According to the rho-to-verbal definition depicted in the figure and the explanation of the ha-rak-ter after the recognition ka (dominant or recessive, linked or not with the floor), you de-len-no-go black color. Determine the genes according to the volumes indicated on the diagram by the numbers 3, 4, 8, 11 and explain the formulas -mi-ro-va-nie of their genes.

Clarification.

The sign, highlighted in black color, is re-cessive, linked with X-chro-mo-my: X a,

because there is a “jump” through the process. The husband has a sign (8), he has a daughter without a sign (11), and grandchildren - one with a sign (12), the second without (13), then there is from the father (10) they receive Y - chro-mo-so-mu, and from ma-te-ri (11) one X a, the other X A.

Gene types of people, indicated on the diagram by numbers 3, 4, 8, 11:

3 - woman-schi-na-no-si-tel - X A X a

4 - man without a sign - X A Y

8 - man with sign - X and Y

11 - woman-schi-na-no-si-tel - X A X a

Source: Unified State Examination in Biology 05/30/2013. Main wave. Far East. Option 4.

Elena Ivanova 11.04.2016 12:36

Please explain why the genotype of the first woman (without number) is HAHA, because she could also be a carrier?

Natalia Evgenievna Bashtannik

Maybe. This is a "guess" based on offspring. Because it is not important for us to solve, we can write both options on the diagram, or we can do it like this: X A X -

Nikita Kaminsky 11.06.2016 23:28

Why can’t there just be a recessive gene that is not sex-linked?

Then the parents in the first generation are homozygous (father aa, mother AA), children 1, 2, 3 are heterozygous Aa, men 4 and 5 are also carriers of Aa, children 7 and 8 in the second generation have the trait, and 6 is a carrier. In the third generation, Father and Mother are again homozygous, daughter 11 and her husband 10 are heterozygous, and they have two sons, one with the trait, the other without, possibly a carrier.

Natalia Evgenievna Bashtannik

maybe, but there is a greater probability that there is clutch, less “?”, and based on the rules for solving these problems.

A mother and father who are phenotypically without the trait give birth to a SON with the trait; it can be assumed that the trait is linked to the X chromosome.

Tobias Rosen 09.05.2017 18:26

The solution is not entirely correct.

This diagram contains an alternative solution - containing fewer assumptions:

In fact, all we can say based on the problem data is a list of what we can exclude. We can exclude dominant linkage to X, we can exclude linkage to Y, we can exclude AA x aa in the cross itself, we can exclude that the trait is provided by a dominant allele.

We cannot exclude recessive linkage with X and we cannot exclude autosomal recessive inheritance - there is not enough data for this and an insufficient number of descendants and crosses.

To ignore the small number of crossings and descendants is to assume that the law of large numbers must also apply to small numbers. Which is complete nonsense. Shouldn't. On the contrary: the statistical fact is that the smaller the sample, the greater the expected deviation from the “correct split”.

Natalia Evgenievna Bashtannik

If a problem can be solved in two ways, then it is better to write both. If the criteria include a decision that the trait is linked to the X chromosome: X a, then they may not give a full point.

The law of cleavage also explains the inheritance of phenylketonuria

(PKU) - a disease that develops as a result of an excess of an important

amino acids - phenylalanine (Phe) in the human body. Excess

phenylalanine leads to the development of mental retardation. Frequency

The incidence of PKU is relatively low (approximately 1 in 10,000 new

born), however, about 1% of mentally retarded individuals

mov suffer from PKU, thus making up a relatively more

largest group of patients whose mental retardation is explained

homogeneous genetic mechanism.

As in the case of CG, researchers studied the frequency of occurrence

PKU in families of probands. It turned out that patients suffering from PKU

usually have healthy parents. In addition, it was noticed that

PKU is more common in families in which parents are blood

other relatives. Example of a family of a proband suffering from PKU

rice. 2.3: sick

phenotypic

healthy

parents-

relatives

suffers

transmitted

inheritance,

sick

contains

received

parents.

Rice. 2.3. An example of a family pedigree, in

suffer

transmitted

illness,

are

inheritance (the proband’s aunt suffers

allele holders PKU and can

this disease).

hand over

A double line between spouses means

rice. 2.4 shown

consanguineous

Rest

formation of PKU alleles from two

the designations are the same as in Fig. 2.1.

phenotypically

normal

parents.

leu has one PKU allele and one normal allele. Probability

that every child can inherit the PKU allele from every

of the parents is 50%. The probability that the child is

follows the PKU allele from both parents at the same time, is 25%

(0.5 x 0.5 = 0.25; probabilities are multiplied as events are inherited

the alleles from each parent are independent of each other).

