Ministry of Health of Ukraine Ukrainian Medical Stomatological Academy

Approved at the meeting of the Medical department. Protocol № 11, February 3, 2020. Head of the department ______S.I. Dubinin

Methodical content of lecture № 6

Academic discipline Medical biology Organismic level of life organization. Module №2 Fundamentals of genetics Human variation as a life characteristic and genetic Topic of lecture phenomenon. Course of study First, second Faculty Stomatological

The number of teaching hours: 2

1. Scientific and methodological basis of the topic (substantiation of the actuality of the topic, its importance for future professional activity, data aimed at forming a positive motivation for the topic of the lecture).

The study of variability is necessary to understand the of the organic world. Variability provides diversity in the structure and physiological functions of organisms. It is the result of different processes. Some of them occur in hereditary material (genotype), others are limited by . Knowledge of various forms of variability is of great importance to the physician, because to , as a species, there is a large range of variability of morphological, physiological and biochemical characteristics. The study of combinative and mutational variability allows to predict the appearance of offspring with burdened heredity in generations. Knowledge of the material of this topic will be required for the study of human anatomy and physiology, general hygiene, neurology, obstetrics and gynecology, pediatrics, etc.

2. Learning aims of the lecture:  to form in students the ideas on the modern scientific level about different forms of variability and their importance in determining the characteristics of a person;  to analyze the mechanisms of variability;  to prove the value of the topic in general biological specialist training;  to learn to solve situational tasks;  to determine the meaning of the law of homologous series for medicine.

3. Goals of the future specialist's development (educational goals), relevant aspects:  to promote the formation of modern scientific ideas about variability, its forms and their significance in determining the characteristics of a person;  to develop the understanding of variability as a property of life and genetic phenomenon;  to direct students to a conscious and qualitative mastery of knowledge and skills, as a necessary objective requirement of modern specialist training.

4. Interdisciplinary integration. The topic of the lecture is integrated both with the complex of disciplines in medical and biological training (human anatomy, histology, cytology, biochemistry, human physiology, pharmacology), as well as with the disciplines of specialist medical training (hygiene, medical genetics, infectious , childhood diseases, etc.).

5. Plan and organizational structure of the lecture. 1. Variability, its forms and manifestations at the organismal level: phenotypic and genotypic variability. 2. Modifications and norm of reaction. Long modifications. Statistical regularities of modification variability. 3. Combinative variability, its sources. Mutational variability in humans and their phenotypic manifestations. Classification of : genomic, chromosomal aberrations, gene mutations. 4. Natural mutagenesis and induced mutagenesis. Mutagens: physical, chemical, biological. Genetic monitoring. Genetic risk of environmental contamination. The concept of antimutagens and comutagens. 5. The law of homologous series of hereditary variability of hereditary variability, its practical significance.

6. Organizational structure of the lecture: Type of lecture. Means of The main stages of the lecture Time № activation of students. Methodical and their content distribution support materials 1. Preparatory stage. Determination of See points 1 and 2 5 % relevance of the topic, educational goals of the lecture and motivation 2. The main stage. Teaching lecture Introductory lecture. 90% according to the plan: An overview generic lecture with 1. Variability, its forms and elements of the problem. manifestations at the organismal Lecture with the use of level: phenotypic and genotypic visualisation. variability. Visual aids: multimedia software 2. Modifications and norm of reaction. and equipment for it (computer, Statistical regularities of modification projector) variability. 3. Combinative variability, its sources. Mutational variability in humans and their phenotypic manifestations. Classification of mutations: genomic, chromosomal aberrations, gene mutations. 4. Natural mutagenesis and induced mutagenesis. Mutagens: physical, chemical, biological. Genetic monitoring. Genetic risk of environmental contamination. The concept of antimutagens and comutagens. 5. The law of homologous series of hereditary variability, its practical significance.

