Dominant type of inheritance. Types of inheritance According to the autosomal recessive type in humans are inherited

Introduction

There is no generally accepted classification of genetic diseases. Based on the genetic principle, gene diseases are distinguished with autosomal dominant, autosomal recessive, X-linked recessive, X-linked dominant, Y-linked (holandric) and mitochondrial (cytoplasmic) types of inheritance.

type of genetic inheritance disease depends on the localization of the pathological mutation on the autosome or sex chromosome, on its dominance or recessiveness, and also on where it arose: in nuclear DNA or mitochondrial.

Autosomal dominant inheritance pattern

Examples of a disease with an autosomal dominant type of inheritance are Waardenburg, Marfan, Marshall, Stickler syndromes, Recklinghausen neurofibromatosis, and mandibular dysostosis.

Diseases with autosomal dominant inheritance

In autosomal dominant disorders, only marriages Ah X aa are of practical importance. Homozygous for the pathological dominant gene genotype of the affected parent (marriage AA X aa) is possible only with assortative (selectivity, non-randomness) marriages in the population. Such marriages are unlikely due to the relatively rare occurrence and reduced reproductive capacity of patients with congenital or childhood diseases with autosomal dominant inheritance. There are data in the literature on the possibility of changes and an increase in the severity of the disease with homozygotization of autosomal dominant genes. So, Vogel and Motulsky (1989) cites a case of oligodactyly in a child (AA), from cousin sibling marriage with brachydactyly (Aa haa).

If one of the parents is heterozygous for an autosomal dominant gene (ah) and the other is homozygous for the normal allele (ah) m, o in such a marriage, the following variants of genotypes in descendants are possible:

Parents Ah X aa

Gametes A A a a

Children Ah; Ah; aa; aa

So every child in a sick marriage (ah) with healthy (ah) has a 50% chance (risk) of getting the normal allele (a) and be healthy, as well as the probability (risk) of inheriting a pathological mutation (BUT) and be sick. At the same time, the ratio of healthy and sick children in the offspring is 1: 1 and does not depend on the sex of the child.

For diseases with an autosomal dominant type of inheritance, the occurrence of pathology in heterozygous carriers is characteristic (ah) in each generation and the ratio of 1: 1 sick and healthy among siblings. For gene diseases with this type of inheritance, incomplete penetrance (manifestation) and varying expressivity (severity) are typical. The latter affects not only different families, but also members of the same family, making it difficult to diagnose. Diseases with an autosomal dominant type of inheritance can be both congenital and detected at any age. For example, Huntington's chorea and Alzheimer's disease appear at the age of 35-40 and after 60, respectively. Finally, autosomal dominant diseases are characterized by increased severity and even a change in the phenotype in homozygous dominant individuals.

Examples of some autosomal dominant diseases are shown in Table 1.

Table 1. Diseases with autosomal recessive inheritance

Almost all patients suffering from pathology with an autosomal dominant type of inheritance have a violation of the reproductive function, and sometimes sterility, which can be associated with both biological and social factors. Thus, 80-90% of all cases of achondroplasia, 30-50% of cases of neurofibromatosis-1 are caused by new mutations. An exception to this rule are diseases with a late onset, when childbearing is already over by the onset of the disease. For the parents of a child with a new mutation that has arisen in the germ cell of one of them, the repeated risk of having a sick child does not exceed the population risk, and for the child itself it is 50%. The probability of occurrence of a dominant mutation in the germ cell in older fathers is higher than in young ones.

For the recognition of an autosomal dominant type of inheritance, the following features are the most important:

The trait (disease) manifests itself in each generation without gaps (vertical type of inheritance), except for cases of incomplete penetrance (manifestation) of the gene;

Any child of a patient with an autosomal dominant disorder has a 50% risk of inheriting the disorder from their parents (in case of complete penetrance);

Unaffected family members (for diseases with 100% penetrance) cannot have affected children;

The occurrence and transmission of autosomal dominant diseases is not related to sex, i.e. males and females are equally affected.

Polygenic diseases include cleft lip (isolated or with cleft palate), isolated cleft palate, congenital hip dislocation, pyloric stenosis, neural tube defects (anencephaly, vertebral cleft), congenital heart defects. 3. The genetic risk of polygenic diseases depends to a large extent on family predisposition and on the severity of the disease in parents. 4. Genetic risk decreases significantly with decreasing degree of relationship. 5. The genetic risk of polygenic diseases is assessed using empirical risk tables. Determining the prognosis is often difficult. B. Recently, other types of inheritance other than monogenic and polygenic inheritance have been studied due to the achievements of molecular genetics. 1. Mosaicism - the presence in the body of two or more clones of cells with different chromosome sets. Such cells are formed as a result of chromosomal mutations.

The type of inheritance is autosomal dominant. types of inheritance of traits in humans

X-linked recessive diseases One of the most frequent and severe forms of hereditary diseases with X-linked inheritance is Duchenne pseudohypertrophic muscular dystrophy, which belongs to the group of neuromuscular diseases. It was first described in 1868. Its frequency is 1:3000 -5000 boys. The disease is caused by a violation of the synthesis of the dystrophin protein, the gene of which is localized in the short arm of the X chromosome.
The main symptomatology of the disease is a progressive increase in dystrophic changes in muscles with a gradual immobilization of the patient. In children under three years of age, it is quite difficult to diagnose the disease. It is known that these children are somewhat behind in motor development in the first year of life, later than normal, they begin to sit and walk.

