allele are susceptible to dominant diseases. In a homozygous state, dominant alleles are usually lethal.

Splitting a trait in the offspring of heterozygotes.

In individuals homozygous for a given gene, all gametes carry the same allele. Among the gametes produced by a heterozygous individual, half carry one allele and half the other. The plus sign in the following table shows which gametes are produced by different individuals at the AB0 blood group locus.

Blood type	I	II	III	IV
Individual genotype	00	A0	AA	B0	BB	AB
Produces washed gametes	0 A B	+	+ +	+	+		+ +

This table shows that people with the second and third blood groups produce different gametes, depending on whether they are homozygous or heterozygous. The table also shows what genotype is expected in children from parents with certain blood groups. If both parents are homozygous, then all of their children will be in the same group. For example, parents with the first blood group form gametes that carry only the allele 0 so their children can only have the first group. If the mother has a second, and the father has a third blood group and at the same time they are homozygous, i.e. their genotype, respectively, AA and BB, then children can only have the fourth blood group (AB).

If one or both parents are heterozygous, then the so-called. split trait in offspring, arising from Mendel's First Rule formulated above and manifested in the fact that children may have traits that are absent from their parents. So, if in the above example the mother was heterozygous, then she would produce two types of eggs - with the allele Aand with allele 0 ... At the same time, she may equally likely have a child with a third or fourth blood group (genotype B0 or AB, respectively). Thus, with the mother's genotype A0 and father BBchildren cannot have the mother's blood group; their blood type will either be the same as that of their father, or such which is not characteristic of either father or mother.

If both parents are heterozygous, then the diversity of genotypes among children is even higher. For example, if the father and mother have a second blood group and their genotype A0, then the genotype and blood group of their child depends on which egg has matured and which sperm it will be fertilized with. Since in this example each parent produces gametes A and 0 , then the genotype of their child may be AA, A0 or 00 , and according to the theory of probability, the chances of getting them are distributed as 1: 2: 1. Since the first two genotypes determine the same blood group, the "blood group" trait has a 1: 3 chance of having a child with the first or second blood group (these ratios in the offspring of heterozygous parents were discovered by Mendel). And finally, if the mother had the second, and the father had the third blood group, and both of them were heterozygous, then with equal probability they could have a child with any blood group.

Inheritance of linked traits.

To date, detailed gene maps have been compiled for many species of plants, animals and humans, from which you can see which genes are on which chromosome. Knowledge of the gene map allows predicting the behavior of several traits in the offspring. If different characters are determined by genes located in non-homologous chromosomes, then they are inherited independently of each other, since in the process of meiotic division, non-homologous chromosomes (and therefore alleles of different genes) diverge along gametes by chance ( cm... GENETICS). The latter is known as Mendel's Second Rule. For example, a trait such as albinism is associated with the absence of melanin, the synthesis of which is controlled by a gene located on chromosome 11. Consequently, the probability that an albino spouse will have an albino child is not associated with the probability of having a certain blood group of the AB0 system, since the latter is determined by a gene located on a different, non-homologous, chromosome 9. Therefore, if one or both parents have defective alleles located on different chromosomes and causing two different diseases, then the probability that the child will receive both defective alleles will be equal to the product of the probabilities of receiving each of these alleles separately.

The situation is different if both genes are on the same chromosome, i.e. linked... For example, on the 2nd human chromosome there is a gene for the blood group system MN with two codominant alleles M and N... Another gene is located close to it, with a dominant allele S and recessive sdetermining the blood group system Ss. Depending on the location of these alleles on homologous chromosomes, there will be a different distribution of genotypes in gametes and in offspring from heterozygous parents. Indeed, if the mother's genotype MNSs, then its chromosomal structure for these two genes can be of one of two types:

In the first case, eggs are produced and, and in the second, and. Let the father be homozygous for both genes and have the genotype MMss... Then, in the first case, their children may have the genotype MMSs and MNss, while in the second case, the possible genotypes of children are different: MMss and MNSs.

Recombination of linked genes.

In meiosis, an event occurs called crossing over, during which homologous chromosomes can exchange their regions. For example, in the example considered above, the exchange site may be between the genes of the MN and Ss systems:

As a result of the exchange, the so-called. recombination genes and obtained crossovergametes and.

Recombination may or may not occur in a given meiosis. The closer the genes are located on the chromosome, the closer their linking and the less often it occurs. In particular, the genes of the MN and Ss systems are so closely linked that their recombination occurs extremely rarely, and in approximate calculations it can be neglected. In general, the probability, or frequency, the recombination is quite significant. Its value ( R) is between 0 (complete linkage) and 0.5 (unlinked genes) and is a measure of the genetic distance between genes on a chromosome; however, it is not identical to the physical distance between genes, since crossing over occurs with different intensities in different parts of the same chromosome. The frequency of each of the crossover gametes is R/2. Since crossing over may not occur (with a probability of 1– R), then this individual produces, in addition to crossover, also non-crossover gametes: and. The frequency of each of them among all the gametes of a given individual is (1– R)/2.

Let's go back to the example above, where the mother has the genotype MNSs with a chromosomal structure.

and the father is the genotype MMss.Taking into account the recombination, the possible genotypes of their children will be not only MMSs and MNss, but also MMss and MNSs... However, their probabilities are not the same, as it would be in the absence of adhesion, but equal 1– R for the first two genotypes and R for the other two.

INHERITANCE OF GENDER AND GENDERED SIGNS

Gender inheritance.

