BASICS OF MEDICAL BIOLOGY - 2012

Organismal Level of Organization of Genetic Information. Manifestations of Basic Inheritance Patterns Using Mendelian Human Traits as an Example

Genetics (from Greek genetikos - pertaining to origin, logos - science) is the science of heredity and Variability. The term "genetics" was first proposed in 1906 by the English scientist W. Bateson. The Subject Matter of genetics is heredity and variability—two fundamental properties inherent in All living organisms. The main objective of genetics is to study the patterns of heredity and variability in order to develop ways to control them in the interest of all humankind. To achieve this goal, genetics employs the method of hybridological analysis, proposed in 1865 by G. Mendel. This is a purely genetic method, unique to genetics and not used in other sciences. The hybridological method is a highly precise method, and genetics is an exact science.

The Basic patterns of trait inheritance were discovered by G. Mendel (1822–1884). Mendel's work, "Experiments on Plant Hybrids," was published in 1866, but at the time it failed to attract the attention of his contemporaries. It was not until 1900 that the same regularities were independently re-established by European scientists: H. de Vries from the Netherlands, C. Correns from Germany, and

E. Tschermak from Austria. Soon afterwards, through Hybridization experiments conducted with numerous objects, it was proven that the regularities discovered by Mendel are characteristic of all organisms.

The year 1900 can be considered the birth year of genetics. The Development of General Genetics stimulated the development of Human Genetics (anthropogenetics) and medical genetics.

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Gregor Johann Mendel (1822–1884)

Selection/3.html">Stages of development of general genetics, anthropogenetics, and medical genetics

Basic Concepts and Terms of Modern Genetics

The subject of genetics is The Study of two fundamental yet opposing properties inherent in all living organisms.

Heredity is the ability of organisms to ensure material and functional continuity from generation to generation (between generations); it is realized in The process of inheritance and the reproduction across a series of generations of a specific character of METABOLISM and individual development that are genetically determined under certain environmental conditions. As a result, each species of Organism preserves and reproduces itself across generations.

Variability is the ability of organisms to acquire new traits or lose previous ones during development. Variability is also defined as the differences between individuals of the same species. Variability ensures The Diversity of forms in the organic world and their adaptability to changing environmental conditions. Variability is the opposite of heredity, yet closely linked to it. Together, they constitute The basis of evolution.

Inheritance is the process of transmitting hereditary information from one generation of organisms to the next.

Alternative (mutually exclusive) traits are contrasting states of a single trait determined by different alleles of a gene. For example, the trait is Hair color; alternative states are dark versus light...

Genotype is the set of all genes of an organism. It is the hereditary foundation (genetic constitution) of a given organism as a whole or with respect to a specific inherited trait.

Phenotype is the totality of all external and internal traits of an organism. The phenotype is the result of the interaction between the genotype and environmental conditions. The phenotype is never a complete reflection of the entire genotype, but always mirrors only that portion of it which is realized under given conditions. The terms "genotype" and "phenotype" were first proposed in 1909 by the Danish geneticist W. Johannsen.

Allelic genes, alleles (Greek allelos - reciprocal, opposite) are genes located at the same loci on homologous Chromosomes that determine a single trait at the molecular level. Allelic genes, like chromosomes, are paired. In every cell of a diploid organism, any given gene is represented by two alleles, one of which the organism received from its father and the other from its mother. The exception is sex Cells (Gametes), which contain only a single allele of a given gene. Allelic genes can be dominant or recessive. A dominant gene (allele) is manifested in the phenotype of a heterozygous organism. A recessive gene (allele) is not manifested in the phenotype of a heterozygous organism.

Homozygous organism is an organism in whose homologous chromosomes contain identical alleles of a specific gene (e.g., AA or aa); it produces a single type of gamete for that gene (A or a). When crossed with each other, homozygotes do not produce segregation in their progeny.

Heterozygous organism is an organism whose homologous chromosomes contain different alleles of a specific gene (Aa); it produces Two Types of gametes for that gene (A and a). When crossed with each other, heterozygotes produce segregation in their progeny.

