Mendel's inheritance rules
Monogenic hereditary diseases are also called Mendelian because they are inherited according to the rules established by Gregor Mendel in 1865.
The main merit of Mendel is that, based on a quantitative evaluation of the results of splitting the progeny of pea hybrids on different qualitative grounds, he assumed the existence of elementary unitsheredity, called genes. In the scientific literature, the attribution of G. Mendel is also attributed to the establishment of a number of inheritance rules for signs, some of which were in fact discovered by G. Mendel's predecessors.
The first rule is the dominance rule. Its essence boils down to the fact that of two copies of each gene, called alleles and contained in each cell, one can suppress or mask the manifestation of the second copy( allele).If the gene alleles are the same, the individual with such a genotype is called homozygous, and if they are different - heterozygous. Consequently, the dominant allele determines the character of the trait, even when in the heterozygous state, and the recessive( masked) allele determines the character of the trait only when it is in the homozygous state. Accordingly, all Mendelian hereditary diseases are divided into dominant and recessive. If a heterozygous individual exhibits both alleles, that is, there is no dominance of one allele over another, then such alleles are called codominant. A well-known example of codomination is the alleles A and B of blood group AB0.Street IV group of blood shows antigens both A and B.
G. Mendel also suggested that one of the alleles of each gene accidentally gets into the parental cells of the parents, so 50% gametes carry one allele and the second 50% - the other. This statement is called the second rule of Mendel or the rule of splitting. If both parents are heterozygous for some gene, then in the offspring of such parents there will be a splitting and 3/4 of the descendants will have a dominant sign and only 1/4 will be recessive, which is due to the random combination of gametes of parents having different gene alleles. In this case, the genotype splitting will be different, namely 1: 2: 1. Accordingly, if only one parent is heterozygous and the second is homozygous for the recessive gene, the splitting according to the presence of the dominant and recessive traits will be 1: 1.If one parent is homozygous, and the other is heterozygous for the dominant gene, then phenotypically all offspring will have only a dominant feature. To understand how the splitting rule works, it is best to use the Penet lattice, which this English geneticist suggested for graphical representation of the results of various crosses( see Table).
Table
Table Pennet reflecting the results of splitting in progeny from marriage of two heterozygous parents
| Gametes of mother | |||
| A | and | ||
| Gametes of father | A | AA | Aa |
| a | Aa | aa |
Table
Pennet lattice reflecting the results of splitting in progeny frommarriage of parents, one of which is heterozygous, and the second is homozygous for the recessive gene
| Gametes of the mother | |||
| and | a | ||
| Gametes of the father | A | aA | aA |
| a | aa | aa |
Table
eshetka Penneta reflecting cleavage results in the offspring of the marriage of parents, one of which is heterozygous and homozygous for the second dominant gene
| Gametes of the mother | |||
| Gametes of the mother | |||
|
| A | ||
| Gametes of the father | A | AA | AA |
| a | Aa | Aa |
G. Mendel it was clear that the observed clefts in the offspring from the crosses of parents with different genotypes are events with a certain probability and can be identifiedonly on a large number of descendants. From the theory of probability, two rules follow - the rule of multiplication and the rule for adding probabilities.
The multiplication rule says that if some events are observed independently of each other, then the probability that two events will occur simultaneously is equal to the product of the probabilities of these events. The probability of formation of gametes with a recessive gene in parents heterozygous for this gene is 1/2 for each parent. The probability of encountering such gametes with a recessive gene upon the formation of zygotes will be equal to the product of the probabilities of formation of such gametes in each of the parents, i.e., 1/2 x 1/2 = 1/4( 25% of all descendants).
The addition rule says that if you need to know the probability of realizing either one or another event, then the probabilities of each of these events add up. Thus, if we are interested in the probability of homozygous progeny in the marriage of heterozygous parents, then we must add the probabilities of recessive and dominant homozygotes, i.e. 1/4 + 1/4 = 1/2.
These rules quite often have to be used by geneticists during medical genetic counseling in calculating the probabilities of certain events in families with a child with a hereditary disease of the child.
The third rule of Mendel, or the rule of independent combination: the genes that determine the various characteristics are inherited independently of each other. It can be seen that this rule does not refer to the inheritance of alternative states of the same attribute, but to two or more features.
We present an example of the cleavage in the offspring from the marriage of parents heterozygous for two genes at the same time( AaB b ), each of these genes influencing different signs. The easiest way to do this is to use the Penet lattice( see table).