3. Final stage (lecture summary, general Educational literature: 5 % conclusions). 1. Medical Biology : text-book / Thus, each organism in the process of Bazhora Yu. I., Bylyk R. Ye., development and life retains inherent in Chesnokova M. M. et al. – 2nd the species certain properties that are ed., revised and updated. – controlled by heredity. Vinnytsia : Nova Knyha, 2019. – 448 p. 2. Organismic level of life organisation. Bases of human Answers to possible questions. genetics. Training text-book on 1. What are the patterns of Medical biology (module II) for modification of human variability? students of medical and Modification variability is a form of stomatological faculties / Dubinin non-inheritance variability associated S.I., Ovcharenko O.V., Vatsenko with changes in phenotype due to the A.V. et al. – Poltava, 2014. – influence of external conditions. 78 p. Modification changes in traits are not 3. Lazarev K.L. Medical Biology: inherited, but their rate of response, i.e. Text-book. – Second edition. – the range of variability, is hereditary and Simferopol: IAD CSMU, 2003. – determined by genotype. Modification 592 p. variability, as a rule, is appropriate, 4. Medical biology: The study guide consistent with the conditions of of the practical classes course / existence and adaptable. The occurrence O.V. Romanenko, O.V. of modifications caused by the fact that Golovchenko, M.G. Kravchuk, environmental conditions affect the V.M. Grinkevych. – Edited by enzymatic reactions that occur in the O.V. Romanenko. – K.: body and in some way alter their course. Medicine, 2008. – 304 p. As an example of adaptive 5. Bekish O.-Y.L. Medical biology: modifications, we consider the Textbook for students of higher mechanism of melanin pigment educational establishments. – formation. Four genes located in Vitebsk: VSMU Press, 2003. – different chromosomes are responsible 346 p. for its production. Under the influence 6. Green N.P., Stout G.W., of radiation, specific Taylor D.I. Biological Science. – microRNAs are released from skin cells Cambridge, 1994. (keratinocytes) into the intercellular 7. Kimball, John W. Cell biology. – space. This leads to activation and Addison-Wesley Publishing enhanced biosynthesis of the tyrosinase company, Inc, 1984. enzyme, which catalyzes the oxidation of the tyrosine amino acid and Questions: subsequent formation of melanine. 1. What is variability and what 2. What is the significance of forms of its manifestation at the hereditary variability for humans? organismal level do you know? Combinational variability is a form 2. What are the features of of hereditary variability that arises from phenotypic and genotypic the redistribution of genetic material variability? into descendants. In combinational 3. What are modifications and variability, new gene combinations are norm of reaction? What are the inherited, and the genes do not change. statistical patterns of Homologous and non-homologous DNA modification variability? recombination is the cause of 4. What is combined variability and manifestations of combinational what are its sources? variability. Sources of combinational 5. What are the phenotypic variability are: 1) crossing over; manifestations of mutational 2) independent divergence of variability in humans? homologous chromosomes in meiosis; 6. By what criteria are mutations 3) accidental fusion of gametes during classified? fertilization. Due to the independent and 7. What is natural mutagenesis and simultaneous implementation of these induced mutagenesis? processes, a wide variety of genotypes 8. What are some examples of arises. Homologous recombination is the physical, chemical and biological process of exchanging mutagens do you know? sequences between homologous 9. What is genetic monitoring and chromosomes or DNA strands. This for what purpose is it used? type of recombination is used by cells to 10. What are antimutagens and repair DNA damage, the formation of commutagens? new combinations of genes during 11. What is the practical meaning of meiosis, the transfer of mobile genetic the Law of Homologous Series elements, the horizontal transfer of of Hereditary Variability? genes between different cells. Non- homologous recombination is the Tasks: process of exchanging nucleotide  to develop the material of the sequences between non-homologous main textbook and manual; chromosomes or DNA strands. An  to solve test assignments on the example of such recombination is the topic of the lecture (see handbook accidental insertion of viral or bacterial materials); DNA fragments into the DNA of human  to browse internet sites for lecture cells. topic material. Tasks for students' self-preparation:  to give the definition of hereditary variability;  to give examples of combinational and mutational variability in humans;  to name the molecular mechanisms of variability;  to explain the significance of hereditary variability for humans;  to give examples of modification variability in humans.

6. Contents of the lecture material (detailed summary of the content of the topic): Variation is the tendency or potential of an organism to vary (Wagner and Altenberg, 1996); is the ability of living organisms to acquire new features in the process of individual development. Variation is realized at the cellular and organismal levels in the process of organism development. By the ability to inheritance it is distinguished phenotypic (not inherited) and genotypic (can be inherited) variation. Phenotypic variation – change of phenotype under the influence of external factors, which do not lead to genotype disturbance. Genotypic variation is the difference in DNA among individuals due to recombination or of genetical material on the different levels of its organization (karyotype, chromosomes, genotype). Norm of reaction (Wilhelm Johannsen, 1909) – hereditarily fixed limits of modification variability of a particular trait (or whole genotype) under fluctuations of environmental conditions. The norm of reaction is inherited (for some features – broad, for others – narrow). Penetrance (Nikolay Timofeev-Ressovsky, 1927) is the frequency of phenotypic manifestation of a gene in different individuals of a population. There is a complete P. (allele manifested in all individuals who have it in genotype) and incomplete P. (allele is phenotypically not manifested in the part of individuals that have it in genotype). Expressivity (Nikolay Timofeev-Ressovsky, 1927) – the degree of phenotypic manifestation of the same gene allele in different individuals. In the absence of variability of the trait controlled by this allele of the gene E. is constant, in cases of different variant of the trait E. is called variable. Reasons: 1) influence of different environmental conditions; 2) modifying effect of other genes in the same environmental conditions; 3) dependence on the combination of certain genes in the genotype. Phenocopy (Richard Goldschmidt, 1935) is a non-hereditary change of phenotype (modifications), which resembles some changes of genotype in mutations and influenced by environmental conditions (physical, chemical or biological factors) in genetically normal organism during its individual development. Combinative variation – is a type of hereditary (genotypic) variation, which is based on recombination of genetical material during sexual reproduction (gene reshuffling) by ways of : 1) іndependent assortment of homologous chromosomes during meiosis I and nonidentical sister chromatids during meiosis II (inter-chromosomal recombination); 2) crossing over – exchange of fragments between homologous chromosomes during prophase I of meiosis (intra-chromosomal recombination); 3) random fusion of gametes during fertilization (genomic recombination). Mutational variation – is a type of hereditary (genotypic) variation, which is caused by violation of hereditary material on all levels of its organization (genomic, chromosomal, gene).

