2. GENETICS an Introduction SDK

3. Lecture Road Map Introduction of the course Details of teaching tools – Lectures – Group activities and – Seminars Evaluation Plan Genetics introduction and clinical examples

4. This course will deals with the Human as well as Medical genetics. Genetic Course The Aim of this course is to provide the student with a sound understanding of normal and disease processes at the genetic level. This course will be comprised of different modalities of expressions such as Lectures, Seminars, Case base discussions and group activities. Each session will cover the general features of the normal and disease condition(s), and will focus on current understanding of the biochemical effects of normal conditions as well as biochemical defects (metabolic, structural or genetic) which underlie the disease state. By the end of these sessions, the students should be able to demonstrate the ability to discuss the normal and genetic mechanisms that underlie several normal and disease processes.

5. Course Plan

6.  Chemistry, classification and characteristics of Purine and Pyrimidine Bases  Chemistry, classification and characteristics of Nucleosides and Nucleotides.  Classification, Function and occurrence of nucleotides in human tissue and role of Nucleotides in the Human Body.  Role of Cyclic AMP and Cyclic GMP in the body.  Protein Synthesis Lectures  Chromosome structure, classification and abnormalities  Genetic Variation and mutations  Genetic patterns of inheritance  Inborn errors of metabolism  Environmental and Genetic Interactions - Complex Patterns of Inheritance  Cancer genetics,  Breast and Ovarian Cancer and Inherited Predisposition  Genetic counseling, and ethical issues and decision making in medical genetics.  Pharmacogenetics/Pharmacogenomics  Chromosome structure, classification and abnormalities  Genetic Variation and mutations  Genetic patterns of inheritance  Inborn errors of metabolism  Environmental and Genetic Interactions - Complex Patterns of Inheritance  Cancer genetics,  Breast and Ovarian Cancer and Inherited Predisposition  Genetic counseling, and ethical issues and decision making in medical genetics.  Pharmacogenetics/Pharmacogenomics

7. Seminars

8. Human genetics is the science of variation and heredity in humans Medical genetics deals with human genetic variation of significance in medical practice and research. Medical Genetics is concerned with how genes and heredity affect human health. Genetics

9. Why Genetics is Necessary Wilt Chamberlain, a famous basketball player (7 feet, 1 inch; 275 pounds) Willie Shoemaker, a famous horse racing jockey ). (4 feet, 11 inches; barely 100 pounds ).

10. Role of Genes in Human Disease Most diseases / phenotypes result from the interaction between genes and the environment Some diseases / phenotypes are primarily genetically determined – Achondroplasia Other diseases / phenotypes require genetic and environmental factors – Mental retardation in persons with PKU Some diseases / phenotypes result primarily from the environment or chance – Lead poisoning

11. 100% Environmental Struck by lightning Infection Weight Cancer Diabetes Height Sex, Down syndrome, achondroplasia 100% Genetic Hair Colour

13. Genetics Review T A C G C T T C C G G A T T C A A Transcription A U G C G A A G G C C U A A G U U DNA RNA Translation ABCDE Protein Amino Acids

14. Human body is made up of 75 trillion cells Every cells has a nucleus In the nucleus they contain Genes 99.9 % of genes are present in nucleus Few genes are present in Mitochondria Genes are small part of DNA DNA - is a nucleic acid that contains the genetic instructions specifying the biological development of all cellular forms of life DNA is made up of Nucleotides Nucleotides is comprised of Sugar, Nitrogenous base and phosphate Genetic Information Gene – basic unit of genetic information. Genes determine the inherited characters. Genome – the collection of genetic information. Chromosomes – storage units of genes. Human has 23 pairs of chromosomes These 46 chromosomes contain 6 billions individual characters of the genetic code. Gene – basic unit of genetic information. Genes determine the inherited characters. Genome – the collection of genetic information. Chromosomes – storage units of genes. Human has 23 pairs of chromosomes These 46 chromosomes contain 6 billions individual characters of the genetic code.