The PKU gene and its structural variants found in different

populations have been well studied. The knowledge at our disposal is

Rice. 2.4. Crossing scheme: allelic mechanism of inheritance of PKU.

F - dominant allele (“healthy”); [f] - recessive allele causing

development of the disease. FF, FF - phenotypically normal children (75% of them); only

about 25% have a normal genotype (FF); another 50% are phenotypically healthy,

but are carriers of the PKU (FF) allele. The remaining 25% of descendants are sick

([f][f]).

marriage, allow for timely prenatal diagnosis

tics in order to determine whether the developing embryo has inherited

breathe two copies of the PKU allele from both parents (the fact of such inheritance

vaniya sharply increases the likelihood of disease). In some countries,

for example in Italy, where the incidence of PKU is quite high

juice, such diagnostics are carried out without fail for each

milk a pregnant woman.

As already noted, PKU is more common among those who enter

marries with blood relatives. Despite the fact that the meeting

The incidence of PKU is relatively low, approximately 1 in 50 people is

carrier of the PKU allele. The probability that one carrier of the allele

PKU will marry another carrier of such an allele, is

approximately 2%. However, when marrying between consanguineous

relatives (i.e. if the spouses belong to the same pedigree, in

which PKU allele is inherited) the probability that

both spouses will be carriers of the PKU allele and at the same time transfer

will give two alleles to the unborn child, it will become significantly higher than 2%.

Anomalies leading to increased levels phenylalanine blood, most often phenylalanine hydroxylase (PAH) deficiency or phenylketonuria (PKU), illustrate almost all the principles of biochemical genetics related to enzyme defects. All genetic abnormalities of phenylalanine metabolism are the result of loss-of-function mutations in the gene encoding PAH or in the genes required for the synthesis or restoration of its cofactor, BH4.

Classic phenylketonuria(PKU) is rightfully considered an exemplary representative of inborn errors of metabolism. It is an autosomal recessive phenylalanine breakdown disorder caused by mutations in the gene encoding PAH, the enzyme that converts phenylalanine to tyrosine. Fehling's discovery of phenylketonuria (PKU) in 1934 was the first to demonstrate a genetic defect as a cause of mental retardation.

Due to inability to recycle phenylalanine patients with phenylketonuria (PKU) accumulate this amino acid in body fluids. Hyperphenylalaninemia damages the developing central nervous system in early childhood and interferes with the functioning of the mature brain. A small portion of phenylalanine is metabolized via alternative pathways, producing increased amounts of phenylpyruvic acid (the ketoacid for which the disease is named) and other metabolites excreted in the urine.

It's interesting that although enzyme defect has been known for decades, the exact pathogenetic mechanism of how increased phenylalanine damages the brain is still unknown. Importantly, the development of neurological damage caused by the metabolic block in classical PKU can largely be prevented by dietary changes that prevent phenylalanine accumulation. Treatment of phenylketonuria (PKU) has become a model for the treatment of many metabolic diseases, the outcomes of which may be improved by preventing the accumulation of enzyme substrate and its derivatives.

Newborn screening for phenylketonuria (PKU)

Population is widely used screening newborns for phenylketonuria (PKU). Phenylketonuria (PKU) is an example of genetic diseases for which mass neonatal screening is warranted; the disease is relatively common in a number of populations (up to 1 in 2900 live newborns). Treatment started early in life is very effective; without treatment, severe mental retardation inevitably develops. Screening tests are performed a few days after birth.

A drop of blood obtained from a puncture heels, applied to filter paper, dried and sent to a centralized laboratory to assess blood phenylalanine levels and the phenylalanine/tyrosine ratio. In the past, samples were collected before the baby was discharged from the hospital. The trend towards early discharge of mother and newborn after delivery has changed this practice. The test should preferably not be done before 24 hours of age, since phenylalanine levels in phenylketonuria (PKU) increase only after birth. Positive test results should be quickly confirmed, since delaying the initiation of treatment more than 4 weeks after delivery does not avoid the impact on the intellectual status of patients with phenylketonuria (PKU).