AB
Ab
aB
ab
gametes
father AB Table
| mother gametes | AABB | AAbV | AABB | AaVb |
| Ab | AAVb | AAbb | aAVb | aAbb |
| aB | AABB | AabV | AABB | aabV |
| ab | AaVb | Aabb | aaBb | aabb |
In the offspring of the marriage of double heterozygotes, there are four phenotypes: dominant by both characters, dominant either one by one or by another, recessive either one by one or by another, recessive on both grounds simultaneously. The relationship between these phenotypes in the order they are recorded above is 9: 3: 3: 1.These relationships are easily obtained by multiplying the probabilities of the corresponding phenotypes under monohybrid splitting. Thus, the probability of a dominant phenotype for each trait in a mono-hybrid cross is 3/4.If they are independent of each other, the probability of their joint manifestation will be 3/4 x 3/4 = 9/16.The ratio of genotypes in dihybrid crosses is different than the ratio of phenotypes.
Specificity of Mendelian rules in medical genetics
It is quite natural that a person for ethical reasons can not have controlled crosses. In addition, the number of children in the family, as a rule, is small. In order to prove the autosomal dominant or autosomal recessive nature of disease inheritance, it is necessary to collect a sufficiently large number of families with a large number of children in these families. If we consider that the absolute majority of hereditary diseases is rare, it becomes clear that most often the medical genetics have to use simplified requirements for evidence of a certain type of inheritance. These simplified requirements follow, however, from the Mendelian rules of inheritance.
Usually in the field of view of medical genetics falls a family in which there is a patient or patients with an alleged hereditary disease. For such a family, they usually collect a pedigree, establish the ancestors of parents and their relatives and describe the status of their health, as well as other information. It is customary to represent the genealogy graphically, using certain symbols for this purpose.
Autosomal dominant inheritance of
The absolute majority of autosomal dominant diseases occurs at a frequency of 1: 10,000 or less. With such a rare occurrence in most families in which there is such a disease, only one parent is affected, and he is a heterozygous carrier of the corresponding mutant gene.
One of the main reasons for the development of these diseases is the newly emerging mutations in individual germ cells of one of the parents, then the autosomal dominant disease will be the only case of the disease in the family. Naturally, the chances for such a patient to transmit the mutation to their children will be common for autosomal dominant inheritance, 50%.The frequency of newly emerging mutations in individual genes is inversely proportional to the extent to which the manifestations of this mutation affect the fitness of the patient. By fitness is the ability of an individual to live to reproduce and leave offspring. All autosomal dominant diseases reduce the fitness of patients in whom they are observed. However, this happens in different degrees. Vulgar ichthyosis( excessive skin peeling on different parts of the body, dryness and excess striation of the palms) or preaxial polydactyly( additional finger from the thumb) practically does not reduce the fitness of the carriers of the mutant genes. Accordingly, mutations in these genes reappear rarely. In contrast, achondroplasia or tanatophoric dysplasia of type 1 dramatically reduces the fitness of their carriers. With achondroplasia, almost all male patients are sterile, and tanatophore dysplasia is lethal: patients due to respiratory failure die in the period of newborns. That is why, with achondroplasia, a new mutation is the cause of the disease in about 80%, and with tanatophoral dysplasia - in 100% of cases.
The second cause of deviation has sent autosomal dominant inheritance - germ cell mosaicism. Such mosaicism occurs in the early stages of the development of the organism, at the moment of isolation of the embryonic path of development as a result of a mutation in one of the cells of the germinal pathway. Since the germ cells are cloned, the mutation may be in a greater or lesser part of the mature germ cells. A consequence of this may be the appearance in the family of healthy parents of several patients with autosomal dominant diseases. So, it is somatic mosaicism that explains the repeated cases of achondroplasia, imperfect osteogenesis and other autosomal dominant diseases in children of clinically perfectly healthy parents.
In connection with autosomal dominant inheritance, it is necessary to introduce the concepts of penetrance and expressivity of the gene.
Penetrantity can be defined as the proportion of individuals in whom a mutant gene is detected from all individuals who inherited this gene. Penetration can be complete or incomplete or expressed in percent. In pedigrees, in which the inheritance of an autosomal dominant disease can be traced, the incomplete penetrance of the gene that causes this disease will manifest itself by the so-called pass of the generation.
