BASICS OF MEDICAL BIOLOGY - 2012

Interaction of allelic and non-allelic genes. The phenomenon of pleiotropy. Multiple allelism. Genetics of blood groups

The genotype comprises A large number of genes that function and interact as an integrated system. In his experiments, G. Mendel discovered only a single form of interaction between allelic genes: complete dominance of one allele and complete recessiveness of the other. An Organism's genotype cannot be viewed as a simple sum of independent genes, each functioning in isolation from the others. The phenotypic expression of a particular trait is the result of the interaction of many genes.

Gene interaction is the result of the Selection/27.html">Realization of Genetic information from a specific group of genes which, depending on their combinations, determine The formation of various variants of traits or phenotypes.

There are two main groups of gene interactions: interaction between allelic genes and interaction between non-allelic genes. However, it should be understood that this is not a physical interaction of the genes themselves, but rather an interaction of the Primary and secondary products that give rise to a particular trait.

Class="center">Interaction of Allelic genes

Genes that occupy identical (homologous) loci on identical (homologous) Chromosomes are called allelic. Every organism has only two allelic genes.

The main forms of interaction of allelic genes (genes of a single allelic pair) are complete

dominance, incomplete dominance, overdominance, and codominance.

Dominance is the predominance in the phenotype of a heterozygous organism of one allele (dominant) over another (recessive) allele of the same gene. Recessiveness is the suppression in the phenotype of a heterozygous organism of one allele (recessive) by another allele (dominant) of the same gene. Dominance can be complete or incomplete. In the case of complete dominance, the dominant homozygote (AA) and the heterozygote (Aa) have the same phenotype. The phenomenon of complete dominance was observed in G. Mendel's experiments, where one allelic gene was always dominant and the other recessive. Therefore, pea seeds were always either yellow or green in color and had no other color. With complete dominance in a cross of heterozygotes (Aa × Aa), the phenotypic segregation ratio is 3:1, and the genotypic ratio is 1:2:1.

Human traits inherited via complete dominance include dimples in the Cheeks, The ability to roll the Tongue into a tube, the ability to flip the tongue backward, free earlobes, as well as many monogenic Hereditary diseases: polydactyly, epidermolysis bullosa, myopathy, cylindroma (cystic-adenoid epithelioma), Achondroplasia, etc.

Incomplete dominance is an interaction of allelic genes in which, in a heterozygous organism, the dominant allele does not fully express its dominance, and the recessive allele of the same gene does not fully express its recessiveness. In incomplete dominance, the phenotype of the heterozygote (Aa) is intermediate between the phenotypes of the dominant (AA) and recessive (aa) homozygotes. Thus, when crossing red-flowered four o'clocks (AA) with white-flowered four o'clocks (aa), all first-generation hybrids (F₁) had pink flowers. When crossing the first-generation hybrids (F₁) among themselves (Aa × Aa), the second generation (F₂) exhibits a phenotypic segregation ratio of 1:2:1, which coincides with the genotypic segregation ratio of 1AA:2Aa:1aa, but deviates from the phenotypic segregation ratio of complete dominance (3:1).

Fig. 19. Monohybrid cross of the four o'clock plant.

Human conditions inherited via incomplete dominance include Sickle-Cell Anemia, cystinuria, Pelger-Huët anomaly, thalassemia, Friedreich's ataxia, etc. In homozygotes for the recessive cystinuria gene (aa), cystine stones form in the Kidneys; in heterozygotes (Aa), stones do not form, but only an elevated cystine content in the urine is observed; homozygotes (AA) are healthy.

Overdominance is an interaction of allelic genes in which the dominant allele in the heterozygous state manifests more strongly in the phenotype than in the homozygous state (Aa>AA). For example, in Drosophila, the AA genotype results in normal lifespan; Aa results in extended lifespan; and aa results in lethality.