Various forms of phenylketonuria and hyperphenylalaninemia

Since (PKU) is associated with a severe deficiency of phenylalanine hydroxylase (PAH) activity (less than 1% compared with controls), mutant PAH with residual activity causes less severe phenotypic manifestations, so-called hyperphenylalaninemia and atypical phenylketonuria (PKU).

Hyperphenylalaninemia phenylketonuria (PKU), other than phenylketonuria (PKU), is diagnosed if the plasma phenylalanine concentration is below 1 mmol/L in the presence of a normal diet. This degree of hyperphenylalaninemia is only 10 times higher than normal and significantly lower than the concentrations found in classical phenylketonuria (PKU) (>1 mmol/L). A moderate increase in phenylalanine in hyperphenylalaninemia is not likely to harm brain function and may even be beneficial if the increase is small (<0,4 ммоль), такие дети обращают на себя внимание врачей только благодаря скринингу. Их нормальный фенотип оказался наилучшим показателем безопасного уровня фенилаланина плазмы, который не следует превышать при лечении пациентов с классической фенилкетонурии (ФКУ).

Atypical(PKU) - a category that includes patients with phenylalanine levels intermediate between classic PKU and hyperphenylalaninemia; such patients require some restriction of phenylalanine in the diet, but less than for patients with classic phenylketonuria (PKU). The complex of these three clinical phenotypes with mutations in the PAH gene is an example of clinical heterogeneity.

Hyperphenylalaninemia: allelic and locus heterogeneity in phenylketonuria (PKU)

Molecular defects in the phenylalanine hydroxylase gene. Patients with hyperphenylalaninemia, including classical phenylketonuria (PKU), atypical phenylketonuria (PKU), and benign hyperphenylalaninemia, display a striking degree of allelic heterogeneity at the phenylalanine hydroxylase (PAH) locus (over 400 different mutations worldwide).

The vast majority of alleles phenylalanine hydroxylase(PAH) are fairly rare mutations that disrupt the enzymatic properties of phenylalanine hydroxylase (PAH) and lead to hyperphenylalaninemia, although benign polymorphisms or less common benign variants have also been found.

In populations European descent about two-thirds of known mutant chromosomes are represented by six mutations. Six other mutations are responsible for just over 80% of phenylalanine hydroxylase (PAH) mutations in Asian populations. Other pathogenic mutations are less common. To make this information widely available, an international consortium has developed a database of mutations in the phenylalanine hydroxylase (PAH) gene.

In all populations There is marked genetic heterogeneity of phenylalanine hydroxylase (PAH). Due to the high degree of allelic heterogeneity at the locus, the majority of patients with phenylketonuria (PKU) in many populations are compound heterozygotes (i.e., they have two different pathogenic alleles), which is fully consistent with the observed enzymatic and phenotypic heterogeneity in phenylalanine hydroxylase (PAH) disorders.

At first it seemed that knowledge of the genotype phenylalanine hydroxylase(FA) reliably predicts phenotype details; this expectation was not fully justified, although a certain correlation was found between the PAH genotype and the biochemical phenotype.

In general terms, mutations that completely suppress or dramatically reduce activity phenylalanine hydroxylase(PAH) cause classical phenylketonuria (PKU), while mutations resulting in sufficiently large residual enzyme activity are associated with mild phenotypes.

However, some mutations phenylalanine hydroxylase(FA) in homozygous patients determine the entire spectrum of phenotypes, from classical phenylketonuria (PKU) to benign hyperphenylalaninemia.

Thus, it became obvious that in the formation phenotype observed in a specific genotype, other unidentified biological factors are involved, undoubtedly including modifier genes. This observation, now recognized as a common characteristic of many monogenic diseases, indicates that even monogenic diseases like phenylketonuria (PKU) are not genetically simple diseases.

Defects in tetrahydrobiopterin metabolism in phenylketonuria (PKU)

Initially it was believed that all children with hereditary hyperphenylalaninemia have primary phenylalanine hydroxylase (PAH) deficiency. It is now clear that approximately 1-3% of patients have a normal PAH gene and their hyperphenylalaninemia is the result of a genetic defect in one of several other genes involved in the synthesis or regeneration of the PAH cofactor, BH4. The association of one phenotype, such as hyperphenylalaninemia, with mutations in different genes is an example of locus heterogeneity.