Variation

Phenotypic Genotypic

Generative Somatic Modification Accidental Mutational Combinative Point

Genomic – ploidy – Chromosomal Gene the change in number of aberrations Frameshift genome – chromosome – euploidy heteroploidy Inter- Intra- (aneuploidy) chromosomal chromosomal Haploidy (n) Translocations Deletions Polyploidy (3n, 4n, 5n, etc.) Polysomy Inversions (2n + x) Trysomy Insertions (2n + 1) Monosomy Duplications (2n – 1)

Mutagenes – the factors which influence on organism results on mutations occurrence.

Classification of mutagenes

Radiation: α- and β-particles, γ-rays, X-rays, Physical UV-rays

Environmental polluters: Mutagens Chemical tobacco smoke, pesticides, heavy metals, etc.

Viruses Biological Bacterias Transposons Mutagenesis – process of occurrence of inherited changes. Depending on the reasons causing mutations, distinguish spontaneous and induced mutagenesis. Spontaneous mutagenesis – process of occurrence of hereditary material changes in alive organisms in natural environment of their existence. The principal causes resulting in spontaneous mutations the following: - Mistakes DNA reduplications (result in replacement of the bases); - Mistakes DNA recombination (change number of ); - Mistakes DNA reparation (fix the arisen changes); - Presence of special genes in genome – mutators which induce mutagenesis; - Accumulation in the cells some chemical substances which influence is harmful on genetic apparatus during the life activity. Induced mutagenesis is an artificial increase of mutations frequency under influence of mutagenes.

The factors lowering frequency of mutations. Mutations only in unusual cases reach a final stage of the realization. During evolution the nature has created a number of mechanisms which reduce number of phenotypical manifestations of mutations: - degeneracy of genetic code (the mutation frequently replaces one triplet with another which codes the same amino acid); - diploidy of organism (mutant genes frequently recessive, one attribute codes two genes and if an organism is heterozygous recessive gene can not be shown); - reparation (restoration of damaged mutagenes and DNA sites).

The law of homologous lines of hereditary forms of variability (Nikolay Vavilov, 1920) Genetically close kinds and species are characterized by similar lines of hereditary variability so, that, knowing a line of forms within the limits of one kind it is possible to provide existence of parallel forms in other kinds and sorts. The genetically closer the organism in the general common system of sorts and kinds, the is more full similarity in the ranks of their variability. N. Vavilov's law has determined the formula: G1 (a + b + c … … …), G2 (a + b + c … … …), G3 (a + b + c … … …), where G – different kinds (species) of organisms, a, b, c – different variable attributes. The law of homologous lines in hereditary variability has the direct attitude to studying human hereditary diseases. The question of treatment and prevention of hereditary diseases cannot be solved without research on animals with hereditary anomalies which are similar to the person one. According to Vavilov's law, which are similar to the human hereditary diseases can be observed on animals. Really, many pathological conditions which are revealed in animals, can be models of human hereditary diseases. So, some dogs have the hemophilia which is X-linked. Hereditary deafness exists in guinea-pigs, mice and dogs. Hereditary diseases of metabolism such as an and diabetes can have the mice. In spite of already known mutations, by influence of mutagen factors, it is possible to receive many new anomalies from the laboratory animals and study them in experiment.

8. Materials for activating students during the lecture: The lecture uses multimedia support, which provides illustrative materials: diagrams, drawings, photographs. Lecture materials are supplemented with tests and situational tasks, which are presented in the manual «Organismic level of life organization. Fundamentals of human genetics».