15. Genotype - the genetic constitution of the organism Phenotype - the observable expression of genotype Locus - a chromosomal location Alleles - alternative forms of the same locus Mutation - a change in the genetic material, usually rare and pathological Polymorphism - a change in the genetic material, usually common and not necessarily pathological Genetic Information

16. Homozygote - an organism with two identical alleles Heterozygote - an organism with two different alleles Hemizygote - having only one copy of a gene – Males are hemizygous for most genes on the sex chromosomes Dominant trait - a trait that shows in a heterozygote Recessive trait - a trait that is hidden in a heterozygote Cytogenetics: Study of chromosomes Genetic Information

17. Genomics: Study of genome, its organization and functions Population genetics: Genetic variation in human populations and factors that affect allele frequencies Clinical genetics: Application of genetics to diagnosis and patient care Genetic counseling: Risk information, psychological and educational support to patients and/or their families Genetic Information

18. Human Genome Human diploid cells contain 46 chromosomes arranged in 23 pairs 2 sex chromosomes (X,Y): XY – in males. XX – in females. 22 pairs of chromosomes named autosomes.  Chimpanzee contain 24 pairs of chromosomes  Cow contain 30 pairs of chromosomes  Chicken contain 39 pairs of chromosomes  Bnana contain 11 pairs of chromosomes  Chimpanzee contain 24 pairs of chromosomes  Cow contain 30 pairs of chromosomes  Chicken contain 39 pairs of chromosomes  Bnana contain 11 pairs of chromosomes

19. Who determines the male or female Gender Is the mother Is the father Or is it by chance from any of the two 50% Girls 50% Boys 50% Girls 50% Boys

20. Genotypes Phenotypes At each locus (location of a gene/marker on the chromosome) there are 2 genes. These constitute the individual’s genotype at the locus. The expression of a genotype is termed a phenotype. For example, hair color, weight, or the presence or absence of a disease.

21. dis·ease (dĭ-zēz') A pathological condition of a part, organ, or system of an organism resulting from various causes, such as infection, genetic defect, or environmental stress, and characterized by an identifiable group of signs or symptoms. Lack of ease; trouble. DISEASES are seen as an abnormality in structure, function of CELLS → ORGANS → SYSTEMS ; generated by biochemical mechanisms. What is a Disease

22.  To examines and identifies the molecules involved in specific diseases. Theses molecules and process are DNA, replication, transcription translation and protein synthesis  All classes of biomolecules found in cells are affected in :  Structure,  Function, or  Amount in one or another disease.  Diseases can be caused by deficiency or excess of certain biomolecules.  Biochemical alterations that cause disease may occur slowly Or rapidly.  Many diseases are determined genetically. What is Genetic level alterations

23. Genetic Basis Of Diseases Genetic Basis Of Diseases Changes an Enzyme Changes an Enzyme inhibitor Changes a receptor Change a transport or carrier protein Changes in Hemostasis Changes in structural Proteins Changes in structural Proteins Growth regulation

24. Changes an Enzyme Phenylalanine hydroxylase Splice site mutation leading to reduced amount of PA hydroxylase Causing phenylketonuria Changes an Enzyme Phenylalanine hydroxylase Splice site mutation leading to reduced amount of PA hydroxylase Causing phenylketonuria Changes an Enzyme inhibitor  1-Antitrypsin Missense mutation that impair secretion of  1-Antitrypsin from liver to serum causing Emphysema and Liver disease Changes an Enzyme inhibitor  1-Antitrypsin Missense mutation that impair secretion of  1-Antitrypsin from liver to serum causing Emphysema and Liver disease Changes a receptor Low density lipoprotein receptor Deletion or point mutation that reduce synthesis, Or transport to the cell surface of LDL receptors or binding to low density lipoprotein Causing Familial hypercholesterolemia Changes a receptor Low density lipoprotein receptor Deletion or point mutation that reduce synthesis, Or transport to the cell surface of LDL receptors or binding to low density lipoprotein Causing Familial hypercholesterolemia Change a transport or carrier protein 1. Haemoglobin Mutations in splice sites (commonest) leading to Reduced  -globin.causing  -Thalassemia. In  -Thalassemia the  -globin gene is usually deleted. 2.Cystic fibrosis transmembrane conductance Regulator. Deletions or point mutation causing Cystic fibrosis. Change a transport or carrier protein 1. Haemoglobin Mutations in splice sites (commonest) leading to Reduced  -globin.causing  -Thalassemia. In  -Thalassemia the  -globin gene is usually deleted. 2.Cystic fibrosis transmembrane conductance Regulator. Deletions or point mutation causing Cystic fibrosis. Changes in Hemostasis Factor VIII deletions, insertions, nonsense mutation reduce synthesis or abnormal factor VIII Causing Hemophilia A. Changes in Hemostasis Factor VIII deletions, insertions, nonsense mutation reduce synthesis or abnormal factor VIII Causing Hemophilia A.