Hemizygous organism (Greek hemi - half) is an organism in which a gene is represented not by two alleles, but by only one, and this allele is always phenotypically expressed, even if it is recessive. A hemizygous organism is a haploid organism, as well as a diploid heterogametic organism, but only for those genes that are localized in the sex chromosomes. For example, human males (XY) are hemizygous for The genes of hemophilia and color blindness, which are localized in the non-homologous region of the X chromosome, because they possess only one X chromosome, while the Y chromosome lacks these genes.

Monohybrid cross is a cross in which parental individuals are analyzed for a single pair of alternative traits (one trait).

Dihybrid cross is a cross in which parental individuals are analyzed for two pairs of alternative traits (two traits).

Polyhybrid cross is a cross in which parental individuals are analyzed for multiple traits (many traits).

Through Experiments on the hybridization of various garden pea varieties, G. Mendel established the fundamental principles of trait inheritance at the organismal level, which are now known as Mendel's three laws and the law of segregation of gametes. These constitute the core principles of genetics. Mendel achieved success in his research due to a well-chosen experimental model and an entirely novel methodology he developed, known as the hybridological analysis method. The garden pea (Pisum sativum) is a self-pollinating plant, which makes it possible to maintain the purity of the studied traits. The scientist meticulously planned his experiments, kept precise quantitative records, and subjected his findings to rigorous mathematical analysis. This experimental design formed the foundation of the hybridological method, which became the principal approach in both classical and modern genetics.

The hybridological method is the analysis of trait inheritance through hybridization (crossing). The heterozygous organism resulting from this process is called a hybrid, and its offspring are referred to as hybrid progeny. The core principles of the hybridological method are:

1) utilizing organisms for crosses that have consistently exhibited stable traits in preliminary trials (homozygous organisms);

2) selecting parental organisms that clearly differ from one another not in their entire complex of traits, but in only one or a few pairs of alternative traits;

3) maintaining precise quantitative records of the manifestation of each individual pair of alternative traits across successive generations; not only the first generation derived from the cross is analyzed, but also the progeny of each individual hybrid. Prior to Mendel, researchers studied the inheritance of numerous traits simultaneously and failed to obtain expected results.

G. Mendel proposed algebraic symbols to designate genetic crossing schemes, which, with minor additions, are still used in modern genetics. In these diagrams, parents are conventionally denoted by the letter P (from Lat. parentes — parents), crossing by the multiplication sign ×, the female sex by the symbol (Venus's mirror), the male sex by the symbol (Mars's shield and spear), a dominant allele by a capital letter of the Latin alphabet (A), a recessive allele of the same gene by a lowercase letter (a), and hybrid generations by F (from Lat. filii — children) with a numerical subscript indicating the sequential number: F₁ — the first generation, F₂ — the second, and so on. The first line of the diagram records the parental genotypes (traditionally placing the female organism first and the male second), the second line shows the types of gametes they produce, and the third line displays all possible genotypes of the offspring.

Laws of Heredity (G. Mendel, 1865; H. de Vries, C. Correns, E. Tschermak, 1900)

First Law of Heredity (Law of Uniformity of F₁ Hybrids)

When crossing homozygous individuals that differ by a single pair of alternative traits, all offspring in the first generation are uniform in both phenotype and genotype.

Notation scheme:

A — gene for yellow pea color;

a — gene for green pea color;

AA — homozygous yellow pea (genotype);

aa — homozygous green pea (genotype).

F₁: Aa — heterozygous yellow pea (uniformity of offspring in phenotype and

genotype)

Cytological basis of this law: homozygous parents (AA × aa) during Meiosis produce gametes of only one type — A and a, respectively. The combination of these gametes during Fertilization yields zygotes of a single type — Aa.

Second Law of Heredity (Law of Segregation)

When crossing two heterozygous individuals (hybrids) analyzed for a single pair of alternative traits, phenotypic segregation is observed in the offspring in a 3:1 ratio, and genotypic segregation in a 1:2:1 ratio.