The sex of an individual is a complex trait formed both by the action of genes and by the conditions of development. A person has one of 23 pairs of chromosomes - genital chromosomes denoted as X and Y... Women - homogametic gender, i.e. have two X-chromosomes, one received from the mother, and the other from the father. Men - heterogametic gender, have one X- one Y-chromosome, and X transmitted from the mother, and Y - from the father. Note that the heterogametic sex is not necessarily male; for example, in birds these are females, while males are homogametic. There are other mechanisms of sex determination. So, in a number of insects Y-chromosome is absent. In this case, one of the sexes develops in the presence of two X-chromosome, and the other - in the presence of one X-chromosomes. In some insects, sex is determined by the ratio of the number of autosomes to sex chromosomes. In a number of animals, the so-called. gender redefinition, when, depending on environmental factors, the zygote develops either into a female or into a male. The development of sex in plants has the same diverse genetic mechanisms as in animals.

Deviation from the balance of sex chromosomes leads to pathology, just as deviation from the normal number of autosomes also leads to serious diseases ( cm... CONGENITAL FAULTS). However, it should be borne in mind that the formation of sex and normal sexual characteristics is a complex physiological process, in which not only genes of sex chromosomes are involved, but also autosomes. Hormonal and other physiological disturbances can lead to the fact that from the "male" zygote XY an outwardly almost normal woman develops, but with certain masculine characteristics - by the type of hair, muscle structure, timbre of voice, etc. - and having underdeveloped testes instead of the uterus, which makes her sterile. The opposite is also possible, when in the presence of a genotype XX the individual develops with secondary male sex characteristics. Similar deviations are found not only in humans, but also in other species.

Genetic sex determination, determined by a set of sex chromosomes, maintains equal reproduction of females and males. Indeed, female eggs contain only X-chromosome, since women have a genotype XX by sex chromosomes. The genotype of men is XY, and therefore the birth of a girl or a boy in each case is determined by whether the sperm X- or Y-chromosome. Since, in the process of meiosis, the chromosomes have equal chances of getting into the gamete, half of the gametes produced by males contain X-, and half - Y-chromosome. Therefore, half of the offspring are expected to be of one sex and half of the other.

It should be emphasized that it is impossible to predict in advance the birth of a boy or girl, since it is impossible to predict which male reproductive cell will participate in the fertilization of the egg: the carrier X- or Y-chromosome. Therefore, the presence of more or less boys in the family is a matter of chance:

Theoretically, selective elimination of sperm with X- or Y-chromosome, leading to different probabilities of the birth of boys or girls in some families; however, on average, this probability remains close to 0.5.

Traits linked to the X chromosome.

If the gene is on the sex chromosome (called floor-locked), then its manifestation in descendants follows different rules than for autosomal genes. Consider the genes found in X-chromosome. Daughter inherits two X-chromosomes: one from the mother, and the other from the father. The son has only one X-chromosome - from the mother; from his father he receives Y-chromosome. Therefore, the father passes on the genes available in his X-chromosome, only his daughter, the son cannot get them. Insofar as X-chromosome is more "rich" in genes in comparison with Y-chromosome, in this sense the daughter is genetically more similar to the father than the son; the son is more like the mother than the father.

One of the historically best-known sex-linked traits in humans is hemophilia, which leads to severe bleeding at the slightest cuts and extensive bruising when bruised. It is caused by a recessive defective allele 0 , blocking the synthesis of a protein necessary for blood clotting. The gene for this protein is located in X-chromosome. Heterozygous woman + 0 (+ means normal active allele dominant over hemophilia allele 0 ) does not develop hemophilia, and neither does her daughter, if the father does not have this pathology. However, her son can get the allele 0 and then he develops hemophilia.

Hemophilia was struck by Tsarevich Alexei, the son of Russian Emperor Nicholas II. His mother, Tsarina Alexandra Feodorovna, was heterozygous for this allele and inherited it from her mother Alice, who, in turn, received it from Tsarevich Alexei's great-grandmother, Queen Victoria of England:

In the heterozygous state, the hemophilia gene does not manifest, and therefore women in the royal families of Europe did not suffer from hemophilia. However, many princes - the descendants of Queen Victoria (the mutation occurred, apparently, it was in her) received this gene and were struck with hemophilia. The likelihood that Tsarevich Alexei could have received a defective allele 0 from the mother was equal to 1/2; with the same probability he could get a normal allele from her. If the second of these equally probable events in the formation of gametes had taken place, the scenario of the fate of the imperial couple would have looked different.

Recessive diseases caused by genes X-chromosomes, much less likely to affect women than men, since their disease manifests itself only with homozygosity - the presence of a recessive allele in each of the two homologous X-chromosome; men get sick in all cases when their only X-chromosome carries a defective allele. This follows quantitatively from the Hardy - Weinberg relations ( cm... POPULATION GENETICS). Let be q means the frequency of the recessive allele in the population, i.e. share X- chromosomes carrying this allele. The proportion of men with this allele and susceptible to the disease it causes is q... At the same time, the proportion of sick women is equal to the frequency of homozygotes, i.e. q 2. Consequently, the number of men with recessive linked to X-chromosome disease, in 1 / q more than the number of sick women. For example, if the frequency located in X- the chromosome of the allele causing color blindness (inability to distinguish colors) is 0.05 (i.e. 5% of men have color blindness), then the number of color blind men is 20 times greater than that of women who are color blind.