The classic picture of the disease manifests itself in children 3-5 years old.

Autosomal dominant inheritance pattern

IX. one). An example is achondroplasia - a severe skeletal lesion with severe shortening of the limbs and an increased head size (pseudohydrocephalus). At the same time, in 80% of patients, the disease is recorded as a sporadic case, which is the result of a mutation that has arisen in the germ cells of one of the parents. It is very important to identify such cases (of a new mutation), since the risk of having the next sick child in a given family does not exceed the population.
In general, the main features that make it possible to suspect an autosomal dominant type of inheritance of the disease are the following: 1) the disease manifests itself in each generation without gaps.

Autosomal recessive inheritance pattern

Attention

Most often, pathology transmits the type of inheritance autosomal dominant. This is monogenic inheritance of one of the traits. In addition, diseases can be transmitted to children by autosomal recessive and autosomal dominant inheritance, as well as by mitochondrial traits. Types of Inheritance Monogenic inheritance of a gene can be recessive or dominant, mitochondrial, autosomal, or sex-linked.

• autosomal recessive;
• autosomal dominant;
• mitochondrial;
• X-dominant linkage;
• X-recessive linkage;
• U-clutch.

Different types of inheritance of traits - autosomal dominant, autosomal recessive, and others, are capable of transmitting mutant genes to different generations.

Autosomal recessive mode of inheritance of the disease

Info

Thus, 80-90% of all cases of achondroplasia, 30-50% of cases of neurofibromatosis-1 are caused by new mutations. An exception to this rule are diseases with a late onset, when childbearing is already over by the onset of the disease. For the parents of a child with a new mutation that has arisen in the germ cell of one of them, the repeated risk of having a sick child does not exceed the population risk, and for the child itself it is 50%.

However, if only one parent is ill in the family, and the second has healthy genes, then the children may not inherit the mutant gene. An example of autosomal dominant inheritance The autosomal dominant type of inheritance can transmit more than 500 different pathologies, among them: Marfan's syndrome, Ehlers-Danlos syndrome, dystrophy, Recklinghausen's disease, Huntington's disease. When studying the pedigree, one can trace the autosomal dominant type of inheritance.

Examples of this may be different, but the most striking is Huntington's disease. It is characterized by pathological changes in nerve cells in the structures of the forebrain.

Autosomal dominant and autosomal recessive mode of inheritance

All the characteristic features of our body are manifested under the action of genes. Sometimes only one gene is responsible for this, but most often it happens that several units of heredity are responsible for the manifestation of a particular trait at once. It has already been scientifically proven that for a person the manifestation of such signs as the color of skin, hair, eyes, the degree of mental development depends on the activity of many genes at once.
This inheritance is not exactly subject to the laws of Mendel, but goes far beyond it. The study of human genetics is not only interesting, but also important in terms of understanding the inheritance of various hereditary diseases. Now it is already becoming quite relevant to turn young couples to genetic consultations so that, after analyzing the pedigree of each spouse, one could confidently say that the child will be born healthy.

Introduction

Important

A disease with an autosomal recessive type of inheritance is clinically expressed only when both autosomes are defective for this gene. The prevalence of autosomal recessive diseases depends on the frequency of occurrence of the recessive allele in the population. Most often, recessive hereditary diseases occur in isolated ethnic groups, as well as among populations with a high percentage of consanguineous marriages.

• medical genetics

1. Tarantul V.Z.

Disease Inheritance Types

The vast majority of hereditary metabolic diseases (fermentopathies) are inherited according to the autosomal recessive type. The most frequent and clinically significant are such diseases with an autosomal recessive type of inheritance as cystic fibrosis (cystofibrosis of the pancreas), phenylketonuria, adrenogenital syndrome, many forms of hearing or vision impairment, storage diseases. To date, more than 1600 autosomal recessive diseases are known. The main methods of their prevention are medical genetic counseling of families and prenatal diagnostics (in case of diseases for which intrauterine diagnostic methods have been developed). Autosomal recessive diseases form a significant part of the segregation genetic load due to the high frequency of the pathological allele in the population.

Autosomal dominant and autosomal recessive mode of inheritance

The most common in clinical practice are the following monogenic diseases with an autosomal dominant type of inheritance: familial hypercholesterolemia, hemochromatosis, Marfan's syndrome, type 1 neurofibromatosis (Recklinghausen's disease), Ehlers-Danlos syndrome, myotonic dystrophy, achondroplasia, osteogenesis imperfecta and others. On fig. IX.6 shows a pedigree characteristic of an autosomal dominant type of inheritance. n A typical example of an autosomal dominant disease is Marfan's syndrome, a generalized lesion of the connective tissue. Patients with Marfan syndrome are tall, they have long limbs and fingers, characteristic changes in the skeleton in the form of scoliosis, kyphosis, and curvature of the limbs. Often the heart is affected, a characteristic sign is a subluxation of the lens of the eye. The intelligence of such patients is usually saved.

Characteristic.

Genetic diseases is a group of diseases that is diverse in clinical presentation and is caused by single gene mutations.