Notation scheme:

Phenotypically: 3/4 of the individuals (75%) exhibit the dominant trait (yellow seeds), while 1/4 (25%) exhibit the recessive trait (green seeds).

Genotypically: 1/4 (25%) are dominant homozygotes AA (yellow seeds); 2/4 (50%) are heterozygotes Aa (yellow seeds); 1/4 (25%) are recessive homozygotes aa (green seeds).

The cytological basis of The Second Law is meiosis: first-generation hybrids F₁ (Aa) produce two types of egg cells and sperm cells during meiosis — A and a, the combination of which during crossing yields Three types of zygotes: AA, Aa, and aa. Therefore, uniformity cannot occur In the second generation F₂, because segregation is fundamentally driven by The phenomenon of non-blending of alleles in hybrids (the law of segregation of gametes).

Based on the results of Monohybrid Crosses, the following Conclusions can be drawn: a) individual traits of organisms do not disappear during crosses, but are passed down to offspring. This is because the alleles of the same gene, located within the same pair of homologous chromosomes, remain unchanged across generations; b) each gamete receives only one gene from a given pair of alleles, and the number of gametes carrying different alleles of the respective gene is equal; c) male and female gametes carrying alleles of the same gene combine randomly during fertilization.

Mendel's Third Law (The Law of Independent Assortment)

When crossing homozygous individuals that differ in two or more pairs of alternative traits, the second generation exhibits independent inheritance and independent assortment of traits (provided their loci are unlinked), resulting in the appearance of individuals with novel trait combinations not found in the parental or grandparental forms.

The third law of inheritance was established through dihybrid cross experiments. Researchers analyzed the inheritance of two pairs of alternative traits: yellow and green seed color, and smooth and wrinkled seed shape in peas.

Upon self-pollination of first-generation hybrids, the second generation shows a phenotypic segregation ratio of 9:3:3:1, distributed as follows: 9/16 (56.25%) yellow and smooth; 3/16 (18.75%) yellow and wrinkled; 3/16 (18.75%) green and smooth; and 1/16 (6.25%) green and wrinkled. Thus, alongside plants with seeds identical to the parental forms, individuals emerged whose seeds exhibited novel combinations of parental traits. The cytological basis of this law is meiosis, during which non-homologous chromosomes segregate independently and can combine in any possible arrangement.

Genotypic segregation ratio — 1 : 2 : 1 : 2 : 4 : 2 : 1 : 2 : 1 (1/16 homozygous yellow and smooth; 2/16 homozygous yellow, heterozygous smooth; 1/16 homozygous yellow and wrinkled; 2/16 heterozygous yellow and homozygous smooth; 4/16 diheterozygous yellow and smooth, etc.)

The inheritance of each trait occurs independently of all other traits.

Random (independent) assortment is manifested by the appearance in F₂ of 3/16 yellow, wrinkled and 3/16 green, smooth individuals — phenotypes with recombined traits.

Independent assortment of traits occurs when genes determining different traits are located on different non-homologous chromosomes (unlinked gene loci). When non-allelic genes reside on the same chromosome (linked loci), linked inheritance is observed in accordance with the patterns established by T. Morgan.

In polyhybrid crosses, The ratio of different F₂ phenotypes is expressed by the formula (3:1)ⁿ, where n is the number of trait pairs analyzed in the heterozygous individual (the degree of heterozygosity). The phenotypic segregation ratio for a monohybrid cross is (3:1)¹ = 3:1, for a dihybrid cross (3:1)² = 9 : 3 : 3 : 1, and for a trihybrid cross (3:1)³ = 27 : 9 : 9 : 9 : 3 : 3 : 3 : 1. Genotypic segregation is determined by the formula (1 : 2 : 1)ⁿ, where n is the degree of heterozygosity.

Crossing Scheme

Given:

A - gene for yellow pea seed color;

a - gene for green pea seed color;

B - gene for smooth pea seed shape;

b - gene for wrinkled pea seed shape.