Codominance is an interaction of allelic genes in which both alleles of the same gene are expressed in the phenotype of a heterozygous organism, resulting in the formation of a new trait. The human fourth Blood group (genotype I^AI^B) is inherited via codominance. In individuals of this group, red Blood Cells simultaneously carry antigen A, controlled by the allele I^A, and antigen B, a product of the expression of the allele I^B. The alleles I^A and I^B are codominant. This type of gene interaction is also observed in the Formation of the MN blood group, where heterozygotes simultaneously possess two Antigens on their Erythrocyte membranes (antigen M and antigen N).

Interaction of Non-Allelic Genes

The main forms of interaction of non-allelic genes are complementarity, epistasis, and polygeny. They predominantly modify the classical phenotypic segregation ratio established by G. Mendel for a dihybrid cross (9:3:3:1).

Complementarity (from Lat. complementum – Complement) is a form of non-allelic gene interaction in which one gene mutually supplements the action of another, non-allelic gene. When complementary genes are simultaneously present in the genotype, they cause The Development of a new trait (new formation).

In humans, normal Hearing is caused by the complementary interaction of two dominant non-allelic genes, D and E, one of which determines the Development of the cochlea and the other the auditory nerve. People with D-E- genotypes have normal hearing, while those with D-ee and ddE- genotypes are deaf. In a marriage where both parents are deaf (DDee × ddEE), all children will have normal hearing (DdEe).

Gray coat color in mice is controlled by two genes. Gene A determines pigment synthesis, while gene B ensures pigment accumulation predominantly at the base and tips of the hairs. Crossing diheterozygotes (AaBb × AaBb) leads to hybrid segregation in a 9:3:4 ratio (9 agouti : 3 black coat : 4 white coat). Numerical ratios can also be 9:7 or 9:6:1 (modifications of Mendelian segregation).

To protect against Viruses, human immunocompetent cells produce a specific protein called interferon. Its production in the body is associated with the complementary interaction of two non-allelic genes located on different chromosomes.

Human adult Hemoglobin contains four polypeptide chains, each encoded by a separate independent gene. Consequently, the synthesis of a hemoglobin molecule requires the presence of four complementary genes.

Fig. 20. Complementary gene interaction in rabbits.

In animals (such as mice, rats, and rabbits), the formation of dark coat color requires the presence of two dominant non-allelic genes (C and A), one of which determines the presence of pigment, while the other controls its distribution along the Hair shafts. If either gene is in a homozygous recessive state (cc), no pigment is produced, resulting in white offspring (albinism).

Epistasis is a form of non-allelic gene interaction in which one gene masks or suppresses the phenotypic expression of another, non-allelic gene. The suppressing gene is called epistatic or a suppressor (inhibitor), whereas the suppressed gene is referred to as hypostatic. When the epistatic gene is dominant, the interaction is termed dominant epistasis (A>B). Conversely, when the epistatic gene is recessive, it is known as recessive epistasis (aa>B or aa>bb). Gene interaction in epistasis is essentially the opposite of complementarity.

In chickens, the dominant allele C of one gene determines feather pigmentation, but the dominant allele I of another gene acts as its suppressor. Consequently, chickens with the genotype I-C- are white, whereas those with iicc and iiCc are colored. When crossing white chickens (IICC x iicc), the first-generation hybrids F₁(IiCc) turn out white; however, intercrossing the F₁ generation yields a phenotypic segregation ratio of 13:3 in the F₂ generation. Out of 16 offspring, 3 will be colored (iiCC, iiCc) because they lack the dominant suppressor gene and possess the dominant pigmentation gene. The remaining 13 offspring will be white. This example illustrates the phenomenon of dominant epistasis.