The number of currently known monogenic hereditary diseases is about 4000-5000 nosological forms.

Different types of mutations occur in the same gene. It is known that the same nosological form can be caused by different mutations. Features of the inheritance of gene diseases are determined by Mendel's laws. Mutations can occur in any genes, leading to a disruption (change) in the structure of the corresponding polypeptide chains of protein molecules. The beginning of the pathogenesis of any gene disease is associated with the primary effect of the mutant allele. It can appear in the following ways:

Lack of protein synthesis

Synthesis of a protein abnormal in its primary structure

Quantitatively excess protein synthesis

Quantitatively insufficient protein synthesis.

There are several approaches to the classification of monogenic hereditary diseases: genetic, pathogenetic, clinical, etc.

First. Genetic principle - by type of inheritance:

1) Autosomal dominant diseases,

2) Autosomal recessive diseases,

3) X - linked dominant diseases,

4) X - linked recessive diseases,

5) U - linked (holandric) and mitochondrial diseases.

This classification is the most convenient, as it immediately allows you to orient yourself regarding the situation in the family and the prognosis of the offspring.

Second the classification is based on clinical principle, i.e. on attributing the disease to one group or another, depending on the system of organs most involved in the pathological process - monogenic diseases of the nervous, respiratory, cardiovascular systems, skin, organs of vision, mental, endocrine, etc.

Third classification is based on the pathogenetic principle. According to it, all monogenic diseases can be divided into:

Hereditary metabolic diseases (hereditary amino acid metabolism disorders, carbohydrate metabolism disorders, lipid metabolism disorders, steroid metabolism disorders, etc.)

Monogenic syndromes of multiple congenital malformations and combined forms.

2. GENE DISEASES X - linked-recessive

a) Such diseases (about 100) (List in the subject of Mendel's laws), for example:

color blindness

Diabetes insipidus (hypofunction of the pituitary gland, sharp dehydration of the body, which inhibits growth in newborns, sharply disrupts the psyche, sometimes fatal)

hypochromic anemia

Anhidrosis ectodermal dysplasia (absence of sweat glands)

Angiokeratoma

Hunter disease (MPS-III) - mucopolysaccharidosis

Martin–Bell syndrome

Hemophilia - several types, boys get sick, and girls rarely (blood loss), therefore it is usually fatal. Women are carriers of X A Xª.

- Duchenne muscular dystrophy . The boys are sick.

Reason: mutation of the dystrophin gene (it is in the short arm of the X chromosome), therefore, the synthesis of this protein is disrupted. Frequency (1:3000 1:5000). Early onset of the disease at 2-3 years. It progresses in the form of muscle damage, which leads to disability at the age of 8-10 (they move with difficulty), at 14-20 they are immobilized. Early symptoms in the form of pseudohypertrophy of the calf muscles, which increase in volume and become dense (replacement of muscle tissue with connective or adipose tissue). Other muscles weaken and lose weight (hips, pelvic girdle, then shoulder, proximal arms). There will be a duck walk. The body is tilted. From squatting, the child rises, as it were, on his own. Further, the respiratory muscles, muscles of the face, heart are affected. Heart rhythm disturbances, ECG changes are detected. Death is usually from acute heart failure. It is combined with mental retardation in 50% of patients (debelism).

XªX-carrier (a characteristic sign of carriage is an increase in the activity of enzymes in the blood serum - creatine phosphokinase) a decrease in urinary excretion of creatine.

Laboratory studies: in the amniotic fluid or in the blood of the fetus, the determination of creatine phosphatase (CPK) and myoglobin. Treatment: cannot be cured, symptoms are treated.

3. X-linked dominant diseases

Rickets D - resistant (curvature of the tubular bones of the ankle and knee joints, deformity. Children do not walk, low phosphorus content in the blood).

Cylindromatosis (bumps-tumors on the head)

Enamel hypoplasia

Favism (primaquine anemia)

Stein-Leventhal Syndrome

4. U - linked diseases (in men

Webbing between toes

Hypertrichosis

Porcupine Man

5 . GENETIC DISEASES AUTOSODOMINANT.

There are about 3000 such diseases: (List in a lecture on Mendel's laws)

a) astigmatism - they cannot see objects in different planes - a violation of the reflex reactions of the eye. Up to 40% of earthlings suffer from this disease.

b) Night blindness (hemerolopia).

c) Pathology of the structure of the limbs

Anonychia (underdevelopment of fingers and nails)

Arachnodactyly (Marfan syndrome)

Brachydactymia (short fingers)

Polydactyly (multi-fingeredness)

Syndactyly (spliced ​​fingers)

d) Hemoglobinopathies (50) violation of the structure of hemoglobin.

Serrovide cell anemia

Thalassemia - a microcytic form of anemia - a characteristic tower skull, its bones are deformed ("hedgehog needles")

e) Achondroplasty dwarfism: sick women and men.

disease of the skeletal system, the clinical picture is due to abnormal growth and development of cartilaginous tissue in the epiphyses of the tubular bones and the base of the skull - the bones are underdeveloped in length.

