Modes of inheritance

A discussion on Modes of Inheritance.

1. Modes of Inheritance 1

2. Your genetics load the gun. Your lifestyle pulls the trigger – Mehmet Oz. All diseases of Mankind except accidental injuries have a genetic component to it . 2

3. Applications: Disease Prediction : - Counselling for prevention. - Early diagnosis & treatment. - Genetic Therap y. 3

4. Genetic Diseases Single gene disorders Mutations at specific locus Sickle cell anemia Multifactorial Disorders Mutations at several loci Diabetes Mellitus Chromosomal disorders Physical changes in the chromosomes Down’s syndrome Mitochondrial Disorders Mutations in Mito DNA Neuropathies 4

5. Gregor Johann Mendel “The Garden Pea” 5

6. Mendelian Inheritance 1. Autosomal Dominant 2. Autosomal Recessive 3. X linked Dominant 4. X linked Recessive 6

7. The law of segregation When any individual produces gametes, the copies of a gene separate so that each gamete receives only one copy (allele). A gamete will receive one allele or the other. 7

8. The Law of Independent Assortment The alleles of different genes assort independently of one another during gamete formation . Pair 1: A and a Pair 2: B and b Pair 3: C and c No. of Combn. 2 n a B C a B c a b C a b c A B C A B c A b c A b C 8

9. Pedigree Construction 9

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11. Autosomal Dominant Most affected parents are heterozygous. Why? Low incidence of the disease per se (1/10,000). Lethality of homozygous individuals. Eg: Achondroplasia, Marfan’s syndrome. 11

12. Hallmarks: No skipping of generations - Longitudinal Inheritance. No sexual predilection. Normal offspring don't transmit the disease. Usually structural proteins are affected. 12

13. Autosomal Dominant 13

14. 1. Variable Expressivity. Eg: Marfan’s syndrome. 2. Late Onset. Eg: Huntington’s chorea. 3. High Recurrent Mutation Rate. Eg: Achondroplasia. 4. Incomplete Penetrance. 14

15. Autosomal Dominant with incomplete penetrance 15

16. Autosomal Recessive Most affected individuals have parents heterozygotes (Normal). Why? Low incidence of the disease per se (1/10,000). The likelihood of two affected persons mating would be1/10,000 x 1/10,000 or 1/100,000,000. Eg: Cystic fibrosis, β- Thalassemia. 16

17. Hallmarks: No sex predilection. Horizontal Inheritance. Parents of affected children may be related. The rarer the trait in the general population, the more likely a consanguineous mating is involved. The trait may appear as an isolated (sporadic) event in small sibships. 17

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20. X linked disorders X-linked genes are never passed from father to son. An affected female must have an affected father. A single dose of a mutant allele will produce a mutant phenotype in the male.(Both dom & rec.) 20

21. X linked Dominant All daughters of an affected male are affected. All sons of an affected male and a normal female are normal. Males are usually more severely affected than females. Females are more likely to be affected than males, even if the disease is not lethal in males. 21

22. X linked Dominant Eg: X linked Hypophosphatasia. Rett’s Syndrome. Alport’s Syndrome. 22

23. X linked Recessive Males are affected. Females are carriers. Oblique mode of transmission. Uncle – Nephew affected. Never occur in females except: Turner’s syndrome. Lyon hypothesis. Born to affected father & carrier female. Testicular feminisation syndrome. 23

24. X linked Recessive 24

25. Skipping of generations? Yes Recessive Both males and females involved X linked recessive only males affected Autosomal recessive Dominant Father to son? All daughters of father affected? Autosomal Dominant X linked Dominant No No Yes 25

26. Mitochondrial inheritance Maternal transmission. The ovum -100,000 copies of mtDNA; The sperm - <100 copies, and these are probably lost at fertilization. Eg: Neurological problems, Lactic acidosis. (MELAS, Kearns Sayre disease, LHON) 26

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28. Multifactorial Disorders Sir Francis Galton. 28

29. Regression to mediocrity. 29

30. Several loci are involved in the expression of the trait. There is no dominance or recessivity at each of these loci. The loci act in concert in an additive fashion, each adding or detracting a small amount from the phenotype. Nature and nurture. 30

31. Most affected children have normal parents. Applicable for traits with continuous distribution. Consanguinity slightly increases the risk for an affected child. 31

32. Chromosomal Abnormalities Numerical abnormalities (Aneuploidy ) Monosomy Trisomy Structural abnormalities Deletion Duplication Translocation Inversion 32

33. Deletion Duplication Inversion 33

34. Insertion Translocation 34

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39. Take Home Message Most diseases have a genetic component to them. Mendelian disorders are potential candidates for gene therapy. Lifestyle modifications have a role to play in preventing Multifactorial diseases. Meticulous pedigree analysis & counselling can reduce the burden of genetic diseases in the society. 39

40. References & Further Reading Robbins & Cotran Pathological Basis of Diseases, 8 th edn. http://www.nature.com/scitable/topicpage/gregor-mendel-and-the-principles-of-inheritance-593 - Website of Nature Publishing Group. http://www.uic.edu/classes/bms/bms655/index.html - Website of Univ. of Illinois at Chicago. 40

41. Thank you ! 41