An example of recessive epistasis is the Bombay phenotype—an unusual inheritance pattern of ABO Blood Groups, first discovered in an Indian family. In a family where the father had blood group I (0) and the mother had group III (B), a girl with blood group I (0) was born. She later married a man with blood group II (A), and they had two daughters: one with blood group IV (AB) and the other with group I (0). The birth of a child with blood group IV (AB) in a family where the father was type II (A) and the mother was type I (0) was highly unusual. Geneticists explained this phenomenon as follows: the girl with blood group IV (AB) inherited the I^A allele from her father and the I^B allele from her mother; however, the mother's I^B allele remained phenotypically unexpressed because her genotype contained a rare recessive epistatic gene s in a homozygous state, which suppressed the phenotypic expression of the I^B allele.

In epistatic gene interactions, phenotypic segregation ratios in the F₂ generation include 13:3, 12:3:1, or 9:3:4, among others.

Hypostasis is a form of non-allelic gene interaction in which the dominant gene of one allelic pair is suppressed by an epistatic gene from a different allelic pair. If gene A suppresses gene B (A>B), this non-allelic interaction is termed hypostasis with respect to gene B, and epistasis with respect to gene A.

Polygeny (multiple gene inheritance) is a type of non-allelic gene interaction in which a single trait is controlled by several dominant non-allelic genes that act additively to reinforce its expression to an equal degree. Such genes are called polygenic (multiple genes, or polygenes) and are typically denoted by the same letter of the Latin alphabet with different numerical subscripts. For example, dominant polygenic genes are designated as A₁, A₂, A₃, etc., and recessive ones as a₁, a₂, a₃, etc. The corresponding genotypes are represented as A₁A₂A₃; a₁a₂a₃, etc. Traits controlled by multiple genes (polygenes) are called polygenic traits, and their inheritance is referred to as polygenic inheritance, as opposed to monogenic inheritance, where a trait is controlled by a single gene. The phenomenon of polygeny was first described in 1908 by the Swedish geneticist H. Nilsson-Ehle while studying grain color inheritance in wheat.

The seed color of wheat, oats, and other cereals can range from red to white. The intensity of pigmentation depends on the number of dominant genes present in the genotype. The presence of all four dominant alleles (A₁A₁A₂A₂) results in a dark red color, the absence of dominant genes (a₁a₁a₂a₂) yields white, while genotypes with three, two, or one dominant gene produce intermediate shades ranging from light red to pink and white (A₁A₁A₂a₂ or A₁a₁A₂A₂ produce light red; A₁A₁a₂a₂ or a₁a₁A₂A₂ produce pink; and a₁a₁b₂b₂ produces white). The phenotypic segregation ratio is 15:1.

Polygeny can be cumulative or non-cumulative. In cumulative polygeny, each individual gene has a minor phenotypic effect (weak dosage), but the combined dosages of all genes are ultimately cumulative, so that the degree of trait expression depends on the total number of dominant alleles. This summation of polygenic dosages (additivity) accounts for the existence of continuous phenotypic ranges in Quantitative Traits.

In humans, traits such as height, body mass, Skin color, intellectual capacity, and blood pressure are inherited via polygenic mechanisms, much like crop yield, egg production, and milk yield in nature. For instance, human skin pigmentation is determined by 4 to 6 pairs of polygenic genes. Indigenous peoples of Africa predominantly carry dominant alleles (P₁P₁P₂P₂P₃P₃P₄P₄), whereas Representatives of the Caucasian race carry recessive ones (p₁p₁p₂p₂p₃p₃p₄p₄). A union between a Black individual and a white woman results in children with an intermediate skin color known as mulattoes (P₁p₁P₂p₂P₃p₃P₄p₄). If both parents are mulattoes, their children can exhibit skin pigmentation ranging from maximally light to maximally dark.

Typically, quantitative traits are inherited polygenically. However, nature also presents Examples of polygenic inheritance of qualitative traits, where the final outcome does not depend on the number of dominant alleles in the genotype—the trait is either fully expressed or not expressed at all (non-cumulative polygeny).