Gene expressiveness means the degree of expression of the gene expression. As a rule, any genotransformed trait varies in its manifestation. For hereditary diseases, especially autosomal dominant, the variation in the severity of each symptom of the disease and even in the number of symptoms of the disease is a well established fact due to the fact that each patient undergoes a clinical examination.
Another reason for deviating from the rules of autosomal dominant inheritance, as well as other types of inheritance, which will be discussed below, is the age dependence in the manifestation of many hereditary diseases. Not all hereditary diseases are manifested at birth or soon after. Many of these diseases occur in adolescence or even in adulthood.
It is very difficult to prove the type of inheritance of a disease with late age of manifestation, and maybe that's why it took so long to prove dominant inheritance for some forms of Alzheimer's disease, or senile dementia, that appear after 50-60 years.
Autosomal recessive inheritance of
Several thousands of diseases have already been identified that are inherited autosomally and recessively. Like autosomal dominant diseases, autosomal recessive affects all organs and systems of the body and, consequently, are extremely diverse in their manifestations. Most autosomal recessive diseases are rare. Frequent recessive diseases include, for example, phenylketonuria, the frequency of which in most countries of Western Europe is 1: 10,000( in Russia 1: 6500).
Because of the rarity of autosomal recessive diseases, as well as the severity of the course of many of them, in the vast majority of cases the parents of sick children are heterozygous carriers and are clinically healthy.
The risk of a patient with an autosomal recessive disorder in the family in which the parents are heterozygous carriers of the mutant gene is 25% and does not change for any pregnancy in this married couple. Pedigrees of patients with autosomal recessive disease are usually inexpressive: parents and all of the immediate relatives of the patient are healthy, brothers and sisters may be sick( both sexes are affected equally often).If a patient with a recessive disease marries, his partner is in most cases a normal homozygote, and therefore all children in such a marriage are healthy, but are heterozygous carriers. However, often in pedigrees with autosomal recessive diseases, the parents of the patients turn out to be close relatives.
The explanation of the higher frequency of closely related marriages in families in which there are patients with autosomal recessive disease is very simple. The less often a recessive gene occurs in a population, the less likely that both parents will be heterozygous for this gene, since the probability of such a couple is equal to the product of the probabilities of being a heterozygous carrier for each partner. Thus, at the frequency of heterozygous carriage of the phenylketonuria gene, which is approximately 0.02, the probability of heterozygous carrier rejection is 0.0004.In other words, every 2500th married couple is represented by heterozygous carriers. In the event that one of the spouses is a heterozygous carrier of the phenylketonuria gene( probability of 0.02), and the second spouse is a relative, the probability for the second spouse to be a heterozygous carrier of the same gene depends on the degree of kinship of the spouses.
Segregation analysis of
It was discussed above how the Mendelian rules of inheritance appear in separate pedigrees, in which there are patients with hereditary diseases.
At the same time, it should be noted that the analysis of pedigrees at best allows you not to reject the assumption of a certain type of inheritance of a disease. However, in medical genetics there is a more rigorous and precise way of proving this or that type of inheritance. This method is called segregation analysis.
Segregation analysis for humans is fundamentally different from this for experimental animals. In the latter case, the geneticist uses controlled crosses of parents with a known genotype, and the number of offspring is quite large. For a person, one can use only an indirect approach, which consists in comparing different probabilistic models with the available family data. In other words, the observed shares of affected siblings are compared with those expected under a certain genetic hypothesis. With this comparison, two problems arise.
The first is the difficulty in determining the method of recording patients and their families;the second - it is necessary for the analysis to unite different families, since the size of any single family in a person does not allow checking statistical hypotheses. As a result, such factors as inaccuracy of the diagnosis, genetic heterogeneity of the disease begin to "interfere".
The simplest kind of segregation analysis can be used to prove autosomal dominant inheritance of the disease, when families with this disease are registered through a sick parent( the second parent is healthy).
Segregation analysis becomes, however, more difficult when testing the hypothesis of autosomal recessive inheritance. When collecting for the analysis of family material, families in which heterozygous parents have only healthy children are ignored. If this is not taken into account, then the segregation frequency, or the frequency of homozygous patients, in the sample of families with sick children will inevitably be overstated.