25. Growth regulation e.g.Rb tumor-suppressor gene causing Retinoblastoma etc Changes in structural Proteins 1. Collagen, Deletions Or point mutation that Produce reduced amount Of normal collagen or Normal amounts of mutant Collagen. Causing Osteogenesis imperfecta 2. Cell Membrane Fibrillin Missense mutations causing Marfan syndrome Or deletion of dystrophin gene Causing Duchene muscular Dystrophy Changes in structural Proteins 1. Collagen, Deletions Or point mutation that Produce reduced amount Of normal collagen or Normal amounts of mutant Collagen. Causing Osteogenesis imperfecta 2. Cell Membrane Fibrillin Missense mutations causing Marfan syndrome Or deletion of dystrophin gene Causing Duchene muscular Dystrophy

26. Molecules and Disease MOLECULEProperty affected DISEASEBASIC CAUSE DNA Structure/ function Sickle cell anemia Mutation RNA Structure/ function Certain types of Thalasemia Mutation (leading to splicing defects) Protein Structure/ function Sickle cell anemia Mutation (Val replaces Glu at position 6 of β-chain of HbS) Lipid Amount ↑Tay Sach’s disease Mutation (Resulting in defective enzyme-hexosaminidase A) Glycogen Amount ↑McArdle’s disease Mutation (Resulting in defective enzyme- muscle glycogen phosphorylase) GAG Amount ↑Hurler syndrome Mutation resulting in defective Iduronidase Electrolyte (Cl-) Amount ↑ (in sweat) Cystic fibrosis Mutation (Resulting in defective chloride transport) Water Amount ↓Cholera Infection (toxin of Vibrio cholerae causes loss of water and electrolytes)

27. Biochemical alterations that cause disease may occur rapidly or slowly – Cyanide (inhibits cytochrome oxidase) kills within a few minutes – Massive loss of water and electrolytes (e.g., cholera) can threaten life within hours – May take years for buildup of biomolecule to affect organ function (e.g., mild cases of Niemann-Pick disease may slowly accumulate sphingomyelin in liver and spleen)) Rate of Biochemical Alterations

28. Deficiency or Excess of Biomolecules Diseases can be caused by deficiency or excess of certain biomolecules – deficiency of vitamin D results in rickets, excess results in potentially serious hypercalcemia – Nutritional deficiencies primary cause - poor diet secondary causes - inadequate absorption, increased requirement, inadequate utilization, increased excretion

29. Genes are associated with the development of diseases. Such as – Single gene disorders – Chromosomal disorders – Mitochondrial disorders – Multi-factorial disorders. Genetic Association of Diseases

30. Characterized by genetic mutations of single genes.  More than 6000 single gene disorders are known.  These gene disorders are inherited in recognizable patterns e.g.:  Autosomal dominant - clinically evident if one chromosome affected (heterozygote). e.g., Familial hypercholesterolemia & Huntington's disease  Autosomal recessive - both chromosomes must be affected (homozygous)  e.g., Sickle cell anemia & PKU  X-linked - mutation present on X chromosome females may be either heterozygous or homozygous for affected gene males affected if they inherit mutant gene e.g., Duchenne muscular dystrophy DMD Single Gene Disorders