In adulthood, patients look like: short stature (up to 120 cm) while maintaining the normal length of the body, tuberous brain part of the skull, a characteristic face, a sharp shortening of the upper and lower extremities - due to the femur and humerus bones, with their deformation and thickening. Neurological symptoms may occur due to narrowing of the spinal canal, possibly compression of the spinal cord with paralysis of the lower extremities. The ability to have offspring is reduced by 80-90%. In girls, gynecological complications are possible: early menstruation, leukomyomatosis, breast enlargement,

early menopause. There is no cure, only symptoms.

f) Neurofibromatosis (Recklinghausen's disease). 7 forms are known, more often peripheral. Caused by a mutation in the NF-1 gene located on chromosome 17. This is a multiple formation of tumors of the nerve trunks. Tumors can be located in any organs and tissues, but are more common on the skin, where they look like pigmented warts or café-au-lait spots, with excessive hair growth. They are located on the back, chest, face, abdomen. The number of spots grows, then turn into tumors. Neurofibromas are soft nodules that, when pressed, seem to fall through - a symptom of the "bell button". There is a change in the skeletal system - kyphosis, scoliosis, local gigantism, craniofacial anomalies. Also, the lag in physical and mental development is 30%, it is not deep. The manifestation of the disease is sometimes detected at birth, but more often in early childhood. Treatment: no, symptomatic.

and) Marfan syndrome - spider fingers.

Connective tissue pathology, the cause is a mutation in the fibrillin gene - chromosome 15. Characteristic appearance: tall, asthenic physique, the amount of adipose tissue is reduced, the limbs are elongated due to the distal sections, the arm span exceeds the body length. Long thin fingers (arachnodactyly, “thumb symptom” (first finger extends beyond the limits when clenched into a fist), overlapping fingers 1 and 5 when clenching the wrist, chest deformity (funnel-shaped, keeled), curvature of the spine (kyphosis, scoliosis), hypermobility joints, clinodactyly of the little fingers.

CCC: expansion of the ascending aorta with the development of aneurysm, prolapse of the heart valves. Subluxations and dislocations of the lenses of the eye, retinal detachment, myopia. Inguinal, umbilical and femoral hernias. Rarely, kidney polyposis, hearing loss, deafness. Mental and mental development is normal. Avg. life expectancy of 27 years, but also to a ripe old age.

Can't be cured.

GENE DISEASES AUTOSOMAL RECESSIVE

780 diseases:

a) Deafness.

b) Malignant diseases:

Ichthyosis (congenital) The entire skin of a newborn is covered with keratinized plates of significant size (reminiscent of fish scales), while skin breathing becomes impossible. The child either dies shortly after birth or is stillborn.

Glioma of the retina.

c) Glaucoma (vision loss) cataract.

e) Wilson's disease (dystrophy)

d) Enzymopathies (metabolic disorders), there are about 600 of them.

Gene diseases with defects in biochemical metabolism - enzymopathies (fermentopathies).

Gene ----- enzyme ----- biochemical reaction -------- trait

(molecularly determined pathology of enzymes) - either it is not present, or its activity is reduced, this leads to blocking of biochemical reactions.

Enzymopathies are almost always accompanied by a change in the content of metabolites not only in tissues, but also in biological fluids (blood, urine, digestive juices) and cells (blood, skin, bone marrow cells).

There are methods that make it possible to make an accurate differential diagnosis for many enzymopathies.

1) Diseases of amino acid metabolism disorders(there are 60 of them: phenylketonuria, albinism, tyrosinosis ...):

- Phenylketonuria (Fehling's disease).

There are several forms. Opened in 1934. Frequency 1:10000. The defect is associated with a deficiency of the enzyme phenylalanine-4-hydroxylase (the gene is located on chromosome 12), which leads to an excess of the amino acid phenylalanine in the blood, and phenylpyruvic acid (phenylacetic acid) in the urine.

A drop of blood is taken from the heel of each newborn on a special test form and sent to the MGK. The diagnosis can be made by the express method: 1 liter of urine + 5 drops of 10% FeCl3 (ferric chloride), with the disease there is a rapidly passing darkening (2 months old child).

Clinical manifestations: the child is born outwardly healthy and in the very first weeks of life phenylalanine enters with food and he has signs of neurological pathology:

Increased excitability (or lethargy and drowsiness),

Enhanced tendon reflexes (not everyone)

Increased muscle tone (not for everyone),

Trembling (tremor),

Convulsive epileptiform seizures,

- "mouse" smell from the child.

Later, by 4-5 months, there are:

Mental retardation, and then by 3 years mental retardation (idiocy, imbecile), behavioral disorder,

Microcephaly,

Paleness of the skin, hair, iris (lack of tyrosine and melanin),

Eczema, 1/3 malformations (non-occlusion of the palate, heart).

Treatment: - early diagnosis, in the first 2 months and strict diet therapy up to 4 years. In early childhood, foods containing phenylalanine are excluded from the food of sick children, it is found in proteins (should be no more than 21% phenylalanine) - cereals with mare's milk, honey, oil (sunflower), vegetables, sago, rice, jam, corn products , Rye bread. The drug berlofen or others (protein hydrolysate).

- Albinism.

1:5000; 1:25000 (in different regions).

Phenotypically, the picture is already expressed in newborns. There are 6 forms.

Lack of melanin in skin cells (pale)

Hair (white) as gray.

Iris (pale blue eyes to red (translucence of blood vessels), like white rabbits).