Pleiotropy (from Greek pleion – more numerous, and trope – direction, turn) refers to the phenomenon where a single gene influences multiple phenotypic traits, also known as the multiple modifying action of a single gene. There is often no simple one-to-one correspondence between genotype and phenotype, as the same gene can affect various bodily characteristics. For example, in higher plants, the gene responsible for flower color also governs the coloration of the stem. In humans, the dominant gene causing arachnodactyly ("spider fingers") simultaneously leads to Connective Tissue disorders, eye lens dislocation, and cardiovascular defects such as aortic aneurysm (Marfan Syndrome). Another example is a gene that causes the absence of Sweat Glands, which concurrently results in congenitally missing Teeth. The manifestation of pleiotropy depends on the stage of ontogeny at which the gene acts: the earlier the action, the more profound the overall effect.

Pleiotropic effects can be primary or secondary. In primary pleiotropy, a gene simultaneously manifests multiple distinct effects. For instance, in Hartnup disease, a gene mutation disrupts the intestinal absorption of The amino acid Tryptophan and its renal tubular reabsorption. This simultaneously damages the membranes of both intestinal epithelial cells and renal tubules, leading to gastrointestinal and urinary disorders. In secondary pleiotropy, There is a single primary phenotypic manifestation of the gene, which triggers a cascading sequence of secondary changes leading to multiple effects. Thus, in sickle-cell anemia, homozygotes exhibit several pathological signs: anemia, Splenomegaly, and damage to the skin, Heart, kidneys, and Brain. Consequently, individuals homozygous for the sickle-cell allele typically do not survive past childhood. All these phenotypic manifestations form a hierarchy of secondary consequences. The ROOT cause—the direct phenotypic expression of the defective gene—is abnormal hemoglobin and sickle-shaped erythrocytes. This sequentially triggers other pathological processes, such as erythrocyte agglutination and destruction, anemia, and defects in The Heart, kidneys, and brain, all of which are secondary manifestations. Secondary pleiotropy is the more common form.

Multiple Allelism

In Gregor Mendel’s experiments, genes existed in only two forms: dominant and recessive. However, the majority of genes are represented not by two, but by a larger number of alleles. Alongside the main alleles (dominant and recessive), intermediate alleles also exist. A series of three or more alternative forms of the same gene is referred to as multiple alleles, and the phenomenon itself is known as multiple allelism. Multiple alleles arise through repeated Mutations at the same chromosomal locus. While a diploid organism's genotype contains only two alleles of a given gene, the total number of such alleles in a population is virtually unlimited. A key feature of interactions among multiple alleles is that they can be arranged in a dominance hierarchy, where each member is dominant to all subsequent ones and recessive to all preceding ones. For example, in rabbits, full dark coloration is determined by the dominant allele A, whereas homozygous recessive animals (aa) are white. However, several other alleles of this gene exist, each producing its own distinct phenotype in the homozygous state, such as chinchilla (a^cha^ch) and Himalayan (a^ha^h). Chinchilla rabbits are grey, while Himalayan rabbits are white with dark pigmentation on the tips of their ears, tail, feet, and Nose. This entire allelic series can be written as a linear dominance hierarchy: A>a^ch>a^h>a. Dark coloration is exhibited by genotypes AA, Aa^ch, Aa^h, and Aa; chinchilla by a^cha^ch, a^cha^h, and a^cha; and Himalayan by a^ha^h and a^ha. Significance: multiple allelism enriches a population's gene pool and enhances its genotypic and phenotypic polymorphism, which is crucial for evolution.

The inheritance of ABO blood groups in humans is governed by a series of multiple alleles.

Inheritance of ABO and MN Blood Groups; Blood group genetics

The Discovery of the ABO blood group system is credited to K. Landsteiner (1901). In humans, the ABO blood group system is inherited as a series of multiple alleles of a single autosomal gene located on chromosome 9, whose locus is designated by the letter I (derived from isohemagglutinogen). Studies on the inheritance patterns of various ABO blood groups have established that they are determined by different combinations of three alleles belonging to a single allelomorphic gene group, designated as I^A, I^B, and I^O. These determine four distinct phenotypes: group I (0), group II (A), group III (B), and group IV (AB) (see table).