As shown by mutations in protein-coding genes phenylalanine hydroxylase(PAH) and the metabolism of its cofactor biopterin, proteins encoded by genes exhibiting locus heterogeneity are usually part of the same chain of biochemical reactions. Patients with BH4 deficiency were first identified because, despite successfully maintaining low phenylalanine concentrations in the diet, they developed early onset profound neurological problems.

The poor results are partly explained the need for cofactor BH4 for the activity of two other enzymes, tyrosine hydroxylase and tryptophan hydroxylase. Both of these hydroxylases are critical for the synthesis of monoamine neurotransmitters such as dehydroxyphenylalanine, norepinephrine, epinephrine and serotonin. Patients with BH4 deficiency have an impairment in either its biosynthesis from GTP or the regeneration of BH4. Like classic phenylketonuria (PKU), the disorder is inherited in an autosomal recessive manner.

It is important to distinguish patients with defects in BH4 metabolism from patients with mutations in phenylalanine hydroxylase(FA), since their treatment differs markedly. First, since the protein structure of phenylalanine hydroxylase (PAH) is normal in patients with BH4 disorders, its activity may be restored if these patients are given large doses of BH4, which leads to a decrease in plasma phenylalanine levels. Therefore, the degree of phenylalanine restriction in the diet of patients with defects in BH4 metabolism can be significantly reduced, and some patients can be switched to a normal diet (i.e., without phenylalanine restriction).

Secondly, you must also try normalize neurotransmitter levels in the brain of these patients by administering tyrosine hydroxylase and tryptophan hydroxylase products: L-dopa and 5-hydroxytryptophan, respectively. For these reasons, all newborns with hyperphenylalaninemia should be evaluated for abnormalities in BH4 metabolism.

Reaction to tetrahydrobiopterin with mutations in the PAH gene in phenylketonuria (PKU)

In most patients with mutations in the gene phenylalanine hydroxylase(PAH), and not in the metabolism of BH4, there was a clear decrease in the level of phenylalanine in the blood during oral administration of large doses of the cofactor phenylalanine hydroxylase (PAH) BH4. Patients with significant residual phenylalanine hydroxylase (PAH) activity (i.e., patients with atypical phenylketonuria (PKU) and hyperphenylalaninemia) respond best to such treatment, but a small number of patients even with classical phenylketonuria (PKU) also respond to this treatment. At the same time, the presence of residual PAH activity does not guarantee an effect on plasma phenylalanine levels when BH4 is prescribed.

It is most likely that the degree of response reactions on BH4 depends on the specific properties of each phenylalanine hydroxylase (PAH) mutant protein, reflecting the underlying allelic heterogeneity of PAH mutations. It has been shown that the introduction of BH4 into the diet has a therapeutic effect through several mechanisms caused by an increase in the amount of normal cofactor that comes into contact with the mutant one.

These mechanisms include stabilization of the mutant enzyme, protection of the enzyme from cell degradation, increased supply of a cofactor to the enzyme that has low affinity for BH4, and other beneficial effects in the kinetic and catalytic properties of the enzyme. Providing increased amounts of cofactor is a common strategy used in the treatment of many inborn errors of metabolism.

Nowadays a huge number of hereditary diseases are diagnosed, which a child receives from his father or mother. The environmental situation, unhealthy diet, unhealthy lifestyle - all this leads to cells mutating and genetic information undergoing significant changes. This is where a huge number of hereditary diseases arise. One of them is phenylketonuria. Not many people know what kind of disease this is, so we’ll try to figure it out.

The essence of the concept

Phenylketonuria is a hereditary disease and is associated with serious disturbances in protein metabolism. This, in turn, leads to damage to the nervous system.

The inability of just one enzyme, phenylalanine, results in serious health problems such as phenylketonuria. What is this condition when a large amount of toxic substances accumulate in the body? All toxic compounds are stored in biological fluids, so it is usually not difficult for doctors to diagnose the disease.

If measures are not taken in time, then serious damage to the nervous system can be observed, and this already leads to disturbances in the functioning of the entire body.

Thus, without appropriate treatment, the patient’s normal life is out of the question.

Causes of the disease

All proteins consist of amino acids, of which there are only 20, but among them there are those that are synthesized in the human body. Some must come only from outside. Phenylalanine is also an essential amino acid. In a healthy person, when it gets inside, it turns into tyrosine. This is a completely different amino acid, and only a few percent of the substance is sent to the kidneys and there it is converted into phenylketone, a rather toxic substance.