BUT.Monogenic inheritance. A trait encoded by one gene is inherited in accordance with the laws of Mendel and is called Mendelian. The totality of all the genes of an organism is called the genotype. The phenotype is the realization of the genotype (in morphological and biochemical respects) under specific environmental conditions.

1. One of the possible structural states of a gene is called an allele. Alleles result from mutations. The potential number of alleles for each gene is virtually unlimited. In diploid organisms, a gene can be represented by only two alleles located on identical regions of homologous chromosomes. The state when homologous chromosomes carry different alleles of the same gene is called heterozygous.

2. The inheritance of monogenic diseases - autosomal or X-linked - can be determined by studying the pedigree. According to the nature of the manifestation of the trait in a heterozygous organism, inheritance is divided into dominant and recessive. With dominant inheritance, the disease manifests itself if at least one of the homologous chromosomes carries a pathological allele, with recessive inheritance, only if both homologous chromosomes carry a pathological allele.

a.Autosomal dominant inheritance. Autosomal dominant diseases include Huntington's disease, achondroplasia (chondrodystrophy), and neurofibromatosis type I (Recklinghausen's disease).

1) Today, about 5,000 monogenic diseases are known. More than half of them are inherited in an autosomal dominant manner.

2) Autosomal dominant diseases are passed down from generation to generation. A sick child must have a sick parent.

3) If one of the parents is sick, the proportion of affected children is approximately 50%. Healthy family members produce healthy children.

4) Autosomal dominant diseases are always inherited, regardless of the sex of the child and the sex of the affected parent. Exceptions occur in cases of new mutations and incomplete penetrance of the gene.

b.Autosomal recessive inheritance. Autosomal recessive diseases include Tay-Sachs disease, cystic fibrosis, and most hereditary metabolic disorders. Autosomal recessive diseases are usually more severe than autosomal dominant ones.

1) If both parents are healthy, but are carriers of the pathological gene, the risk of having a sick child is 25%.

2) In this case, a healthy child in 2/3 of cases turns out to be a heterozygous carrier of a pathological gene.

3) In a child with an autosomal recessive disorder, which is especially rare, the parents are often blood relatives.

4) Males and females are equally affected.

in.X-linked inheritance. Diseases with this type of inheritance include hemophilia A and B, as well as Duchenne myopathy. X-linked dominant inheritance is rare. Diseases inherited by this type include X-linked hypophosphatemic rickets (vitamin D-resistant rickets) and ornithinecarbamoyltransferase deficiency.

1) Men are predominantly ill.

2) With a recessive type of inheritance, all the sons of the patient are healthy. Daughters do not show the disease (heterozygous carriage), but their sons have a 50% risk of the disease.

3) With a dominant type of inheritance, all the sons of the patient are healthy, all the daughters are sick. The risk of disease in children born to the daughters of the patient is 50%, regardless of gender.

G.Gene expression. The quantitative characteristics of the phenotypic manifestation of the gene are as follows.

1) Penetrance- the frequency of manifestation of the gene in the phenotype of its carriers. If in some individuals carrying this gene, it does not manifest itself phenotypically, they speak of incomplete penetrance.

2) expressiveness- the degree of phenotypic manifestation of the same gene in different individuals. Differences of the same trait in blood relatives are explained by different expressivity of the gene that controls this trait. Different expressivity is found in most monogenic diseases.

3) Beginning of clinical manifestations. Not all hereditary diseases appear immediately after birth. For example, Huntington's disease usually manifests itself after 30-40 years. Phenylketonuria does not manifest itself in utero, the first signs of the disease appear only after the child begins to feed.

4) Pleiotropy. Mutation of one gene leads to structural and functional disorders of only one protein. However, if this protein is involved in several physiological processes, then its damage will manifest itself simultaneously in several forms. An example is Marfan syndrome, an autosomal dominant disorder. Mutation of the gene encoding fibrillin protein synthesis is accompanied by numerous clinical manifestations: lens subluxation, ascending aortic aneurysm, mitral valve prolapse, etc.

B.Polygenic inheritance does not obey the laws of Mendel and does not correspond to the classical types of autosomal dominant, autosomal recessive and X-linked inheritance.

1. A trait (disease) is controlled by several genes at once. The manifestation of a trait largely depends on exogenous factors.

2. Polygenic diseases include cleft lip (isolated or with cleft palate), isolated cleft palate, congenital hip dislocation, pyloric stenosis, neural tube defects (anencephaly, vertebral cleft), congenital heart defects.

3. The genetic risk of polygenic diseases depends to a large extent on family predisposition and on the severity of the disease in the parents.

4. The genetic risk decreases significantly as the degree of relatedness decreases.

5. The genetic risk of polygenic diseases is assessed using empirical risk tables. Determining the prognosis is often difficult.

AT. More recently, thanks to advances in molecular genetics, other types of inheritance other than monogenic and polygenic inheritance have been studied.

1. mosaicism- the presence in the body of two or more clones of cells with different chromosome sets. Such cells are formed as a result of chromosomal mutations. Mosaicism is observed in many chromosomal diseases. It is believed that somatic mutations and mosaicism play an important role in the etiology of many types of malignant neoplasms. Mosaicism is also found among germ cells. During oogenesis, 28-30 mitotic divisions occur, and during spermatogenesis, up to several hundred. In this regard, non-somatic mosaicism increases the frequency of manifestation of the mutation and the risk of its transmission to the next generations. Non-somatic mosaicism is observed in osteogenesis imperfecta and some X-linked diseases.

