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1. Genetics 1 BY DR MARYAM WAQAR

2. WHAT IS GENETICS????? The branch of biology that deals with heredity, especially the mechanisms of hereditary transmission and the variation of inherited characteristics among similar or related organisms

3. Terminology: Gene. Alleles- Dominant. - Recessive. Nucleotides. Codon. Genetic Code.

4. GENE Biological unit of heredity Gene hold the information to build and maintain their cells and pass genetic traits to offsprings In cells, a gene is portion of DNA

5. Gene (DNA) RNA formation Protein formation Cell structure Cell enzymes cell function

6. ALLELE Is one member of a pair or series of different forms of a gene. Homozygous:- an organism in which 2 copies of genes are identical i.e. have same alleles Heterozygous:- an organism which has different alleles of the gene

7. Chromosomes: Chromatin : DNA, RNA & proteins that make up chromosme Chromatids: one of the two identical parts of the chromosome. Centromere: the point where two chromatids attach 46 chromosomes. 22 pairs Autosomes and 1 pair Sex chromosomes.

8. NUCLEOTIDE: group of molecules that when linked together, form the building blocks of DNA and RNA; composed of phosphate group, the bases:adenosine,cytosine,guanine and thymine and a pentose sugar .In case of RNA,thymine base is replaced by uracil. CODON : series of three adjacent bases in one polynucleotide chain of a DNA or RNA molecule which codes for a specific amino acid. GENETIC CODE : the sequence of nucleotides in a DNA or RNA molecule that determines the amino acid sequence in the synthesis of proteins.

9. Congential Disease: Diseases which are present at birth. Hereditary/Familial Disease: Diseases which are derived from one’s parents and trasmitted in the gametes through the generations. Not all congenital diseases are genetic( congenital Syphilis) and not all genetic diseases are congenital (Huntington disease).

10. Mutations.

11. Definition: Permanent changes in the DNA. Those that affect germ cells are transmitted to the progeny. Mutations in the somatic cells are not transferred to the progeny but are important in the causation of cancer and some congenital diseases.

12. CAUSES OF MUTATIONS Chemicals Nitrous acid Alkylating agents 5- bromouracil Antiviral drug iododeoxy uridine Benzpyrene in tobacco smoke

13. X – rays & ultraviolet light Certain viruses such as bacterial virus

14. Types Of Mutations

15. Point Mutation: Substitution of a single nucleotide base by a different base. Categorized as: Missense Mutations . Nonsense Mutations .

16. Frameshift Mutations: Insertion or deletion of one or two base pairs alters the reading frame of the DNA strand.

17. Trinucleotide Repeat Mutations: Such type of mutation leads to amplification of a sequence of 3 nucleotides as in fragile X chromosome syndrome in which there is a 250 or more repeat of CGG (normally upto 29)

18. Classification Of Genetic Diseases Single Gene Defects/Mendelian Disorders. Disorders with Multifactorial or Polygenic inheritance. Cytogenetic Disorders. Disorders showing atypical patterns of inheritance.

19. Mendelian Disorders A genetic disease caused by a single mutation in the structure of DNA, which causes a single basic defect with pathologic consequences

20. Patterns Of Inheritance: Autosomal Dominant. Autosomal Recessive. X-Linked Recessive. X-Linked Dominant .

21. Autosomal Dominant Disorders

22. Manifested in heterozygous states. Individuals with these diseases usually have one affected parent .* Variable to late onset. These disorders usually involve non-enzymatic proteins; Proteins involved in metabolic pathway regulation. Structural Proteins.

23. Inheritance Pattern: Typical mating pattern is a heterozygous affected individual with a homozygous unaffected individual. Every child has one chance in two of having the disease Both sexes are affected equally..

24. Disorders:

25. Structural Protein Defects: Marfan’s Syndrome. Ehler-Danlos Syndrome.

26. Marfan’s Syndrome: Mutation in the fibrillin gene. Fibrillin important component of microfibrils in Elastin . Tissues affected are Skeleton, Eyes and the CVS. C/F include tall stature, long fingers, pigeon breast deformity, hyper-extensible joints,high arched palate, BL subluxation of lens, floppy Mitral valve, Aortic aneurysm and dissection, defects in skin,lungs .