An example of sex-linked codominant inheritance is the red coloration of a domestic cat, determined by an allele at... In the heterozygous state, both alleles are active (normal and at), and therefore in some places the cat's coat has the usual color, and in some places it is red. Homozygous cats are completely red (except for possible white spots caused by another gene that blocks the synthesis of pigments). Males cannot be partially red; they are either non-red or completely red (with possible white spots). Based on the same reasoning as in the paragraph above, one could conclude that completely red cats are found much more often than completely red homozygous cats: their frequencies in the population, respectively, q and q 2, where q - the frequency of the "red" allele y... However, in cases of codominant inheritance, this reasoning does not apply. In fact, cats with a red color (both completely and partially) are much more common than red cats: their frequency is equal to the sum of the frequencies of homo- and heterozygotes: q 2 + 2q(1- q) = 2q – q 2. For example, if the frequency of the "ginger" allele is 0.05, then pure ginger cats should be 0.25%, ginger cats - 5%, and cats with ginger spots - almost 10%.

Chromosomal rearrangements sometimes lead to the fact that a fragment of one chromosome "breaks off" and joins another chromosome. This can happen with sex chromosomes as well. So, for example, sometimes there are cats with a partially red color; this is due to the fact that part X-chromosome carrying the allele y, joined Y-chromosome. As a result, inheritance at this locus occurs in the same way as for autosomal genes, i.e. cats with the indicated chromosomal abnormality can also be heterozygous, and therefore partially red. However, chromosome breakage leads to pathologies, in this case - deafness and infertility. This was noticed long ago and was expressed in the phrase "tricolor deaf cats." The third color here means white spots. However, this pathology also affects "two-colored", partially red without white spots (do not confuse red with brown, which is caused by another, autosomal, gene and is common in a number of cat breeds).

Linkage to the Y chromosome.

Information about genes located in Y-chromosome are very scarce. It is assumed that it practically does not carry the genes that determine the synthesis of proteins necessary for the functioning of the cell. But she plays a key role in the development of the male phenotype. Lack of Y-chromosomes in the presence of only one X-chromosome leads to the so-called. Turner syndrome: the development of a female phenotype with poorly developed primary and secondary sexual characteristics and other abnormalities. There are men with an extra Y-chromosome ( XYY); they are tall, aggressive, and often abnormal. IN Y-chromosome, several genes have been identified that are responsible for the regulation of the synthesis of specific enzymes and hormones, and violations in them lead to pathologies of sexual development. There are a number of morphological traits believed to be determined by genes Y-chromosomes; among them - the development of the hairline of the ears. Traits of this kind are transmitted only through the male line: from father to son.

INHERITANCE OF DIFFICULT TRADITIONS

We examined the rules for the transmission of a trait to offspring in the case when it is determined by one gene. They are valid for all organisms, but nevertheless they are only the basis for understanding how the properties of an organism are inherited. The fact is that many traits are determined by two or more genes. Alleles of each of these genes are inherited as described above. However, the character of inheritance of the trait that they define depends on the interaction of these alleles and can be very complex.

Consider coloring as an example. The color of wool in animals or flowers in plants is determined by the type of pigment, its distribution over the hair, feathers or petals, the spatial distribution of differently pigmented structures, etc. All these particular properties are controlled by different genes, and in the aggregate they all determine what we call color.

For example, the coloration of a highly studied experimental animal such as a mouse is determined by at least five genes. The usual color of the mouse is gray. However, the hair itself cannot be gray, there is no such color pigment. In fact, in such a mouse, black pigment is synthesized and migrates into the hair, but the black pigmentation at the base and tip of the hair is interrupted by a yellow ring in which the yellow pigment is located. This color is called "agouti", it is she who makes the mouse "gray". The yellow bar is controlled by the agouti gene, A, allele A which controls the formation of the yellow stripe. The recessive allele of this gene, a, blocks the flow of yellow pigment into the hair and causes homozygous mice to become black. Another gene, B, controls pigment synthesis: the dominant allele B causes the formation of black, and the recessive allele b brown pigment. As a result, a mouse with both dominant alleles A and B, Is an ordinary "gray mouse", and the mouse aa and with allele B - black. However, the mouse is homozygous for the second gene, i.e. bb, and with the allele A has a cinnamon color (combination of brown hair and yellow agouti ring). The mouse is homozygous for both genes, aabbcompletely brown. There is gene C, the recessive allele of which can interrupt the synthesis of pigments, and the mouse homozygous for this allele is a white (albino) mouse. Gene D controls the amount of pigment in the hair, so that differences in color intensity (eg, light to dark brown) perceived by the eye are determined by different alleles of this gene. The S gene determines the distribution of pigments throughout the body and can lead to mottled coloration. Similar genes have been described in other mammals: domestic cats, horses, fur-bearing animals. The color of the plumage in birds, the elytra in beetles, and the flower in plants are also controlled by many genes; the variety of combinations of different alleles determines the variety of colors that we see in nature.

Many complex features are quantitative in nature, i.e. their severity varies and can be measured. For example, the activity of an enzyme is measured by the rate of the reaction it catalyzes, i.e. the amount of a substance that has undergone transformation per unit of time. This indicator depends on the physicochemical properties of the enzyme, which, in turn, are determined by its spatial structure, and ultimately - by the genes that control the synthesis of its constituent polypeptide chains. Different alleles of each of these genes can influence in different ways the final (most important) trait - enzyme activity, forming an almost continuous series: from weak to very high activity. Moreover, the influence of these alleles affects other, equally important properties, such as, for example, the stability of the protein at low or high temperatures, low or high acidity, lack or excess of substrate. The different intensity of the work of hundreds of enzymes and protein hormones, caused by the difference in allelic composition, leads to differences between individuals in growth and development, in the ability to assimilate food, to tolerate a lack of oxygen, temperature changes and other changes in environmental conditions.