2. Mitochondrial diseases. Mitochondria have their own DNA; mtDNA is located in the matrix of the organelle and is represented by a circular chromosome. It is believed that during cell division, mitochondria are randomly distributed between daughter cells. Mitochondrial diseases are characterized by different expressivity, since the phenotypic manifestation of a pathological gene depends on the ratio of normal and mutant mitochondria. Among mitochondrial diseases, Leber's syndrome is the best studied. The disease is manifested by the rapid development of atrophy of the optic nerves, which leads to blindness. Mitochondrial diseases are inherited only through the maternal line.

3. Genomic imprinting. According to Mendel, the manifestation of a trait should not depend on whether the gene was received from the mother or from the father. There are exceptions to this rule, such as genomic imprinting.

a. The most famous examples of genomic imprinting are Prader-Willi syndrome and Angelman syndrome. Both diseases are caused by a deletion of the long arm of chromosome 15. However, if the child inherits the mutant chromosome from the father, Prader-Willi syndrome develops. Clinical manifestations - obesity, hypogonadism, small hands and feet, mental retardation. If the mutant chromosome is obtained from the mother, Angelman syndrome develops. The clinical manifestations of Angelman's syndrome are a characteristic gait (on legs wide apart with arms bent at the elbows) and characteristic facial features (progenia, macrostomia, wide interdental spaces, divergent strabismus).

b. The reasons for genomic imprinting have not yet been established; it may be associated with a different type of DNA folding in male and female gametes.

4. Uniparental disomy- the transition to the descendant of a pair of homologous chromosomes from one of the parents. Uniparental disomia may be related to the transmission of hemophilia A from father to son. It is not yet clear whether uniparental disomy should be considered a special case of mosaicism or whether it is a separate chromosomal anomaly.

Monogenic inheritance is the inheritance of one trait. It can be dominant and recessive, autosomal or sex-linked, nuclear or mitochondrial. As a result, the following variants of monogenic inheritance are possible:

• automosaic dominant;
• autosomal recessive;
• X-linked dominant;
• X-linked recessive;
• U-linked;
• mitochondrial

Let's consider each of them in more detail.

I. Dominant inheritance Occurs when a trait is encoded by a dominant gene. A gene is considered dominant if the trait encoded by it appears phenotypically in the presence of the opposite gene. Dominant genes are usually denoted by capital letters of the alphabet. Two variants of dominance are genetically possible - homozygous and heterozygous. Homozygous dominance (AA) - when the dominant gene A is on both chromosomes in a pair. An individual with such a genotype will pass on this trait to all its descendants (regardless of the genotype of the second parent). Heterozygous dominance (Aa), when the dominant gene A is on one chromosome, and the recessive gene a is on the other. An individual with such a karyotype will pass on the dominant gene A to half of its descendants, and the recessive gene a to the other half. The phenotype of the offspring will be largely determined by the genes of the second parent.

An example of dominant inheritance is the inheritance of the disease Huntington's chorea. Huntington's chorea is a degenerative disease of nerve cells in the basal structures of the forebrain. It is manifested by progressive forgetfulness, dementia and the appearance of involuntary movements. The disease manifests itself in adulthood (45-60 years). By the way, this is a feature of dominant hereditary diseases: they usually appear only in adulthood, when the patient has already managed to leave offspring. If the disease had begun earlier, the chances of leaving offspring would be small and the disease would gradually disappear due to natural selection. The method of treatment is unknown. The frequency of occurrence is 1 in 20,000.

When studying the relatives of patients, it turned out that the disease can be traced in the families of patients for many generations back and that in each case at least one of the parents also suffered from this disease. Most often, the patient is heterozygous (Aa), so he will pass on the gene for the disease to only half of his children, so that they will pass them on to half of theirs, and so on.

Another example of dominant monogenic inheritance is brachydactyly (short-fingered). An analysis of family forms of manifestation of this trait indicates precisely the dominant form of inheritance (Fig. 3.1).

Figure 3.1.

II. recessive inheritance. In recessive inheritance, the trait is encoded by a recessive gene. A gene is considered recessive if the trait it encodes does not appear in the presence of the opposite gene. Recessive traits are indicated in small letters. There are two variants of the existence of this gene in the genome. Heterozygous (Aa) - in this case, the gene is located on one of the chromosomes, and on the second - the dominant gene, in this case, the phenomenon of carriage occurs, when there is a gene in the cell, and the trait does not appear phenotypically. Homozygous (aa) - in this case, recessive genes are located on both chromosomes. Only in this case the trait will manifest itself phenotypically.

Features of recessive inheritance:

• 1. The trait appears only in recessive homozygous individuals, with the genotype (aa).
• 2. The phenomenon of carriage is possible when the gene (a) is present in the genome, but the trait does not manifest itself phenotypically. This is possible in heterozygous forms, which, along with the recessive gene, have a dominant gene (Aa) on the second chromosome.
• 3. The gene can be passed down through generations, "from grandfathers to grandchildren." A gene can be transmitted through many generations in the form of carriage, and then it will suddenly appear in the next descendant (Fig. 3.2).