AABB - genotype of homozygous yellow and smooth peas,

aabb - genotype of homozygous green and wrinkled peas.

Solution

F₁: AaBb - diheterozygous yellow smooth peas (uniformity of first-generation hybrids).

F₂:

Punnett square

To solve problems, you need to correctly write out the types of gametes, the number of which is determined by the formula 2ⁿ, where n is the number of genes for which the given hybrid is heterozygous. Monohybrids Aa have two kinds of gametes: 2¹ = 2 (two kinds: A, a), dihybrids have 2² = 4 (AB, Ab, aB, ab), and trihybrids have 2³ = 8 types of gametes. The number of genotypes in F₂ is determined by the formula 3ⁿ, where 3 represents the number of possible combinations of male and female gametes in a monohybrid cross, and n is the number of allele pairs for which the hybrid is heterozygous.

The results of a dihybrid cross and Mendel's third law of heredity are determined by the fact that:

a) the genes being analyzed are located in different non-homologous chromosomes; only in this case will independent inheritance and random combination of traits occur;

b) during meiosis in anaphase I, independent assortment of homologous chromosomes takes place;

c) in anaphase II, independent Separation of chromatids (allelic genes) occurs. As a result of the independent assortment of chromosomes and chromatids, gametes with various gene combinations are formed;

d) upon fertilization, a random combination of gametes with diverse combinations of allelic and non-allelic genes occurs, resulting in The formation of zygotes (organisms) with various genotypes and trait combinations. A certain proportion of the offspring (6/16 or 37.5%) exhibits phenotypes with novel combinations of traits.

Law of Segregation of Gametes

Allelic genes, when in a heterozygous state, do not blend or alter each other, and they are transmitted into gametes without losing their individuality. Gametes are "pure": they carry only one of the two alleles of a given gene.

The fact that a recessive trait (green seed color), which was absent in the first-generation hybrids F₁, reappeared in 1/4 of the second-generation hybrids F₂ was explained by G. Mendel through the premise that traits themselves are not inherited, but rather hereditary factors (genes) that determine their development, and that these factors are discrete. In F₁ hybrids (Aa), There are two hereditary factors: one of them, A, is responsible for the yellow seed color, and the other, a, for the green color. This regularity became known as the law of segregation of gametes and received cytological substantiation: a) each trait in an organism is governed by two allelic genes located in homologous chromosomes; b) during meiosis, a haploid set of chromosomes enters the gamete (one of the homologous chromosomes, and thus one of the allelic genes). Gametes remain "pure" because they normally possess a single gene allele that determines one of the alternative traits; c) during fertilization, upon gamete fusion, the diploid set of chromosomes is restored, and consequently, the pairing of allelic genes as well.

Test Cross

As is well known, under complete dominance, individuals homozygous for the dominant allele and heterozygous individuals have the same phenotype. Their genotype can be determined by the phenotype of the offspring obtained from various types of hybridization, for example, through a test cross.

A test cross is performed between an individual with a recessive phenotype and one with a dominant phenotype. It is based on the principle that individuals homozygous for the recessive allele always have a uniform phenotype and produce only one type of gamete. Therefore, a test cross makes it possible to determine the genotype of an individual with a dominant phenotype as early as the first generation of hybrids.

The crossing scheme when the individual whose genotype is to be determined is homozygous:

Thus, if no phenotypic segregation occurs among the offspring resulting from a test cross, the individual with the dominant phenotype proves to be homozygous.

In the case of heterozygosity, the test cross scheme looks as follows:

Thus, if a phenotypic segregation in a 1:1 ratio occurs among the offspring as a result of a test cross, the individual with the dominant phenotype is heterozygous for the given trait.

Dihybrid test cross.

Options:

The uniformity of the offspring in a dihybrid test cross proves that the analyzed individual is homozygous for two pairs of dominant alleles (AABB).

A 1:1 segregation ratio for the first trait combined with uniformity for the second trait proves that the individual under analysis is heterozygous for the first pair of alleles and homozygous for the second pair of dominant alleles.