A number of traits, in particular height, body size, fertility, resistance to infection, are also controlled by many genes and show continuous, quantitative variability. In medical genetics, the so-called. multifactorial diseases that often manifest themselves in the form of slight deviations from the norm and are diagnosed as a disease when these deviations are significant. Such diseases can be considered as a different severity of certain quantitative signs (or signs) that create a predisposition to this disease.

In the formation of complex traits, the conditions of the environment in which the organism develops play an important role. So, human growth is mainly determined genetically, but with good nutrition and good living conditions, people are on average taller than in a population with the same genetic data, but in worse conditions. Susceptibility to tuberculosis and poliomyelitis is determined by specific genes, but even people predisposed to them do not get sick if they are not infected with the corresponding bacteria or viruses. The level of intelligence is also inherited, but the contribution of the environment to the formation of such differences between people is so great that in fact we should talk more about social, rather than genetic, differences ( cm... INTELLIGENCE).

Literature:

Ayala F., Keiger J. Modern genetics, vols. 1–3, M., 1988
Fogel F., Motulski A. Human genetics, vols. 1–3, M., 1990



four . Forms of interaction of allelic genes. The pleiotropic action of the gene. Multiple allelism.

five . Interaction of non-allelic genes, their types.

6. Regularities of the inheritance of traits according to Mendel. Mendelian signs in humans.

7. Types of traits inheritance, their characteristics. Expressiveness and penetrance.

X-linked inheritance

9. Inheritance of blood groups of the ab0 system in humans

10. Rh factor. Rhesus conflict. Rhesus - incompatibility.

Rh incompatibility of blood

11. Modern methods of genetic research.

12. Chromosomal diseases. Their classification, diagnosis.

All chromosomal diseases can be divided into 3 large groups:

13. Gene diseases in humans. Their classification, diagnosis.

Classification

14. Cytogenetic method for genetic analysis of the human hereditary apparatus

15. Cytogenetic and phenotypic characteristics of patients with Down syndrome. Diagnostics.

16. Cytogenetic and phenotypic characteristics of patients with Shereshevsky-Turner syndrome. Diagnostics. Shereshevsky-Turner syndrome (monosomy of the x-chromosome).

17. Cytogenetic and phenotypic characteristics of patients with Klinefelter's syndrome. Diagnostics. Klinefelter's syndrome is a genetic disorder.

Klinefelter syndrome symptoms

Diagnostics of the Klinefelter syndrome

18. Human populations, factors of their subdivision. Gene pool of populations.

19. Biological factors of population gene pool dynamics.

20. Socio-demographic factors of the dynamics of the gene pool of populations.

21. Genetic load of populations, determination of its value by the Hardy-Weinberg equation.

22. Clinical and genealogical method, its use in

23.Biochemical method, its essence, possibilities of application in medical and genetic counseling.

24. Twinning in humans, criteria for determining the identity of twins. The twin method in genetic analysis.

25. Dermatoglyphic method, its essence and possibilities of use in genetic analysis.

26. Molecular genetic method, its current capabilities and prospects for use in medicine.

27. Hybridological analysis, its use in genetic research.

28. Sexual dimorphism in humans, its genetic and phenotypic characteristics.

29. Medical genetic counseling, its tasks, organization. Medical genetic counseling

30. Inbreeding (random, non-random, total), its role as a factor in changing the population's gene pool.

31. Natural selection, determination of its value in the human population.

32. Chromosomal mosaicism, its formation, phenotypic manifestation in humans. Phenocopies, their essence.

8. The concept of "linkage" of genes. X-linked inheritance of traits in humans.

A phenomenon based on the localization of genes on one chromosome. The linkage of genes was first discovered in 1906 by W. Batson and R. Pennett in experiments on crossing sweet peas. Later, gene linkage was studied in detail by T. Morgan and colleagues in experiments with Drosophila. Linkage of genes is expressed in the fact that alleles of linked genes that are in the same linkage group tend to be inherited together. This leads to the formation of gametes preim in the hybrid. with "parental" combinations of alleles. The symbols AB / AB or AB / Ab are used to denote linkage of genes. Linkage of dominant (or recessive) alleles to each other AB / AB is used. the linkage phase, and the linkage of dominant alleles with recessive AB / aB - the repulsion phase. In both cases, gene linkage results in a lower frequency of individuals with "unparental," recombinant combinations of traits than would be expected with independent inheritance of traits. With complete linkage of genes, only two types of gametes are formed (with the original combinations of linked genes), with incomplete - and new combinations of alleles of linked genes. Incomplete linkage of genes is the result of crossing over between linked genes, therefore, complete linking of genes is possible in organisms in whose cells crossing over does not normally occur (for example, germ cells of male Drosophila). Thus, complete gene linkage is rather an exception to the rule of incomplete gene linkage. In addition, complete gene linkage can be mimicked by the phenomenon of pleiotropy. In some cases, non-random divergence of non-homologous chromosomes to one pole regularly occurs in meiosis, which leads to the formation of gametes preim. with certain combinations of alleles of unlinked genes. Different pairs of genes within the same linkage group are characterized by different degrees of linkage depending on the distance between them. The greater the distance between genes in the chromosome, the less the cohesion force between them and the more often the recombinant types of gametes are formed. The study of gene linkage and linked inheritance of traits served as one of the confirmations of the chromosomal theory of heredity and the initial impetus for the analysis and development of the theory of crossing over.