Figure 3.2.

An example of a well-studied recessive inheritance is phenylketonuria disease. This disease develops due to an excess in the body of the amino acid - phenylalanine. An excess of phenylalanine leads to the formation of mental retardation. The frequency of occurrence is 1: 10,000. When studying this disease by genealogy, it turned out that patients most often have healthy parents. But such patients are usually found in families in which the parents are blood relatives. In addition, in the families of such patients, the disease can occur in distant blood relatives or distant ancestors.

The parents of such patients are carriers of the phenylketonuria gene. Blood relatives very often turn out to be carriers of recessive genes for a disease. By the way, the frequency of carrying the phenylketonuria gene is not so low: 1 out of 50 people is a carrier of this gene. If close relatives marry and they were carriers of this gene, the likelihood of having a sick child will increase.

An example of recessive inheritance is also the inheritance of the Rh factor. Let's dwell on this moment in more detail.

The inheritance of the Rh factor of the blood also belongs to the Mendeleevian inheritance according to the dominant-recessive type. The gene encoding the Rh factor B (Kb) is dominant, the c1 allelic gene is recessive (Rh-positive people can have the genotype BB or BsS, Rh-negative people have only the genotype<С<С). Человек получает от каждого из родителей по 1 гену - Б или <С, и у него возможны, таким образом, 3 варианта генотипа - ББ, БсС или <С<С. В первых двух случаях (ББ и БсС) анализ крови на резус-фактор даст положительный результат. Только при генотипе <С<С человек будет иметь резус-отрицательную кровь.

Consider some options for combining genes that determine the presence of the Rh factor in parents and a child:

• 1) the father is Rh-positive (homozygote, genotype BB), the mother is Rh-negative (genotype
• 2) Rh-positive father (heterozygote, BcS genotype), Rh-negative mother (genotype
• 3) father and mother are heterozygous for this gene (BS), both are Rh-positive. In this case, it is possible (with a probability of about 25%) the birth of a child with a negative Rh.

Rh-conflict is a humoral immune response of a Rh-negative mother to erythrocyte antigens of a Rh-positive fetus, in which anti-Rh antibodies are formed. These antibodies cause the breakdown of red blood cells (erythrocytes), resulting in hemolytic jaundice in newborns.

An increase in the liver, spleen and heart can be detected in the fetus, anemia is observed, in more severe cases - erythroblastosis, jaundice. In the most severe cases, dropsy of the fetus and edematous syndrome of the newborn develop, which can lead to stillbirth or death of the newborn.

As a rule, during pregnancy, the blood of the fetus does not enter the mother's bloodstream. Therefore, during the first pregnancy, the mother does not produce antibodies to antigen B, and the child remains healthy. However, during childbirth, most often there is a mixture of the blood of the mother and child, which is why the mother becomes susceptible to the Rh antigen and forms antibodies against it. The developed immune memory during the next pregnancy leads to a new and increased formation of antibodies to antigen B. The latter are able to penetrate into the child's bloodstream and bind to the child's Rh-positive erythrocytes. The antibody-laden erythrocytes are destroyed prematurely in the fetal spleen. Hemolytic anemia sets in.

About 15% of the European population are Rh negative (c#, always homozygous), 50% are heterozygous (Be) and 35% are homozygous (BB) positive. It follows that in about every tenth pregnancy, the mother is Rh-negative and the fetus is Rh-positive.

Options for the occurrence of Rhesus conflict:

• If the mother is Rh negative and the father is homozygous Rh positive, then either fetus will be heterozygous Rh positive.
• If the mother is Rh negative and the father is heterozygous Rh positive, then the fetus will be heterozygous Rh positive with a 50% chance and Rh negative with a 50% chance.

In African and Asian populations, as well as among the Indians of North America, the negative Rh factor occurs with a frequency of about 1% or less, so the Rh conflict occurs with extremely low frequency.

In the vast majority of cases, Rh conflict can be prevented by intramuscular administration of special anti-B antibodies (commercial name - MuOAM) to an Rh-negative mother during pregnancy or within 72 hours after childbirth or any other event that can lead to sensitization of the mother. With the introduction of MuOAM, the erythrocytes of the Rh-positive fetus that have entered the mother's body are destroyed before the mother's immune system has time to respond to them. The antibodies themselves, introduced during passive immunization, are usually destroyed within 46 weeks.

Prior to the introduction into practice of the prevention of Rh conflict by the introduction of anti-Rh antibodies to women in certain cases, 1% of all pregnancies proceeded with manifestations of anti-Rh sensitization, that is, the appearance of anti-Rh antibodies in the mother's blood. Now, thanks to timely prevention, Rh sensitization occurs in 10 cases per 10,000 births.

III. incomplete dominance- in this case, the heterozygote occupies an intermediate position between the dominant and recessive homozygote. For example, hypercholesterolemia. The homozygote has a normal number of receptors in the liver cells for the absorption of cholesterol, the heterozygote has a reduced number (individuals die at adolescence), and the recessive homozygote does not have it at all (they die at birth). Another example is straight (recessive), curly (dominant), wavy hair.