Uniformity of offspring for the first trait and a 1:1 segregation ratio for the second trait prove that the individual under analysis is homozygous for the first pair of dominant alleles and heterozygous for the second pair.

A 1:1:1:1 phenotypic segregation ratio in the offspring indicates that the individual under analysis is dihybrid (AaBb).

While test crosses cannot be applied in medical genetics and anthropogenetics, understanding the patterns of such crosses makes it possible to determine potential genotypes of parents and offspring when analyzing pedigrees and real-life clinical scenarios.

In animal breeding, test crosses are used to identify individuals that are homozygous for specific traits, whose descendants will not show phenotypic segregation. For instance, a farm was breeding Chinchilla rabbits. These rabbits have a beautiful grey coat, making their pelts highly valuable. However, interbreeding Chinchilla-colored rabbits often resulted in the birth of pied (spotted with large white patches) kits whose pelts were discarded because they lacked a uniform color. To determine the genotypes of rabbits with Chinchilla and pied coloration, they were crossed in various combinations (Chinchilla with Chinchilla, pied with pied, and Chinchilla with pied). The pied individuals proved to be homozygous for the recessive allele, whereas the Chinchilla-colored individuals included both homozygotes and heterozygotes for the dominant allele.

To eliminate heterozygous individuals (since their offspring exhibit trait segregation), a test cross was performed by mating Chinchilla-colored animals with pied ones. Chinchilla rabbits whose offspring showed no phenotypic segregation were kept for breeding, while the heterozygous ones, whose offspring exhibited segregation, were culled.

Lethal Genes

Deviations from expected segregation ratios are frequently associated with the phenotypic expression of lethal alleles, where segregation among second-generation hybrids may differ from expectations because homozygotes and heterozygotes for certain alleles have varying viability. An allelic gene that, when expressed in the phenotype, causes the death of the individual is referred to as a lethal gene.

For example, platinum coat color in foxes is highly prized for fur products. It arose in the early 20th century as a result of a mutation and is determined by a dominant allele (P): when platinum foxes are interbred, their offspring include individuals with both platinum and silver coats.

Attempts to breed homozygous platinum foxes yielded no results, although theoretically it seemed possible. Using a test cross, it was established that all platinum foxes are heterozygous, as segregation occurs among their offspring: across 58 litters, there were 127 platinum and 58 silver pups (i.e., a ratio close to 2 : 1 rather than 3 : 1 as would be expected under the law of segregation). Furthermore, when silver foxes were mated with each other or with platinum ones, litters typically consisted of 4–5 pups, whereas interbreeding platinum foxes produced only 3–4. It turned out that individuals homozygous for the platinum coat allele do not exist at all, because embryos with such a genotype (PP) die at Cytology/cytology/16.html">Early stages of development. A similar phenomenon is known in grey Karakul sheep, where lambs homozygous for the dominant grey wool allele die due to underdevelopment of the Digestive System. A lethal short-tail allele is also known in mice.

Thus, quantitative ratios of different phenotypic offspring groups are influenced by lethal alleles which, upon phenotypic expression, destroy the organism before its development is fully complete. In the case of platinum foxes, the dominant allele was lethal, but its negative effect manifested only in the homozygous state. Most lethal alleles are recessive and therefore cause the death of individuals homozygous for them (for example, the allele causing hydrops in Ayrshire calves).

Mendelian traits in humans, Monogenic Diseases, monogenic inheritance

Traits that are inherited According to the patterns established by G. Mendel are called Mendelian traits. Some human Mendelian traits are listed in the table; their total number exceeds 2,300.

Mendelian Traits in Humans

All Mendelian traits are discrete and controlled monogenically, meaning by a single gene (monogenic inheritance). Mendelian traits include Monogenic Disorders, which are also controlled by a single gene. The following types of monogenic inheritance are distinguished: autosomal dominant, autosomal recessive, X-linked (dominant and recessive), and Y-linked. Traits associated with these inheritance patterns are identified using the genealogical method through the construction and analysis of pedigrees.