X-linked inheritance

Since the X chromosome is present in the karyotype of each person, the traits inherited linked to the X chromosome are manifested in both sexes. Women receive these genes from both parents and pass them on to their offspring through their gametes. Males receive the X chromosome from their mother and pass it on to their female offspring.

Distinguish between X-linked dominant and X-linked recessive inheritance. In humans, the X-linked dominant trait is transmitted by the mother to all offspring. A man passes on his X-linked dominant trait only to his daughters. An X-linked recessive trait in women is manifested only when they receive the corresponding allele from both parents. In males, it develops when the recessive allele is received from the mother. Females pass on the recessive allele to offspring of both sexes, and males only to daughters.

With X-linked inheritance, an intermediate character of the manifestation of the trait in heterozygotes is possible.

Y-linked genes are present in the genotype only for males and are passed down from generation to generation from father to son.

More than 370 diseases linked (or presumably linked) to the X chromosome have been described. The severity of the disease depends on gender. Full forms of the disease are manifested mainly in men, since they are hemizygous for genes localized on the X chromosome. If the mutation affects a recessive X-linked gene (XR disease), then heterozygous women are healthy, but they are carriers of the gene (and homozygotes are in most cases lethal). If the mutation affects the dominant gene linked to the X chromosome (XD disease), then in heterozygous women the disease manifests itself in a mild form (and homozygotes are lethal). The most important property of diseases linked to the X chromosome is the impossibility of their transmission from father to son (since the son inherits the Y chromosome, not the X chromosome of the father).

The genes that cause X-linked diseases are located on the X chromosome, so such diseases manifest themselves in different ways in individuals of different sexes. Since women have two X chromosomes, the manifestation of a mutant gene depends on many factors: a woman is heterozygous or homozygous for the mutant gene, a dominant or recessive mutation. An additional factor is the random nature of inactivation of one X chromosome in the cells of the female body. Men have only one X chromosome, so their mutation often manifests itself completely, regardless of whether it is a dominant mutation in women or recessive.

Thus, the terms X-linked dominant or X-linked recessive only refer to the manifestation of the mutation in women. Due to the inactivation of one X chromosome in women, it is difficult to distinguish between dominant and recessive X-linked diseases. And with ornithinecarbamoyltransferase deficiency, often described as an X-linked dominant disease, and Fabry disease, often described as an X-linked recessive disease, heterozygotes often show signs of pathology. In the absence of clear definitions, these diseases should be considered simply as X-linked, without dividing them into recessive and dominant.

This division is more suitable for X-linked diseases in which heterozygotes are usually healthy (for example, Gunther's syndrome) or have the same symptoms as hemizygous men (for example, X-linked hypophosphatemic rickets).

An important feature of X-linked inheritance is that the trait is not transmitted through the male line, since the son receives the Y chromosome from the father. But all daughters of a father with an X-linked disease will inherit the mutant allele, since they necessarily receive this X chromosome from their father.

X-linked dominant inheritance is shown using the pedigree example in Fig. 65.21:

There are about twice as many sick women as men.

A sick woman has a 50% chance of transmitting the disease to both sons and daughters.

A sick man transmits the disease only to all daughters.

In women who are heterozygotes, the disease is milder, and its symptoms are more variable than in men.

Sometimes X-linked dominant inheritance occurs in rare diseases that are fatal to male fetuses (Fig. 65.22):

The disease manifests itself only in women who are heterozygous for the mutant gene;

A sick woman has a 50% chance of transmitting the disease to her daughters;

Sick women have an increased likelihood of spontaneous abortions caused by the death of male fetuses.

An example of such a disease is pigment incontinence.

Some X-linked diseases disrupt reproductive function in women, but for men they are detailed at the stage of intrauterine development, and therefore they arise mainly or exclusively as sporadic diseases in women due to a new mutation. Such diseases include Ecardi's syndrome, Holtz's syndrome and Rett's syndrome.

There is a pseudo-autosomal region on the X chromosome, the genes of which have homologous copies on the Y chromosome and are inherited in the same way as autosomal ones.

Features of the inheritance of pathologywith Y-linked type are: ‑ transmission of the sign from the father to all sons and only sons; ‑ daughters never inherit the trait from their father, because they do not have a Y chromosome; ‑ "Vertical" character of trait inheritance; ‑ 100% probability of inheritance for males is equal; ‑ the genes responsible for the development of the pathological trait are localized on the Y chromosome.

Examples of traits transmitted by the Y-linked type of inheritance: -hypertrichosis of the auricles, – excessive hair growth on the middle phalanges of the fingers of the hands, – azoospermia. The pedigree with the Y-linked type of inheritance of excessive hairiness in the auricles in four generations is shown in Fig. 4-12.

Y LAYOUT insert file "PF Fig 04 12 Pedigree with Y linked Dutch type of inheritance"

Rice.4–12 .Pedigree with Y-linked (Dutch) inheritance

Mitochondrial inheritance

Important features of the mitochondrial type of inheritance of pathology are: -the presence of pathology in all children of a sick mother; – the birth of healthy children from a sick father and a healthy mother. These features are explained by the fact that mitochondria are inherited only from the mother. The proportion of the paternal mitochondrial genome in the zygote is DNA from 0 to 4 mitochondria, and the maternal genome is DNA from about 2500 mitochondria. In addition, replication of paternal DNA is blocked after fertilization.