ABO Blood Group System

Each phenotype is distinguished by specific protein antigens located On the surface of erythrocytes and corresponding antibodies circulating in the blood serum. Phenotype I (0) is due to the absence of antigens A and B on the erythrocytes and the presence of antibodies α and β in the serum. Phenotype II (A) is characterized by the presence of antigen A on the erythrocytes and antibody β in the serum. Phenotype III (B) is associated with the presence of antigen B on the erythrocytes and antibody α in the serum. Phenotype IV (AB) depends on the presence of both antigens A and B on the erythrocytes and the absence of antibodies α and β in the serum.

Antigen A and antibody α never coexist in the same blood, nor do antigen B and antibody β. When antigens interact with their corresponding homologous antibodies, erythrocyte clumping (agglutination) occurs, indicating incompatibility between donor and recipient blood. During blood transfusion, it is vital to ensure that donor antigens do not encounter matching recipient antibodies. Because blood group I lacks antigens, individuals with this blood type are referred to as universal Donors, whereas those with blood group IV are known as universal recipients.

The inheritance of any two alleles out of the three possible ones obeys Mendelian principles. Blood groups II (A) and III (B) are inherited in an autosomal dominant manner, while group I (0) is inherited as an autosomal recessive trait. The genes I^A and I^B are dominant relative to gene I^O. If both parents have blood group II (A), their children may have blood group II (A) or I (0), but not III (B) or IV (AB). The fourth blood group (AB) is inherited not according to G. Mendel's classical rules, but rather through codominance. Because blood groups are genetically determined and remain unchanged throughout life, their determination can be useful in disputed paternity cases. However, it must be kept in mind that blood group analysis alone cannot definitively prove that a particular man is the father of a child; it can only establish whether he could potentially be the father or whether paternity is excluded.

In 0.1–0.2% of individuals with blood group IV (AB), a rare gene arrangement known as cis-position occurs, where both genes I^A and I^B reside on the same chromosome. Consequently, if such a person marries an individual with blood group I (0), it is possible for them to produce children with blood group I (0). This factor must be taken into account during MEDICAL Genetic Counseling and forensic medical examinations.

People with the I^aI^a genotype are phenotypically indistinguishable from those with the I^aI⁰ genotype, but the difference manifests in their offspring. In a marriage where one parent has the I^aI⁰ genotype and the other I⁰I⁰, half of the children will have phenotype A (with the I^aI⁰ genotype) and the other half phenotype 0. If one parent has the I^aI^a genotype and the other I⁰I⁰, all children will have phenotype A (with the I^aI⁰ genotype). A similar distinction is observed in individuals with the I^BI^B and I^BI⁰ genotypes.

Expected offspring from marriages according to parental blood groups

Note. Within each of the ten mating types, the specific blood group genotype can only be identified by analyzing the offspring.

Phenotypic expressions of the ABO blood group system are among the most stable traits and remain entirely unchanged throughout a person's life.

More than 20 different blood group systems are distinguished based on the presence of antigens, including the Rhesus factor and the MN system.

The Inheritance of the MN blood group system, discovered in 1927, also exhibits codominance. This system is determined by two alleles: I^M and I^N. Both alleles are codominant, which is why there are individuals with the I^MI^M genotype (expressing the M factor phenotypically), I^NI^N (expressing the N factor phenotypically), and I^MI^N (expressing both M and N factors phenotypically). Unlike the ABO system, the blood serum of individuals with any given MN phenotype lacks antibodies against the corresponding antigens. Therefore, this system can be disregarded during blood transfusions. Among Europeans, the I^MI^M genotype occurs in approximately 36%, I^NI^N in 16%, and I^MI^N in 48%.