31. Excess or loss of chromosomes, deletion of part of a chromosome, or translocation – e.g., Trisomy 21 (Down syndrome) Recognized by analysis of karyotype (chromosomal pattern) of individual (if alterations are large enough to be visualized) Translocations important in activating oncogenes – e.g., Philadelphia chromosome - bcr/abl) Chromosomal Disorders

32. Klinefelter Syndrome  47 XXY or XXY syndrome  Has Extra X chromosome  It occurs in every 500 to 1000 births (in the USA).  Since the condition is relatively mild, many cases are not diagnosed till puberty.  The gynaecomastia confers an increased risk of breast cancer

33. Turner Syndrome (45, X)  Absence of an entire sex (X) chromosome  Obviously, only in females - a result of nondisjunction of the X-chromosomes during meiosis.  The ovaries are rudimentary  Stature is small.  About 30 percent of females with Turner syndrome  have extra folds of skin on the neck (webbed neck)

34. MITOCHONDRIAL DISORDERS Caused by mutations in non- chromosomal DNA of mitochondria. e.g. : Leber’s hereditary optic neuropathy [LHON] Moyclonus epilepsy with ragged red fibers [MERRF] Mitochondrial encephalopathy with lactic acidosis and stroke like episodes [MELAS]. Caused by mutations in non- chromosomal DNA of mitochondria. e.g. : Leber’s hereditary optic neuropathy [LHON] Moyclonus epilepsy with ragged red fibers [MERRF] Mitochondrial encephalopathy with lactic acidosis and stroke like episodes [MELAS].

35. multifactorial Disorders COMPLEX OR POLYGENIC DISORDERS : Interplay of number of genes and environmental factors  Pattern of inheritance does not conform to classic Mendelian genetic principles  Combination of environmental & genetic mutations involved in this group. e.g. : Cardiovascular diseases Hypertension Diabetes Cancer [susceptibility genes for breast cancer found on chromosomes 6,11,13,14,15,17 & 22].

36. Definition : replacement or change of a nucleotide base with another, in one or both strands, or addition or deletion of a base pair in a DNA molecule. Hb A β chain Glu 6 to Hb (S) β chain Val 6 Mutations

37. Inborn error of Metabolism Group of genetic disorder, in which a specific enzyme is affected, producing a metabolic block, that may have pathological consequences It is results from a mutation in a structural gene that may affect structure of the encoded protein (an enzyme) an inborn error of metabolism may result.

38. Phenylketonuria phenylalanine hydroxylase  Mutant enzyme is phenylalanine hydroxylase  Synthesize less tyrosine, have ↑ plasma levels of Phe and other metabolites of Phe ( e.g. phenylpyruvate)  ↑ excretion of phenylpyruvate and other metabolites in urine Inborn error of Metabolism

39.  Knowing exact cause of disease at molecular level –better understanding of etiopathogenesis of disease process.  Correction at level of missing biochemical end product e.g. thyroxine administration  Correction at level of excess substrate e.g. low Phe diet in PKU  Replacement of a defective enzyme e.g. Gaucher disease. Advantages of Knowing Genetics

40.  Replacement of defective protein e.g. Factor VIII in hemophilia  Increasing the action of less active mutant enzyme by giving more cofactor or co enzyme e.g. Vit. B12 for methylmalonic aciduria  Gene therapy – an ongoing area of research which would is expected to offer the final solution to genetic diseases. Advantages of Knowing Genetics

41. Gene Therapy  Gene therapy is a technique used for correcting defective genes responsible for disease development  Gene therapy is permissible in humans at present for somatic cells only.  Major problem is complexity and efficacy

42. Types of gene therapy :  Replacement : Mutant gene removed and replaced with a normal gene  Correction : Mutated area of affected gene would be corrected and remainder left unchanged  Augmentation : introduction of foreign genetic material into a cell to compensate for defective product of mutant gene “ only gene therapy currently available today's”. Gene Therapy

43. Genetics I might be turning into my mother. After all, I have her straight nose and her broad bones her stubbornness to hold on to the truths you know and the lies you don't. I might be turning into my father. After all, I have his brown eyes and his quick mind his readiness to leave things behind and let the road unfold like twine.

44. Thank You