Currently, the mitochondrial genome has been sequenced. It contains 16 569 base pairs and encodes two ribosomal RNAs (12S and 16S), 22 transport RNAs and 13 polypeptides – subunits of enzymatic complexes of oxidative phosphorylation. The other 66 subunits of the respiratory chain are encoded in the nucleus.

Examples of diseases with mitochondrial inheritance (mitochondrial diseases): optic nerve atrophy Leber, syndromes Lei (mitochondrial myoencephalopathy), MERRF (myoclonic epilepsy), dilated familial cardiomyopathy. Pedigree of a patient with a mitochondrial type of pathology inheritance (optic nerve atrophy Leber) in four generations is shown in Fig. 4-13.

S LAYOUT insert the file "PF Fig 04 13 Pedigree with mitochondrial type of inheritance of the disease"

Rice.4–13 .Pedigree with mitochondrial inheritance of the disease... Circle - female gender, square - male gender, dark circle and / or square - sick.

Examples of monogenic diseases most frequently encountered in clinical practice

Phenylketonuria

All forms of phenylketonuria are the result of a number of enzyme deficiencies. Their genes are transcribed in hepatocytes and inherited in an autosomal recessive manner. The most common form of phenylketonuria occurs with mutations in the phenylalanine 4-monooxygenase gene (phenylalanine 4-hydroxylase, phenylalaninase). The most common type of mutation – single nucleotide substitutions (missense, nonsense mutations and mutations at splice sites). Leading pathogenetic link in phenylketonuria – hyperphenylalaninemia with the accumulation of toxic metabolic products (phenylpyruvic, phenylacetic, phenyl lactic and other keto acids) in the tissues. This leads to damage to the central nervous system, impaired liver function, protein metabolism, lipo- and glycoproteins, hormone metabolism.

Phenylketonuria manifests itself: increased excitability and muscle hypertonicity, hyperreflexia and convulsions, signs of allergic dermatitis, hypopigmentation of the skin, hair, iris; "Mouse" smell of urine and sweat, delayed psychomotor development. Untreated children develop microcephaly and mental retardation. Another name for the disease is associated with this. – phenylpyruvate oligophrenia.

Phenylketonuria treatmentcarried out with the help of diet therapy (excluding or reducing the content of phenylalanine in food). The diet must be followed from the moment of diagnosis (the first day after birth) and the blood phenylalanine level must be monitored for at least 8-10 years. (see the article "Hemophilia" in the Appendix "Reference of Terms")

Syndrome Marfana

Syndrome frequency Marfana is in the range 1: 10,000-15,000. The syndrome is inherited in an autosomal dominant pattern. The cause of the syndrome – fibrillin gene mutation ( FBN1). About 70 mutations of this gene (mostly missense type) have been identified. Mutations of various exons of a gene FBN1 cause various changes in the phenotype, from moderate (subclinical) to severe.

Marfan syndrome manifests itself generalized damage to the connective tissue (since fibrillin is widely represented in the matrix of the connective tissue of the skin, lungs, blood vessels, kidneys, muscles, cartilage, tendons, ligaments); damage to the skeleton, high growth, disproportionately long limbs, arachnodactyly, lesions of the cardiovascular system, dissecting aortic aneurysms, mitral valve prolapse, eye damage: dislocation or subluxation of the lens, iris tremor.

Hemoglobinopathy S

Hemoglobinopathy S (autosomal recessive inheritance) is common in the countries of the so-called malarial belt of the Earth. This is because HbS heterozygotes are resistant to tropical malaria. In particular, carriers of HbS are common in Transcaucasia and Central Asia; in Russia, the maximum frequency of heterozygous carriers of HbS is noted in Dagestan.

The reason for HbS is the substitution of one base in 6 ‑ m triplet (missense mutation)  ‑ globin chains. This results in the replacement of glutamic acid with valine. This Hb has extremely low solubility. Intracellularly, crystalline tactoids are formed from HbS. They give the red blood cells a sickle shape. Hence the name of the disease – "Sickle cell anemia".

Heterozygous carriers of HbS are normally healthy, but with low pO2 (caisson work, high altitude conditions, etc.) or with hypoxemia (congenital malformations of the heart, respiratory failure, prolonged anesthesia, etc.), hemolytic anemia develops.

Homozygotes suffer from severe hemolytic anemia with 4–6 ‑ months of age. As a result of thrombosis of capillaries or venules by sickle-shaped erythrocytes, trophic ulcers (often on the lower leg), abdominal pain, heart and eye damage develop. Lesions of the osteoarticular system, hepatosplenomegaly are characteristic.

Cystic fibrosis

Cystic fibrosis is a multiple lesion of exocrine glands, accompanied by the accumulation and release of viscous secretions by them. Among newborns, the frequency of cystic fibrosis is 1: 1500–1: 2000. Cystic fibrosis is one of the most common monogenic diseases in Europe. Cystic fibrosis is inherited in an autosomal recessive manner. More than 130 mutant alleles are known; most common mutation – delF508. It leads to the absence of phenylalanine at the 508th position of the transmembrane regulatory protein. Depending on the type of mutations and their localization, the function of a gene can be completely or partially impaired. In this case, the regulation of the transfer of Cl - through the membranes of epithelial cells is upset (the transport of Cl - is inhibited, and Na + is increased).