IV. Codominance- in the phenotype of a heterozygote, two signs are manifested. An example is the inheritance of the fourth blood group according to the ABO system.

At the beginning of the last century, scientists proved the existence of 4 blood groups. The Austrian scientist Karl Landsteiner, mixing the blood serum of some people with erythrocytes taken from the blood of others, found that with some combinations of erythrocytes and sera, "gluing" occurs - erythrocytes stick together and form clots, while others do not. Studying the structure of red blood cells, Landsteiner discovered special substances. He divided them into two categories - A and B, highlighting the third, where he took the cells in which they were not. Later, his students - A. von Decastello and A. Sturli - discovered erythrocytes containing both A- and B-type markers at the same time.

As a result of research, a system of division into blood groups arose, which was called ABO. We are still using this system.

• I (0) - blood type is characterized by the absence of antigens A and B;
• II (A) - is established in the presence of antigen A;
• III (B) - antigen B;
• IV(AB) - antigens A and B.

Inheritance of blood groups of the ABO system in humans has some features. The formation of I, II and III blood groups occurs according to this type of interaction of allelic genes as dominance. Genotypes containing the A allele in the homozygous state or in combination with the O allele determine the formation of the second (A) blood type in a person - AA or AO. The same principle underlies the formation of the third (B) blood type - BB or BO. The formation of the fourth (AB) blood group follows the path of codominance. Alleles A and B, which separately form the second and third blood groups, respectively, determine the AB (fourth) blood group in the heterozygous state (Table 3.1).

Table 3.1. Inheritance of the blood type of a child depending on the blood type of the father and mother

The discovery of blood groups made it possible to avoid losses during transfusions caused by the incompatibility of the blood of patients and donors. For the first time successful transfusions were carried out before. So, in the history of medicine of the XIX century, a successful blood transfusion to a woman in labor is described. But until the end of the 20th century, such manipulations were rare and carried out only in emergency cases, sometimes doing more harm than good. However, thanks to the discoveries of Austrian scientists, blood transfusions have become a much safer procedure, which has saved many lives.

v. Sex-linked inheritance. Genes can be located on the sex chromosomes, in which case they are said to be sex-linked. Sex-linked inheritance has some important features. The fact is that the Y chromosome carries much fewer genes than the X chromosome. This circumstance leads to the fact that for many X-chromosome genes there are no corresponding alleles on the Y-chromosome. As a result, if a male has a recessive allele on the X chromosome, then it will appear in the phenotype. For example, there is a hereditary form of hemophilia - a disease associated with a violation of normal blood clotting. With these disorders, the patient has prolonged bleeding even with minor damage to the blood vessels.

There are two forms of hemophilia, A and B, and both are determined by recessive genes located on the X chromosome. Theoretically, hemophilia is also possible in a woman, but this probability is very low, since this requires the marriage of a hemophilic patient with a woman carrier of the hemophilia gene (and even in this case, the probability of having a sick girl will be only 0.25). Due to the low frequency of occurrence of the hemophilia gene and the fact that patients with hemophilia often die before marriageable age, such cases are practically not observed. So, if a recessive gene is linked to the X chromosome, then it is much more often manifested in the phenotype in men than in women.

The most famous carrier of hemophilia in history was Queen Victoria (Fig. 3.3); apparently, this mutation occurred in her de novo genotype, since no hemophilia was registered in the families of her parents. One of Victoria's sons (Leopold, Duke of Albany) suffered from hemophilia, as well as a number of grandchildren and great-grandchildren (born from daughters or granddaughters), including the Russian Tsarevich Alexei Nikolayevich. For this reason, this disease has received such names: "Victorian disease" and "royal disease". Also, sometimes in royal families, marriages between close relatives were allowed to preserve the title, which is why the frequency of hemophilia was higher.

Other sex-linked genes include genes associated with color blindness and ichthyosis.

There are also dominant genes linked to the X chromosome. Thus, there is a hereditary form of rickets that cannot be treated with vitamin D. A variety of diseases transmitted by this mode of inheritance are given in Appendix B.

If the genes are located on the Y chromosome, then they should only be passed from fathers to sons. As an example of such a gene, the gene that causes the appearance of a tuft of hair on the outer edge of the ear is usually mentioned. Hypertrichosis of the auricles is often found in residents

Figure 3.3.

India, Sri Lanka, Israel. Recently, a marker gene has been reported on the Y chromosome that is linked to the gene responsible for male hypertension. If a marker gene is found on the chromosome, then in men the systolic pressure is higher by an average of 10 mm Hg.

Sex-linked inheritance must be distinguished from sex-limited inheritance. In the case of sex-limited inheritance, the genes that determine the development of a trait are located in autosomes, but their expression in the phenotype is strongly influenced by sex. For example, a hereditary predisposition to early baldness is associated with a gene localized in the autosome. However, its activity is highly dependent on the level of testosterone (male sex hormone). In this regard, in men, this gene behaves as a dominant one, and in women - as a recessive one.

VI. Mitochondrial inheritance.

Mitochondrial DNA is a single ring-shaped chromosome. Patterns of mitochondrial inheritance:

• Both men and women get sick.
• A sick woman transmits the trait to all children, regardless of gender.
• A sick man does not pass on the trait to offspring.
• There is no hidden carrier.