Basics of Medical Genetics - Buzhiyevska T.I. 2001

General Genetics
Chromosomal Basis of Heredity

The chromosomal basis of heredity was established by the studies of T. Boveri and W. Sutton in 1902 during the initial stage of the Selection/4.html">Development of Genetics, long before molecular mechanisms were discovered.

Studies by histologists and cytologists working on various experimental models established that each species of living organisms has a characteristic number and Structure of Chromosomes; that most living organisms have a double (diploid, 2n) set of chromosomes in their somatic Cells; and that in sexual reproduction, the chromosome composition of a particular pair (sex chromosomes) differs between sexes. Mature Germ Cells possess a haploid (n) set of chromosomes As a result of reduction during Meiosis.

Diploidy is restored during Fertilization, which initiates a new life and marks the starting point from which time begins for this new Organism.

A chromosome is a single circular double-stranded DNA molecule wrapped around a chain of histone spools, resulting in its 4-level supercoiling. The tighter the bond between DNA and Histones, the greater the degree of chromosome coiling; the latter becomes more inactivated, and the Genetic information is excluded from the process. The highest degree of chromosome coiling is observed during the final phases of mitosis (anaphase, telophase), which protects the genetic material from damage during its distribution between daughter cells. The lowest degree of chromosome coiling and a comparatively weak DNA-histone bond occur in the G₀ phase of the Cell Cycle, when The Cell performs its differentiated function. During this interphase period, the bulk of functional genes are expressed; "housekeeping" genes operate—which are identical in all Cells of the organism, satisfying the cells' basic needs for RNA, Proteins, Glycoproteins, Lipoproteins, Enzymes, energy, etc. At this time, the Specialized Functions of cells in differentiated Tissues and Organs are also carried out through the expression of "luxury" genes, whose products are necessary for all cells of the organism and are released into the intercellular environment as enzymes, Hormones, Neuropeptides, etc. In the G₁ phase, which cells enter in preparation for division, genes responsible for reproduction begin to function, and necessary proteins and energy compounds accumulate in the Cytoplasm. The cell then enters the S period, the phase of METABOLISM/36.html">DNA Replication. Prior to the S phase, the so-called interphase chromosome consists of a single chromatid with one arm on either side of the centromere.

During semi-conservative template synthesis, new daughter DNA strands complementary to the parental strand are formed; chromosomes acquire a second chromatid, joined at the centromere region to the existing one. At this time, the expression of genes operating in previous periods ceases, and the chromosome begins to coil rapidly. Passing through the G₂ phase, in which mitotic spindle structures appear (also due to the function of corresponding genes), the cell enters mitosis, sequentially passing through prophase (breakdown of the nuclear envelope, asynchronous chromosome Condensation), metaphase (when well-formed two-chromatid chromosomes align along the cell equator, attached by their centromeres to the spindle fibers), anaphase (the chromosome splits longitudinally at the centromere into two single chromatids that migrate to opposite poles of the spindle), and telophase (single-chromatid chromosomes begin to form new nuclei and individual cell membranes for each new cell). Instead of one parental cell, two new daughter cells emerge; instead of one old cell, two newborns are created. As long as cells divide, they do not die or age, but rather rejuvenate. At the level of unicellular organisms, time can be reversed.