27. Ehler-Danlos Syndrome(Cutis Hyperelastica ): Characterized by defects in collagen synthesis. Clinical Features include fragile, hyper-extensible skin, hyper-mobile joints, rupture of internal organs like the colon, cornea and large arteries, poor wound healing.

28. Defects in metabolic pathway proteins: Familial Hypercholesterolemia : One of the most common mendelian disorders. Mutation in the LDL receptor gene. Hypercholesterolemia due to impaired LDL transport into cells. Increased risk of atherosclerosis and coronary artery disease. Increases Cholesterol leads to formation of Xanthomas .

29. Autosomal Recessive Disorders

30. Largest group of Mendelian Disorders Affected individuals usually have unaffected (carrier) parents. Uniform, early age of onset. These disorders usually involve Enzymatic Proteins.

31. Pattern Of Inheritance: Typical mating pattern is two heterozygous unaffected (carrier) individuals. The triat does not usually affect the parent, but siblings may show the disease. Siblings have one chance in four of being affected. Both sexes affected equally.

32. Disorders:

33. Glycogen Storage Diseases. Category Disease Enzyme Hepatic Type. Von Gierke’s Disease type 1. Glucose-6-phosphotase. Myopathic Type. McArdle Syndrome. Muscle Phosphorylase . Miscellaneous Type. Pompe’s Disease type II Lysosomal Glucosidase .

34. X-Linked Recessive Disorders.

35. Most common X-linked disorders. Usually expressed only in males. Rarely, due to random X-inactivation, a female will express disease, called manifesting heterozygotes .

36. Pattern Of Inheritance: Disease usually passed on from carrier mother. Expressed in male offspring, females are carriers. In this case, Recurrence risk is half of sons are affected, half of the daughters are carriers.

37. Recurrence risk: All the daughters are heterozygous carriers and all the sons are homozygous normal .

38. Disorders:

39. DISORDERS WITH MULTIFACTORIAL (POLYGENIC)INHERITANCE Involved in many physiologic characteristics of humans e.g. height, weight, hair color Defined as one governed by additive effect of two or more genes of small effect but conditioned by environmental, non genetic influences

40. The disorder becomes manifested only when a certain number of effector genes, as well as conditioning environmental influences are involved Rate of recurrence is 2 to 7%

41. COMMON DISEASES ASSOCIATED: Diabetes mellitus Hypertension Gout Cleft lip and palate Schizophrenia Bipolar disorder Congenital heart disease Skeletal abnormalities Neural tube defects Coronary artery disease

42. Thankyou

43. Genetics 2 BY DR MARYAM WAQAR

44. Cytogenetic Disorders

45. KARYOTYPING Basic tool of cytogeneticist Karyotype is a photographic representation in which chromosomes are arranged in order of decreasing length Giemsa stain (G banding) technique—each chromosome can be seen to possess a distinctive pattern of alternating light and dark bands of variable widths

46. Shorthand of Cytogenetics: Short arm denoted as p, long arm denoted q . Each arm divided into numbered regions from the centromere onwards. Each region numerically arranged into bands . For e.g., 5p24 would denote chromosome 5, short arm, region 2 and band 4.

47. Cytogenetic disorders may result from structural or numeric abnormalities of chromosomes It may affect autosomes or sex chromosomes

48. Numeric Abnormalities: Normal Chromosomal number is 46. (2 n =46). This is called euploid state. (Exact multiple of haploid number). Polyploidy : posession of more than two sets of homologous chromosomes. Chromosomal numbers like 3n or 4n. (Incompatible with life); generally results in spontaneous abortion Aneuploidy : Any Chromosomal number that is not an exact multiple of haploid number . E.g 47 or 45.

49. Aneuploidy: Most common cause is nondisjunction of either a pair of homologous chromosomes during meiosis I or failure of sister chromatids to separate during meiosis II. The resultant gamete will have either one less chromosome or one extra chromosome.

50. Fertilization of such gamete will result in zygote being either trisomic ( 2 n +1 ) or monosomic ( 2 n -1 ). Monosomy in autosomes is incompatible with life. Trisomy of certain autosomes and monosomy of sex chromosomes is compatible with life.