The disease is characterized by the closure of the ducts of the glands with a viscous secretion, which is formed in connection with the increased resorption of Na + by the cells of the ducts of the exocrine glands. Often, cysts form in the ducts and inflammation develops. With a chronic course, an excess of connective tissue (sclerosis) develops in the glands. In newborns, intestinal obstruction (meconial ileus) is often detected. In children, the most common form of the disease is pulmonary or pulmonary-intestinal. It is manifested by repeated bronchitis, pneumonia, emphysema of the lungs, as well as disorders of cavity and parietal digestion, up to the development of malabsorption syndrome (malabsorption syndrome). With a long course, respiratory failure, liver cirrhosis, portal hypertension develop, often leading to death.

Chromosomal diseases

Chromosomal diseases are detected in newborns with a frequency of 6: 1000. The initial link of pathogenesis – genomic or chromosomal mutation. Chromosomal imbalance leads to a stop or disruption of embryonic development, including the early stages of organogenesis. As a result, multiple VLOOKS are formed. The severity of the disorders usually correlates with the degree of chromosomal imbalance: the more chromosomal material is involved in the aberration, the earlier the chromosomal imbalance manifests itself in ontogenesis, the more significant the disorders in the physical and mental development of the individual. As a rule, the loss of a chromosome or part of it leads to more severe clinical consequences than the attachment of a chromosome or part of it.

Chromosomal diseases are classified (Fig. 4-14) according to the criteria for changes in the structure and number of chromosomes, as well as depending on the type of cells (sexual or somatic).

S LAYOUT insert the file "PF Rice 04 14 Types of chromosomal diseases"

Rice.4–14 .Types of chromosomal diseases.

Similar information.

The human karyotype contains 22 pairs of autosomes and one pair of sex chromosomes. The sets of autosomes in men and women are the same in shape, and the pairs of sex chromosomes are different. In women, these are two X chromosomes, in men - an X chromosome and a Y chromosome. The X chromosome does not differ from medium-sized autosomes (No. 5, 6). The male sex Y chromosome is morphologically similar to the smallest chromosomes (No. 21, 22, Fig. 2.7, 3.7).

Sex chromosomes are found in every human somatic cell. In the process of gamete formation during meiosis, homologous sex chromosomes diverge into different sex cells. So, each egg, except for 22 autosomes, carries one sex chromosome X, and its haploid set includes 23 chromosomes. All sperm also have a haploid set of chromosomes, of which 22 are autosomes, and one is sexual. One half of the sperm contains the X chromosome, the other half contains the Y chromosome.

The sex of a person is determined at the time of fertilization, when the chromosome sets of gametes are combined. The zygote contains 22 pairs of autosomes and one pair of sex chromosomes. If an egg is fertilized with a sperm with an X chromosome, then there will be a pair of XX sex chromosomes in the zygote, and a girl will develop from it. When fertilization was performed by spermatozoa with a Y-chromosome, the set of sex chromosomes in the zygote is XY, and a male body will develop from it. So, the sex of the unborn child is determined by the person's sex chromosomes. The sex ratio at birth roughly corresponds to the 1: 1 ratio (Table 4.1).

Table 4.1. Genetic sex determination in humans

		female gametes
male gametes

However, in reality, neonatal sex ratios (known as the secondary sex ratio as opposed to the primary fertilization ratio) are not biased towards boys (102-106 boys per 100 girls). The primary sex ratio is not exactly known, but there is some evidence that it is also variable. It turned out that the primary and secondary sex ratio depends on the length of the period between intercourse and ovulation, the frequency of intercourse, general conditions, taking into account also the state of war or peace in society.

Even with artificial insemination, the proportion of boys among newborns is significantly higher than girls.

The sex of the unborn child is determined not only by the combination of sex chromosomes. An important role in this process in humans is played by hormonal regulation, carried out under the influence of sex hormones synthesized by the sex glands.

Human beings are bisexual by nature. The rudiments of the reproductive system are the same in embryos of both sexes. If the Y chromosome is absent or its activity is suppressed, then the rudiments of the genital organs develop in a female pattern. their development does not require special regulatory mechanisms and is arbitrary.

Normal males develop only when all the male sex hormones act on the rudiments of the external and internal genital organs, functioning at a certain time and in a certain place.

Described are about 20 different gene defects that, with a normal male karyotype (CK), cause disturbances in the formation of external and internal sexual characteristics. As a result, the Hermaphrodite organism develops. These gene mutations are associated with impaired synthesis of sex hormones, receptor sensitivity to them, etc.

Inheritance of sex-linked traits

Sex chromosomes X and Y are partially homologous, since they have common homologous regions in which allelic genes are localized. However, they differ in shape, size and genetic content, because, in addition to homologous regions, X- and the Y chromosomes contain a large number of non-allelic genes. The X chromosome contains genes that are not on the Y chromosome, and certain genes on the Y chromosome are absent on the X chromosome.

So, in the sex chromosomes of men, some genes do not have the corresponding allele in the homologous chromosome. In this case, the trait is determined not by a pair of allelic genes, as the usual mendelating trait, but only one allele. This position of the gene is called hemizygotic, and signs, the development of which is due to a single gene located in one of the alternative sex chromosomes - bonded to the floor. Such traits develop mainly in individuals of the same sex and are inherited differently in males and females.

Traits linked to the X chromosome can be dominant and recessive.

