GENETICS an Introduction

1. GENETICS an Introduction SDK

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

3. Genetic Course 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. • 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. • This course will deals with the Human as well as Medical genetics.

4. Course Plan

5. Lectures • 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 • 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

6. Seminars • Topics will be allocated according to the groups.

7. Genetics • 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.

8. 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).

9. 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

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

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

13. 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. • 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

14. Genetic Information • 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

15. Genetic Information • 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

16. Genetic Information • 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

17. 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

18. 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

19. 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.

20. What is a Disease • 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.

21. What is Genetic level alterations • Toexamines 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.

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

23. 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 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 transmembraneconductance 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.

24. Growth regulation e.g.Rbtumor-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 Osteogenesisimperfecta 2. Cell Membrane FibrillinMissensemutations causing Marfansyndrome Or deletion of dystrophingene Causing Duchene muscular Dystrophy

25. Molecules and Disease

26. Rate of Biochemical Alterations • Biochemical alterations that cause disease may occur rapidly or slowly • Cyanide (inhibits cytochromeoxidase) 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))

27. 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

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

29. Single Gene Disorders 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

30. Chromosomal Disorders • 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)

31. 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

32. 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)

33. 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] .

34. multifactorial DisordersCOMPLEX 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] .

35. Mutations 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 Glu6to Hb (S) β chain Val 6

36. 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 .

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

38. 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

39. 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 methylmalonicaciduria Gene therapy – an ongoing area of research which would is expected to offer the final solution to genetic diseases. Advantages of Knowing Genetics

40. 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

41. Gene Therapy • 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”.

42. Genetics I might be turning into my mother.After all,I have her straight noseand her broad bonesher stubbornness tohold on to the truths you knowand the lies you don't.I might be turning into my father.After all,I have his brown eyesand his quick mindhis readiness to leave things behind and let the roadunfold like twine.

43. Thank You