51. Mosaicism : The presence of two or more types of cell populations in the same individual. Postzygotic mitotic nondisjunction will result in one trisomic and one monosomic daughter cell. The descendants of these cells will produce a mosaic.

52. Structural Abnormalities: Usually result from chromosomal breakage, resulting in loss or rearrangement of genetic material. Patterns of breakage: Translocation. Isochromosomes . Deletion. Inversions. Ring Chromosomes.

53. TRANSLOCATION Transfer of a part of one chromosome to another chromosome Translocations are indicated by t E.g. 46,XX,t(2;5)(q31;p14) Balanced reciprocal translocation is not harmful to the carrier, however during gametogenesis, abnormal gametes are formed, resulting in abnormal zygotes

54. Centric fusion type or robertsonian translocation: The breaks occur close to the centromere, affecting the short arms of both choromosomes Transfer of the chromosome leads to one very large and one extremely small chromosome The short fragments are lost, and the carrier has 45 chromosomes Such loss is compatible with survival However, during gametogenesis difficulties arise

55. ISOCHROMOSOMES: Result when one arm of a chromosome is lost and the remaining arm is duplicated, resulting in a chromosome consisting of two short arms only or of two long arms. DELETION: Loss of a portion of chromosome This can be terminal (close to the end of the chromosome on the long arm or the short arm), or it can be interstitial (within the long arm or the short arm). A ring chromosome is a variant of deletion.It occurs when break occurs at both the ends of chromosome with fusion of the damaged ends.

56. INVERSIONS: Occur when there are two breaks within a single chromosome with inverted reincorporation of the segment. Since there is no loss or gain of chromosomal material, inversion carriers are normal. An inversion is paracentric if the inverted segment is on the long arm or the short arm . The inversion is pericentric if breaks occur on both the short arm and the long arm .

57. General Features of Cytogenetic Disorders: Associated with absence, excess, or abnormal rearrangements of chromosomes. Loss of genetic material produces more severe defects than does gain. Abormalities of sex chromosomes generally tolerated better than those of autosomes .

58. Sex chromosomal abnormalities are usually subtle and are not detected at birth. Most cases are due to de novo changes (i.e. parents are normal and recurrence in siblings is low).

59. Cytogenetic Disorders involving Autosomes .

60. Trisomy 21/Down’s Syndrome: Most common chromosomal disorder. Down syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 21 st chromosome Trisomy 21 is caused by a meiotic nondisjunction event.

61. With nondisjunction , a gamete ( i.e. , a sperm or egg cell) is produced with an extra copy of chromosome 21; the gamete thus has 24 chromosomes When combined with a normal gamete from the other parent, the embyo now has 47 chromosomes, with three copies of chromosome 21. About 4% of cases are due to Robertsonian translocations. Maternal age has a strong influence

62.                                     Karyotype for trisomy Down syndrome. Notice the three copies of chromosome 21

63. Other Trisomy Syndromes: Trisomy 18 :Edwards Syndrome. Trisomy 13 :Patau Syndrome.

64. Cytogenetic Disorders involving Sex Chromosomes.

65. Extreme karyotypic variations seen frequently with Sex Chromosomes, with females having 4-5 extra X Chromosomes. Males with two to three Y chromosomes have also been identified.

66. Klinefelter’s Syndrome: Defined as Male Hypogonadism , develops when there are at least two X chromosomes and one or more Y chromosomes. Usual karyotype is 47,XXY. The extra X may be maternal or paternal.

67. Results from nondisjunction of sex chromosome during meiosis. Risk factors include advanced maternal age and a history of exposure to radiation in either parent.

68. Clinical Manifestations: Increase in body length between soles and pubis. Reduced facial, body and pubic hair. Gynecomastia. Testicular atrophy. Infertility. Mild mental retardation.

69. Turner Syndrome: Primary hypogonadism in phenotypic females. Results from partial or complete monosomy of the X chromosome.

70. Most common cause is absence of one X chromosome. Less commonly, mosaicism, or deletions on the short arm of the X chromosome.

71. DIAGNOSIS OF GENETIC DISEASE Conventional Cytogenetic Analysis FISH Molecular Analysis

72. THANK YOU