If a person lacks the enzyme phenylalanine-4-hydroxylase or the one that converts phenylalanine into another substance does not work correctly, then phenylketonuria develops. Every doctor will tell you that this is a fairly serious symptom, so urgent measures must be taken.

A gene mutation on chromosome 12 can lead to the absence of the required enzyme.

Types of phenylketonuria

If we consider the forms of the disease, they can be as follows:

1. Classic. In this case, we observe that phenylketonuria is a recessive trait. This form occurs in one child out of ten thousand healthy children. If measures are not taken, it is unlikely that a sick person will live to be thirty years old.
2. Variable form. It is not inherited, but is caused by a mutation in genes. Its course is more severe, and early mortality is predicted with a probability of almost 100%.

In addition to forms, doctors also distinguish between types of phenylketonuria:

1. The first type is characterized by a deficiency of the enzyme phenylalanine 4-hydroxylase, which is responsible for the conversion of phenylalanine. In 98% of cases it is he who is diagnosed.
2. Second. It is distinguished by a low content of the enzyme dihydropteridine reductase. Such patients experience seizures and mental retardation. Despite its rare occurrence, mortality from this type can occur at 2-3 years of age.
3. The third type is characterized by a deficiency of tetrahydrobiopterin. As a result, there is a decrease in brain volume, which leads to mental retardation.

Symptoms of the disease

Immediately after the birth of a child, it is difficult to diagnose the disease by its appearance or behavior. The main signs will begin to appear a little later. However, even in the maternity hospital, doctors are quite capable of diagnosing “phenylketonuria”. The symptoms of this disease are as follows:

• frequent vomiting for no apparent reason;
• tearfulness;
• lethargy;
• rashes may appear all over the body;
• urine has a “mouse” smell;
• the child lags behind his peers in physical and mental development.

It is enough to take a blood and urine test to make the correct diagnosis.

Signs of phenylketonuria

Gradually, in the absence of proper treatment, the patient will experience the following symptoms:

1. Convulsive syndrome. It begins to appear in early childhood and persists into adulthood.
2. Lack of pigment in the skin and hair. Therefore, such patients are usually fair-haired and have white skin.
3. Inflammatory processes that, unknowingly, can be mistaken for an allergic reaction.

The first signs of mental retardation can be noticed in a child as early as six months of age. He stops remembering new information and seems completely unable to learn. Parents should also be wary when the baby forgets what he has learned a long time ago, for example, how to hold a spoon, sit, or play with a rattle. The alarm should also be sounded if the child ceases to recognize parents and loved ones, and if excessive tearfulness does not go away with age.

These are the signs that phenylketonuria has; the symptoms of the disease must be considered only as a whole, because individually they may well occur in healthy children.

Detection of the disease

There are two ways to make a correct diagnosis:

1. Carry out a blood and urine test for the newborn while still in the maternity hospital. this is usually done in all cases.
2. Determine the presence of phenylketones in the biological fluids of an adult if the corresponding signs are present.

From children in the maternity hospital, blood is taken on the 4-5th day and the phenylalanine content is determined. If one is detected, the child and mother are sent for consultation with a geneticist.

Before discharge, be sure to ask whether your child has been tested for phenylketonuria. Despite the low incidence of this disease, the best solution would still be to play it safe.

Inheritance

Since phenylketonuria is inherited as a recessive trait, for it to manifest itself in a child, both parents must have the defective gene. This is why consanguineous marriages are prohibited in many countries.

If we consider the case of the birth of children in an ordinary family, then carriers of such a mutation may have:

1. There is a 25% chance that the baby will be born sick.
2. In 50% of cases, the baby is healthy, but is a carrier of a defective gene.
3. A quarter of the offspring will be absolutely normal.

This scheme does not give a complete picture of the birth rate of sick children. It only reflects probability, so each married couple may have a different percentage of defective genes, and, unfortunately, it is impossible to predict the outcome. Now there are consultations in which geneticists help couples predict the birth of a sick child, telling them how phenylketonuria is inherited.

Treatment

As soon as a child is diagnosed with this, measures must be taken immediately. First of all, you need to exclude protein foods from your diet. It is necessary to observe such a strict restriction until the age of 10-12, or better yet, for the rest of your life.