X -sinking dominant a type inheritance.

According to this type, mainly diseases are inherited - hypophosphatemic rickets, "cleft lip", follicular hyperkeratosis (excessive keratinization of the skin epidermis), focal hypoplasia (underdevelopment of an organ or its part), spotted chondrodysplasia (anomalies in the transformation of cartilage tissue into bone enamel), dark ...

Such signs appear in hemozygous men and heterozygous women. However, the sons of an affected father and a healthy mother are not carriers of pathological signs, and their children are also healthy. However, all daughters of the defeated father will be amazed. From affected mothers, the disease is transmitted to children regardless of gender with a frequency of 1: 1, similar to an autosomal dominant mode of inheritance. If affected individuals have normal reproductive capacity, then in the population, sick women happen about twice as often as sick men.

A typical example of X-linked dominant inheritance may be insufficient phosphorus in the blood (hypophosphatemia), which often causes hypophosphatemic rickets. In the pedigree in Fig. 4.6 all daughters of affected men married to healthy women suffered from hypophosphatemia or rickets, and all of their sons were healthy. The affected mothers had both sick and healthy sons and daughters approximately equally.

In men, the symptoms of the disease are, as a rule, more acute than in women, because in them the effect of the abnormal dominant allele is partially compensated by a homologous normal number in the paired X chromosome.

X -disintegration recessive type inheritance.

The recessive signs, which are determined by the genes of the X chromosome, are also mainly diseases - hemophilia, color blindness (inability to distinguish between red and green colors), optic nerve atrophy, Duchenne myopathy (damage to skeletal muscles), etc.

Figure: 4.6.

Inheritance linked to the X chromosome can be seen in the example of the recessive hemophilia gene. In a man, the hemophilia gene is localized on the X chromosome, has no zero in the Y chromosome, that is, it is in a hemizygous state and, as a rule, turns out to be. To better understand the genetic mechanism of inheritance of this disease, the appropriate designations are used: H - gene for the normal ability of blood to skip, B - hemophilia gene, HNU - healthy person, HLU - person with hemophilia;

In women, hemophilia can only be homozygous: KhNKhN - a woman is healthy, HJHL is a heterozygous healthy woman, but carries the hemophilia gene, HLHL is a woman with hemophilia.

The disease affects men. All of them are healthy daughters are heterozygous carriers of the hemophilia gene, since they received an X chromosome with an abnormal gene from their father.

Among the sons of heterozygous mothers (HnHk) the ratio of sick and healthy is 1: 1, since gametes Xn and CL are formed with the same probability.

The most famous example of X-linked recessive inheritance was the inheritance of classic hemophilia type A among the descendants of Queen Victoria of England (Fig. 4.7). Queen Victoria was heterozygous for the hemophilia gene and passed it on to her hemophiliac son and three daughters. One of the Queen's descendants - Tsarevich Alexei (the son of the last Russian Tsar Nicholas II and the granddaughter of Queen Victoria Alice, who was a carrier of the hemophilia gene) was also struck by this disease. The pedigree presented, as would be expected for recessive X-linked inheritance, indicates that hemophilia patients are only males. However, in families in which there were closely related marriages, hemophilia is sometimes manifested in women as well.

Inheritance of traits linked to the Y chromosome.

In addition to the fact that the presence of the Y-chromosome in the human genome clearly determines the male sex, this chromosome contains at least several dozen genes, including those genes that determine the development of the testes, hairiness of the middle phalanges of the fingers, the presence of hair on the outer edge of the auricles (hypertrichosis), control the intensity of growth and some other signs. The trait, the gene of which is localized in the Y-chromosome, is transmitted from the father to all sons, and only to sons (Fig. 4.8.). Pathological mutations that cause a violation of the structure and functions of the testes, and are not inherited due to the sterility of their carriers.

Figure: 4.7. Rodovid with X-linked hemophiliaAND in the royal families of Europe

Figure: 4.8. A genus with a Y-linked type of trait inheritance (hairiness of the middle phalanges of the fingers)

Homologous zones X- and Y chromosomes contain allelic genes that are equally likely to be present in individuals of both sexes. The features determined by these genes include the inability to distinguish between colors and pigmented xeroderma (malignant skin damage from sunlight). Recessive pathology.

Traits due to allelic genes located in X- and Y chromosomes are inherited according to the classical Mendelian rules.

Mitochondrial or cytoplasmic inheritance.

The mitochondrial genome is a circular double DNA molecule that contains up to 17 thousand base pairs, about 10 thousand times smaller than the average chromosome.

More than 10 mutations of mitochondrial genes have been identified that cause various diseases, the symptoms of which are severe damage to the central nervous system, organs of vision, heart and muscles. The most common pathologies are Leber's optic nerve atrophy, Leigh's disease, etc., which are combined into the group of mitochondrial encephalomyopathies.

Since a child inherits mitochondria from a mother with an oocyte cytoplasm, all children of a sick woman inherit the pathology, regardless of their gender. Affected girls give birth only to sick children, while in sick men all children will be deprived of this disease (Fig. 4.9).

Figure: 4.9. Genus with mitochondrial inheritance, pathological signs (atrophy of the optic nerve Leber)

The presence in a person of the phenomenon of linkage of signs with sex provides the most important information for medical genetic counseling. It is highly probable that the genotypes and phenotypes of the sons and daughters of spouses can be assumed if the father, mother, or both have traits linked to the sex chromosome or the mitochondrial genome.