9. Materials for students' self-preparation for the lecture (on the topic presented in the lecture): Literature: 1. Medical Biology : text-book / Bazhora Yu. I., Bylyk R. Ye., Chesnokova M. M. et al. – 2nd ed., revised and updated. – Vinnytsia : Nova Knyha, 2019. – 448 p. 2. Organismic level of life organisation. Bases of human genetics. Training text-book on Medical biology (module II) for students of medical and stomatological faculties / Dubinin S.I., Ovcharenko O.V., Vatsenko A.V. et al. – Poltava, 2014. – 78 p. 3. Lazarev K.L. Medical Biology: Text-book. – Second edition. – Simferopol: IAD CSMU, 2003. – 592 p. 4. Medical biology: The study guide of the practical classes course / O.V. Romanenko, O.V. Golovchenko, M.G. Kravchuk, V.M. Grinkevych. – Edited by O.V. Romanenko. – K.: Medicine, 2008. – 304 p. 5. Bekish O.-Y.L. Medical biology: Textbook for students of higher educational establishments. – Vitebsk: VSMU Press, 2003. – 346 p. 6. Green N.P., Stout G.W., Taylor D.I. Biological Science. – Cambridge, 1994. 7. Kimball, John W. Cell biology. – Addison-Wesley Publishing company, Inc, 1984.

Questions: 1. What is variability and what forms of its manifestation at the organismal level do you know? 2. What are the features of phenotypic and genotypic variability? 3. What are modifications and norm of reaction? What are the statistical patterns of modification variability? 4. What is combined variability and what are its sources? 5. What are the phenotypic manifestations of mutational variability in humans? 6. By what criteria are mutations classified? 7. What is natural mutagenesis and induced mutagenesis? 8. What are some examples of physical, chemical and biological mutagens do you know? 9. What is genetic monitoring and for what purpose is it used? 10. What are antimutagens and commutagens? Tasks:  to develop the material of the main textbook and manual;  to solve test assignments on the topic of the lecture (see handbook materials);  to browse internet sites for lecture topic material: https://www.slideshare.net/E_neutron/human-variability-as-property-of-life-the-genetic- phenomena https://www.slideshare.net/Annieanila/lethal-genes-and-gene-therapy https://present5.com/x-and-y-chromosomes-sex-chromosomes/

Materials on the topic of future lecture: Literature: 1. Medical Biology: text-book / Bazhora Yu. I., Bylyk R. Ye., Chesnokova M. M. et al. – 2nd ed., revised and updated. – Vinnytsia : Nova Knyha, 2019. – 448 p. 2. Organismic level of life organisation. Bases of human genetics. Training text-book on Medical biology (module II) for students of medical and stomatological faculties / Dubinin S.I., Ovcharenko O.V., Vatsenko A.V. et al. – Poltava, 2014. – 78 p. 3. Lazarev K.L. Medical Biology: Text-book. – Second edition. – Simferopol: IAD CSMU, 2003. – 592 p. 4. Medical biology: The study guide of the practical classes course / O.V. Romanenko, O.V. Golovchenko, M.G. Kravchuk, V.M. Grinkevych. – Edited by O.V. Romanenko. – K.: Medicine, 2008. – 304 p. 5. Bekish O.-Y.L. Medical biology: Textbook for students of higher educational establishments. – Vitebsk: VSMU Press, 2003. – 346 p.

List of main questions: 1. Human genetics as a branch of biology. Methods of studying of human heredity. 2. Genealogical method and pedigree analysis. Types of . 3. method. 4. Dermathoglyphic method. 5. Cytogenetic method. Chromosomal diseases. 6. Biochemical method. Molecular diseases. 7. Population method. Medical and genetic consulting. Prenatal diagnostics.

10. Recommended literature. Base: 1. Medical Biology : text-book / Bazhora Yu. I., Bylyk R. Ye., Chesnokova M. M. et al. – 2nd ed., revised and updated. – Vinnytsia : Nova Knyha, 2019. – 448 p. 2. Organismic level of life organisation. Bases of human genetics. Training text-book on Medical biology (module II) for students of medical and stomatological faculties / Dubinin S.I., Ovcharenko O.V., Vatsenko A.V. et al. – Poltava, 2014. – 78 p. 3. Lazarev K.L. Medical Biology: Text-book. – Second edition. – Simferopol: IAD CSMU, 2003. – 592 p. 4. Medical biology: The study guide of the practical classes course / O.V. Romanenko, O.V. Golovchenko, M.G. Kravchuk, V.M. Grinkevych. – Edited by O.V. Romanenko. – K.: Medicine, 2008. – 304 p. 5. Bekish O.-Y.L. Medical biology: Textbook for students of higher educational establishments. – Vitebsk: VSMU Press, 2003. – 346 p.

Additional: 1. Green N.P., Stout G.W., Taylor D.I. Biological Science. – Cambridge, 1994. 2. Kimball, John W. Cell biology. – Addison-Wesley Publishing company, Inc, 1984