Since babies are breastfed and usually do not consume anything other than mother’s milk, doctors recommend that the mother reduce her child’s consumption. This can be done only under one condition: give the baby expressed milk in order to accurately see its quantity.

Supplemental feeding will have to be done with mixtures that do not contain phenylalanine. When the time comes to introduce complementary foods, you need to choose purees and cereals without adding milk. You can give juices and vegetable purees.

The doctor must also prescribe medication. Usually these are drugs that contain phosphorus, because it is not for nothing that this element is considered “the element of life and thought,” since it plays an important role in the functioning of our brain. Medicines containing iron and calcium are also prescribed; they help improve blood circulation and brain activity.

Treatment should not be limited to the complete exclusion of phenylalanine, since in this case there may be a deficiency of it, which leads to loss of strength and loss of appetite. In addition, diarrhea begins and skin rashes occur.

To find out how effective the treatment is, you should periodically have your blood and urine tested for phenylalanine.

Disease in children

It is in childhood that the body develops at a pace that will not occur in other periods of life. Therefore, at this time it is important to take all measures for the normal development of the nervous system. Children with phenylketonuria need not only medication and special nutrition, but also special treatment.

First of all, this is constant attention so that the slightest deviations in development do not escape the watchful eye of the mother. The following treatment methods can be used:

• physical therapy, which will help the child develop normally physically;
• massage;
• psychological assistance;
• correctional pedagogy.

Parents must understand that the life and health of their child will largely depend on themselves. What kind of environment they can create around a sick baby, how accurately doctors’ recommendations on nutrition will be followed, whether loved ones will react to deviations in mental and physical development - all these points are very important.

Traditional medicine to get rid of illness

Traditional recipes are used in the treatment of many diseases. Phenylketonuria is no exception. That this disease will require a revision of your entire lifestyle is a fact. The child must grow up and have an understanding of his illness. Parents are obliged to explain to him in an accessible form, when he is able to understand the information received, how serious his situation is. Diet and treatment must be followed throughout life. Only in this case can a full existence be guaranteed.

Traditional healers for phenylketonuria recommend consuming more plant proteins. There is much less phenylalanine in such foods than in animal products. It is not prohibited to include fruits and vegetables in the diet. They contain a lot of vitamins and microelements, which are essential for the normal functioning of the nervous system. That is, traditional medicine is of the opinion that it is advisable for such a patient to follow a vegetarian diet.

Nutrition for phenylketonuria

Phenylalanine is found in almost all foods that contain protein. You should try to exclude them from your diet, and first of all this applies to milk and meat.

If a diagnosis of phenylketonuria is made, nutrition should be reviewed first. All products can be divided into several groups:

1. Always allowed for use: potatoes, sugar, tea, vegetable oils.
2. Can be consumed in small quantities: rice, honey, butter, baked goods, vegetables and fruits.

It is completely necessary to exclude from your menu: eggs, fish and meat, milk, pasta, legumes, nuts, corn, dairy products, chocolate.

Considering the fact that phenylalanine is converted into tyrosine in a healthy body, patients with phenylketonuria should include foods containing it in sufficient quantities in their diet. Such foods include mushrooms and plant components.

Future prognosis for phenylketonuria

Obviously, this disease requires immediate action, otherwise a person’s life will be short.

The disease “phenylketonuria” requires careful attention to the patient. If you follow a strict diet and follow all doctor’s recommendations, the child will be able to grow and develop normally. The prognosis will also depend on what diseases accompany the genetic disease and whether there are other pathologies.

Gradually, with age, the body can to some extent adapt to the increased content of phenylalanine, so you can sometimes allow relaxations in the diet. The main thing is not to get carried away by these weaknesses and stop in time and switch to proper nutrition.

If a woman suffers from this disease, then she will have to be even stricter in following all recommendations, because she is an expectant mother. Only in this case does she have the opportunity to give birth to a healthy child.

This is especially true considering that there are practically no methods for preventing this disease.

RECESSIVE INHERITANCE: PHENYLKETONURIA

The law of cleavage also explains the inheritance of phenylketonuria

(PKU) - a disease that develops as a result of an excess of an important

amino acids - phenylalanine (Phe) in the human body. Excess

phenylalanine leads to the development of mental retardation. Frequency

The incidence of PKU is relatively low (approximately 1 in 10,000 new

born), however, about 1% of mentally retarded individuals

mov suffer from PKU, thus making up a relatively more

largest group of patients whose mental retardation is explained

homogeneous genetic mechanism.