The most complete, however, is the complex segregation analysis developed by Morton. This analysis includes as a basis the maximum likelihood method and allows obtaining the most plausible estimates of not only the segregation frequency, but also the probability of registration. In terms of calculations, this method is very laborious, but there are computer programs that can overcome this difficulty.
Of course, segregation analysis was used to prove the type of inheritance of a relatively small number of hereditary diseases due to the rarity of most of them. For most hereditary diseases, the type of inheritance attributed to them by only a limited number of pedigrees should be regarded as established in advance. This situation began to be quickly corrected by the development of new molecular genetic methods that allow us to first identify genes and then mutations in these genes and prove not only the etiological significance of these mutations in the occurrence of the corresponding hereditary disease but also the type of inheritance of this disease.
X chromosome-linked inheritance of
The number of known X-linked diseases is much less than the dominant or recessive, whose genes are "scattered" into 22 autosomes. Nevertheless, about 300 genes localized in chromosome X are known, which cause hereditary diseases( genes localized in chromosome X are called X-linked).These include the genes of hemophilia A, Duchenne's myopathy, X-linked ichthyosis, retinal pigmentary dystrophy, the fragile X chromosome syndrome with mental retardation, hydrocephalus, Coffin-Lowry, Payne, Opitz syndrome, one of the forms of mucopolysaccharidosis, X-linked neural amyotrophy, insufficiencyglucose-6-phosphate dehydrogenase and many other diseases.
Before proceeding to the consideration of inheritance linked to chromosomes X and Y, and the characteristics of pedigrees under these types of inheritance, we recall that in humans, sex is heterogametic. Women have in all cells two chromosomes X, and men - one X- and one Y-chromosome. Men are hemizygotes( contain one X chromosome) on chromosome X and all the genes contained in it. Inheritance of sex chromosomes occurs as an inheritance of simple Mendelian characters.
The behavior of genes that are located in the sex chromosomes strictly corresponds to the behavior of the chromosomes themselves. If the mutant gene is in one of the X chromosomes of the mother, then 50% of the sons and 50% of the daughters of the carrier mother will receive this chromosome. If the gene is "responsible" for the recessive disease, then the mother herself should be healthy, since she has a second normal X chromosome, but it will develop in the half of the sons who received the X chromosome with the mutant gene, since the Y chromosome is not homologous to the X chromosome.
Daughters who have received an altered chromosome from their mother will not develop the disease, since they will get a normal second chromosome X from their father. Thus, if the mother is the carrier of the X-linked recessive gene, the risk of sickness in her sons will be 50%, and her daughters - 0%.At the same time, the risk of being heterozygous carriers in daughters is 50%.
In the event that the father is still sick, all his sons will be healthy, and all the daughters are heterozygous carriers of the X-linked gene. This situation occurs when the X-linked recessive disease does not greatly reduce the fitness of the patient. An example of such a disease is X-linked recessive ichthyosis, or color blindness to red, inherited X-linked.
Fragile chromosome syndrome X
This syndrome has its name due to cytogenetic studies conducted in boys with mental retardation.
It is now known that, firstly, such a phenomenon - the fragility of chromosome X - is not always observed.
It should be noted that inheritance of the disease differs from Mendelian. In addition, the syndrome is an example of a dynamic mutation.
Clinical manifestations of the syndrome are not very specific. The main symptom is mental retardation, which in some patients is very moderately expressed. The majority of patients suffer from attention deficit, some observe autism. Older patients describe an elongated face, protruding forehead, large protruding ears and macrochorchism.
Until recently, it was extremely difficult to explain the nature of the inheritance syndrome, which manifested itself in both men and women, although in women less often and their clinical symptoms are less pronounced.
Y chromosome-linked inheritance of
Chromosome Y contains a relatively small number of genes. By the beginning of 2002, a little over 35 genes are mapped in it, only 7 of them cause hereditary diseases, including retinitis pigmentosa, several forms of azoospermia, dyschondrosteosis and gonadoblastoma, a violation of sex differentiation.
It is convincing to prove that the trait is inherited in a coherent way with the Y chromosome, it is extremely difficult to use the genealogy, because it must be differentiated from autosomal dominant inheritance. Only large families, in which both girls and boys are found among the sick, but the sign is the same as that of the father, is only among the boys, allow one to suspect that it is a question of Y-linked inheritance.
With Y-linked disease, only men will be ill, but unlike X-linked pathology, the affected father will transfer the disease only to his sons, his daughters and their children are always healthy.