The number of chromosomes containing all The genes of an organism is constant for each species. Tjio and Levan (1948) first determined that each human body cell contains 46 chromosomes, meaning humans possess a chromosome set of 2n=46, or 23 pairs of chromosomes, which include one pair of sex chromosomes (XX in females and XY in males) and 22 pairs of autosomes identical in both sexes. Germ cells are formed as a result of two consecutive meiotic Divisions of the germinal epithelium, during which one division occurs without a period of DNA Synthesis (equational division, or reduction of the chromosome number). Therefore, each mature germ cell has a haploid, halved (n) set of chromosomes. The totality of genes contained in the chromosomes of haploid cells is called The Genome. All ovum cells carry 22+X chromosomes, while spermatozoa carry either 22+X or 22+Y chromosomes (in a 1:1 ratio). The sex of the future child (46, XX or 46, XY) depends on the chromosome set of the spermatozoon that fertilizes the egg. At the same time, the egg may exhibit differential selective affinity for certain spermatozoa. The female organism is entirely diploid, whereas the male is hemizygous for the X and Y chromosomes. That is, male cells contain all genes located in autosomes in double copy (just like females), whereas genes located on sex chromosomes exist in a single copy in males. As a result of sexual reproduction, a girl receives each Gene from both her mother and her father, whereas a boy receives genes located on the X chromosome exclusively from his mother, and those on the Y chromosome exclusively from his father. This mechanism underlies Sex-Linked Inheritance. The localization of genes on chromosomes and their linked inheritance cause deviations from Mendel's law of independent assortment of hereditary traits in second-generation offspring (grandchildren) during polygenic crossbreeding. This segregation is limited to linkage groups, the number of which corresponds to the haploid chromosome Complement (n)+1. In humans, there are 24 such groups (22+X+Y). The Y chromosome is significantly smaller than the X and contains less DNA, fewer genes, and less genetic information. The difference in gene count between male and female genotypes is partially compensated for in female interphase cells by the condensation of one of the two X chromosomes. In most cases, only one X chromosome is active in a female somatic cell, while the other is inactivated, highly condensed, and appears as a triangular, oval, or round Chromatin mass located most frequently near the nuclear membrane. This structure is called sex chromatin, or a Barr body (named after the Canadian histologist who first drew attention to it), and is used for rapid determination of an individual's biological sex from cell samples, as well as for detecting abnormalities in X chromosome number.

Different X chromosomes undergo inactivation selectively in different cells. In some cells, the maternally derived X chromosome is inactivated, while in others, the paternally derived one is. This increases the mosaicism of the female organism compared to the male. A human is not merely a clone of a single cell (the zygote); they are a mosaic defined by the expression of different genes in different cells, which is linked to the differentiated function of pluripotent cells in a multicellular organism. The 46 Human chromosomes constitute the karyotype. Most commonly, the karyotype is studied during the metaphase stage of peripheral Blood lymphocytes after in vitro cultivation and specialized Preparation and Staining of Microscope slides (Fig. 6).

The presence of two copies of each chromosome in the cells of diploid organisms determines the presence of two copies of each gene, located at identical loci (isoloci) of homologous chromosomes, which are referred to as alleles. Genes can be allelic (located at isoloci and encoding the same trait) or non-allelic (differing in localization, structure, and function). An organism whose genome contains identical alleles of a given gene is called homozygous for that gene, whereas one possessing different alleles is termed heterozygous. Some genes have A large number of various variants within a population (though each individual possesses only two of them). They encode polymorphic proteins that differ in Structure and function. For instance, the genes responsible for erythrocyte proteins and defining the major Blood Groups exist in three distinct variants: gene A (J^A) encodes protein A, gene B (J^B) encodes protein B, and gene O (J°) does not encode a protein at all.

The presence of the J°J° genotype results in homozygosity (two identical alleles) and blood group I (O); the J^AJ^A set also indicates homozygosity, but corresponds to blood group II (A), which is the same in the case of heterozygosity—J^AJ°. A similar situation occurs with blood group III (B): either the homozygous set J^BJ^B or the heterozygous set J^BJ°. Blood group IV (AB) is always the consequence of heterozygosity for J^AJ^B. The gene encoding alpha-1-protease inhibitor has more than 60 different alleles, and the glucose-6-phosphate dehydrogenase gene has over 100 variants.

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Fig. 6. Human Karyotype. Chromosomes processed using FISH (fluorescence in situ Hybridization). Probes specific to different chromosomes and their regions are labeled with multicolor fluorophores

What actually are different alleles, and where do they come from? Different gene variants drive The Diversity of living organisms within a single species and serve as the source of evolution; that is, they arise as a result of mutational Variability of the ancestral gene.