As in the case of CG, researchers studied the frequency of occurrence

PKU in families of probands. It turned out that patients suffering from PKU

usually have healthy parents. In addition, it was noticed that

PKU is more common in families in which parents are blood

other relatives. Example of a family of a proband suffering from PKU

shown in Fig. 2.3: sick

the child was born with a phenotypic

healthy parents -

blood relatives (two-

cousins), but

the child's father's sister is suffering

PKU is transmitted recessively

strong type of inheritance,

those. the patient's genotype contains

two PKU alleles obtained

from both parents. Descendants,

who have only one

such an allele do not suffer from

disease, but are But-

allele holders PKU and can

pass it on to your children. On

rice. 2.4 shows the paths of inheritance

formation of PKU alleles from two

phenotypically normal

parents. Each of the parents

leu has one PKU allele and one normal allele. Probability

that every child can inherit the PKU allele from every

of the parents is 50%. The probability that the child is

follows the PKU allele from both parents at the same time, is 25%

(0.5 x 0.5 = 0.25; probabilities are multiplied as events are inherited

the alleles from each parent are independent of each other).

The PKU gene and its structural variants found in different

populations have been well studied. The knowledge at our disposal is

Rice. 2.4. Crossing scheme: allelic mechanism of inheritance of PKU.

F - dominant allele (“healthy”); [f] - recessive allele causing

development of the disease. FF, FF - phenotypically normal children (75% of them); only

about 25% have a normal genotype (FF); another 50% are phenotypically healthy,

but are carriers of the PKU (FF) allele. The remaining 25% of descendants are sick

([f][f]).

Rice. 2.3. An example of a family pedigree, in

which PKU is transmitted via

inheritance (the proband’s aunt suffers

this disease).

A double line between spouses means

consanguineous marriage. Rest

the designations are the same as in Fig. 2.1.

marriage, allow for timely prenatal diagnosis

tics in order to determine whether the developing embryo has inherited

breathe two copies of the PKU allele from both parents (the fact of such inheritance

vaniya sharply increases the likelihood of disease). In some countries,

for example in Italy, where the incidence of PKU is quite high

juice, such diagnostics are carried out without fail for each

milk a pregnant woman.

As already noted, PKU is more common among those who enter

marries with blood relatives. Despite the fact that the meeting

The incidence of PKU is relatively low, approximately 1 in 50 people is

carrier of the PKU allele. The probability that one carrier of the allele

PKU will marry another carrier of such an allele, is

approximately 2%. However, when marrying between consanguineous

relatives (i.e. if the spouses belong to the same pedigree, in

which PKU allele is inherited) the probability that

both spouses will be carriers of the PKU allele and at the same time transfer

will give two alleles to the unborn child, it will become significantly higher than 2%.

4. LAW OF INDEPENDENT COMBINATION

(INHERITANCE) OF CHARACTERISTICS

(MENDEL'S THIRD LAW)

This law says that every pair of alternative

signs behave in a number of generations independently of each other, in re-

As a result, among the descendants of the first generation (i.e. in the generation F 2)

in a certain ratio, individuals appear with new ones (compared

differences with parental combinations of traits. For example, in case

tea of ​​complete dominance when crossing the original forms, di-

distinguished by two characteristics in the next generation (F2 ) revealing

There are individuals with four phenotypes in the ratio 9:3:3:1. At

In this case, two phenotypes have “parental” combinations of traits, and

the remaining two are new. This law is based on independent

maintenance (splitting) of several pairs of homologous chromosomes. So,

during dihybrid crossing, this leads to the formation of hybrid

first generation (F1) 4 types of gametes (AB, Av, aV, av), and after

the formation of zygotes - to a natural splitting according to the genotype and,

accordingly, according to the phenotype in the next generation (F2 ).

Paradoxically, in modern science great attention is paid to

depends not so much on Mendel’s third law itself in its original

formulation, how many exceptions are there from it. Independent Law

combination is not observed if the genes controlled

the main characteristics being studied, linked, those. are located next door

with each other on the same chromosome and are transmitted along

inheritance as a connected pair of elements, and not as individual elements

You. Mendel's scientific intuition told him what signs should

should be chosen for his dihybrid experiments, he chose

ral unlinked signs. If he had chosen the signs at random,

controlled by linked genes, then its results would be

different, since linked traits are not inherited independently

from each other.