Inheritance of the Rhesus factor

The Rhesus factor is a protein (antigen) named so because it was first isolated in 1940 from THE RED BLOOD cells of rhesus macaques (Macacus rhesus) and subsequently found in humans. About 85% of Europeans are able to synthesize it, comprising the Rhesus-positive (Rh⁺) group, while 15% are unable to do so and are termed Rhesus-negative (Rh^-). The Rhesus factor is controlled by three closely linked dominant genes (C, D, E) located on the first chromosome. They are inherited as in a monohybrid cross. The primary role belongs to the D antigen: if it is present, the blood is Rhesus-positive (DD or Dd); if absent, it is Rhesus-negative (dd). The Rhesus factor must be considered in blood transfusions and transplantation because it can stimulate Antibody production in the body. Furthermore, the Rhesus factor can cause Rhesus incompatibility between a mother and a fetus. If a Rhesus-negative woman marries a Rhesus-positive homozygous man, all children will be Rhesus-positive; if he is heterozygous, 50% will be Rhesus-positive and 50% Rhesus-negative.

Incompatibility arises when the mother is Rhesus-negative and the child inherits the dominant D allele from the father, making them Rhesus-positive. Maternal and fetal blood do not normally mix, so the first Pregnancy usually proceeds without complications. However, during the delivery of the first child, as the Placenta separates, fetal red blood cells enter the mother's Circulation, triggering The production of antibodies against the Rhesus antigen. During subsequent pregnancies, these antibodies cross the placental barrier, enter the fetal bloodstream, and bind to the Rhesus antigen, causing agglutination and lysis of red blood cells (erythroblastosis fetalis, or hemolytic disease of the newborn). With each successive delivery, the severity of the condition in the children tends to increase. If a Rhesus-negative girl receives a Rhesus-positive blood transfusion prior to pregnancy, even her first Rhesus-positive child will be non-viable. Therefore, even a single transfusion of Rhesus-positive blood is strictly contraindicated for females with Rhesus-negative blood.

In Japan, Korea, China, and India, hemolytic disease of the newborn is extremely rare. This is explained by the very low prevalence of the Rh(-) phenotype in these populations (ranging from 0 to 1.5%). The Rh(-) blood group is also uncommon among Eskimos and Evenks. Among Australian aborigines, Rhesus incompatibility in pregnant women does not occur, as the frequency of the Rh(+) gene among them is 100%.

Hemolytic disease of the newborn was described over 400 years ago. It can be caused by incompatibility not only in the Rhesus system but also in the ABO system—most frequently when the mother has blood group I (0) and the child has group II (A) or III (B).

Immunogenetics

Immunogenetics is the branch of science that studies the Patterns of inheritance of antigenic Specificity and the GENETIC BASIS OF immune responses. The Human Body possesses the Major Histocompatibility Complex (MHC)—a system of cell-surface antigens unique to an individual that determines tissue incompatibility between a donor and a recipient. MHC antigens are strongly expressed on The surface of peripheral Blood Leukocytes, which is why the human MHC is also known as the HLA system (Human Leucocyte Antigens). The synthesis of these antigens is controlled by a cluster of closely linked genes located on the 6th pair of chromosomes. This region contains loci A, B, C, D₁, and D₂R, with each gene possessing multiple alleles. There are over 20 known alleles for the A gene, about 50 for the B gene, and 8 for the C gene. The combination of these alleles generates vast diversity in human antigenic genotypes across populations. Panels of sera in microcytotoxicity tests are used to determine a person's HLA antigens. Identifying Histocompatibility Antigens is of paramount importance for Organ and tissue transplantation, as well as for maintaining registries of recipient and donor antigen profiles. Additionally, evidence links certain diseases to specific HLA antigens; for instance, the HLA-B27 antigen is found in 70–100% of patients with Ankylosing spondylitis compared to only 3–12% of healthy individuals. The GENES OF THE major histocompatibility complex regulate immune system function and govern transplantation Immunity.