What is the importance of exceptions to Mendel’s law of independence?

dependent combination? The fact is that it is these exceptions

make it possible to determine the chromosomal coordinates of genes (the so-called

my locus*).

In cases where the heritability of a certain pair of genes is not subordinate

follows Mendel's third law, most likely these genes are inherited

are located together and, therefore, are located on the chromosome directly

close proximity to each other. Dependent inheritance of genes called

varies clutch, and the statistical method used for analysis

such inheritance is called clutch method. However, when op-

under certain conditions, patterns of inheritance of linked genes

are newly violated. The main reason for these violations is the phenomenon cross-

singover, leading to recombination (recombination) of genes. Bio-

the logical basis of recombination is that in the process

formation of gametes homologous chromosomes before separation

thread, exchange their sections (more about recombination-

tions - in ch. I and IV).

Crossing over is a probabilistic process, and the probability of

whether or not a chromosome break will occur on this particular

area, is determined by a number of factors, in particular the physical dis-

standing between two loci of the same chromosome. Crossin-

transfer can also occur between neighboring loci, but it is likely

probability is significantly less than the probability of rupture (leading to

exchange areas) between loci with a large distance between them.

This pattern is used when compiling genetic data.

maps of chromosomes (mapping). Distance between two loci

is estimated by counting the number of recombinations per 100 gametes.

This distance is considered a unit of measurement for gene length and is called

yes centimorgan in honor of the geneticist T. Morgan, who first described

groups of linked genes in the fruit fly Drosophila - favorite

object of geneticists. If two loci are located at a significant distance

standing apart from each other, then the gap between them will occur as follows

as often as when these loci are located on different chromosomes.

Using the patterns of reorganization of the genetic mother-

* Let us recall that a locus (lat. locus - place) is a location

a specific gene or marker (polymorphic DNA region) on the genetic

chromosome map. Sometimes the term "locus" is unjustifiably used as a synonym

concept of "gene". This use of it is inaccurate, since we can talk about sex

not only the gene, but also the marker located in the intergenic space.

ala in the process of recombination, scientists have developed a statistical

an analysis method called linkage analysis.

Mendel's laws in their classical form operate when there is

under certain conditions. These include:

1) homozygosity of the original crossed forms;

2) the formation of gametes of hybrids of all possible types in equal

ratios (provided by the correct course of meiosis; one

high viability of gametes of all types; equal probability

meeting of any gametes during fertilization);

3) equal viability of zygotes of all types.

Violation of these conditions can lead either to the absence of

splitting in the second generation, or splitting in the first generation

lenition; or to a distortion of the ratio of various genotypes and pheno-

types. Mendel's laws are universal in nature for all dip-

loid organisms that reproduce sexually. Generally

they are valid for autosomal genes with full penetrance

(i.e. 100% frequency of manifestation of the analyzed trait;

100% penetrance implies that the trait is expressed in everyone wear-

allele that determines the development of this trait) and constant

new expressiveness (i.e., a constant degree of expression of the

sign); constant expressivity implies that the phenotypic

What severity of the symptom is the same or approximately the same for everyone

carriers of the allele that determines the development of this trait.

Knowledge and application of Mendel's laws is of great importance

in medical genetic counseling and genotype determination

phenotypically “healthy” people whose relatives suffered

hereditary diseases, as well as in determining the degree of risk

the development of these diseases in relatives of patients.

Chapter I I I

NON-MENDELIAN GENETICS

The genius of Mendel's laws lies in their simplicity. Stro-

a gay and elegant model, built on the basis of these laws, serves

la geneticists have been a reporting point for many years. However, during

Further research revealed that Mendel’s laws are subject to

Only relatively few genetically controlled

signs. It turned out that in humans the majority of both normal and

pathological signs are determined by other genetic factors

mechanisms that began to be designated by the term “non-Mendelian

genetics". There are many such mechanisms, but in this chapter

we will consider only a few of them, turning to the corresponding

general examples, namely: chromosomal aberrations(Down syndrome);

sex-linked inheritance(color blindness); imprinting(syn-

dromes of Prader-Willi, Engelmann); emergence of new mutations(once-

development of cancer); expansion (insertion) of repeating nucleotides

leotide sequences(Duchenne myotonic dystrophy); on-

following quantitative characteristics(complex behavioral