Genetics

1. Genetics Dr.S.Chakravarty, MBBS,MD

2. Mom’s eyes Dad’s eyes What will I get?

3. Learning objectives • Explain the Mendelian laws and its application in various clinical conditions • Describe the Dominant and Recessive genes in Autosomal and x-linked inheritance patterns in various single gene disorders • List the special features of Autosomal dominant inheritance • Analyze the pattern of mitochondrial inheritance and compare it autosomal and x-linked inheritence • Describe the Punnet squares and calculate the risk in various generations

6. Human Genome Most human cells contain 46 chromosomes: • 2 sex chromosomes (X,Y): XY – in males. XX – in females. • 22 pairs of chromosomes named autosomes.

7. Locus1 Possible Alleles: A1,A2 Locus2 Possible Alleles: B1,B2,B3 Chromosome Logical Structure • Locus – location of a gene/marker on the chromosome. • Allele – one variant form of a gene/marker at a particular locus.

8. Genotypes & Phenotypes • At each locus (except for sex chromosomes) 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.

9. Population Frequency and RFLP Allelle 1 Allelle 2 Phenotype 2 Phenotype 3 Phenotype 1 Homozygous for allele 1 Heterozygous Homozygous for allele 2

10. Dominant vs. recessive A dominant allele is expressed even if it is paired with a recessive allele. A recessive allele is only expressed when paired with another recessive allele.

11. Dominant allele – UPPERCASE eg A • Recessive allele – lower case eg a

12. Gregor Johann Mendel

13. Mendel’s first law • Law of segregation: The two coexisting alleles of an individual for each trait segregate (separate) during gamete formation so that each gamete gets only one of the two alleles. Alleles again unite at random fertilization of gametes. Spermatogonia Oogonia Meiosis I

14. Consequences • Each of the parents transmits only half of its hereditary factors to offspring. • The possible combinations of gametes depends on the number of paternal alleles. • E.g. if a parent has two pairs of alleles (dominant – A,B and recessive – a,b), there are four combinations transfer to children (AB,Ab,aB,ab). • An offspring receives always just one member of allelic pairs (A or a, B or b).

15. Mendel’s second law • Law of independent assortment: alleles of different genes assort independently of one another during gamete formation

17. Coat color B (brown, dominant) or b (white), • Tail length S (short, dominant) or s (long). • Parents are homozygous for each trait (SSbb and ssBB)

18. FOIL method of Multiplying two binomials

19. Application of Mendelian genetics in humans • Disorders caused by a defect in a single gene follow the patterns of inheritance described by Mendel and the term Mendelian inheritance has been used to denote unifactorial inheritance

20. Pedigree symbols

21. Autosomal dominant inheritance • Both males and females equally affected ( as mostly located on AUTOSOMES) • NO SKIPPED GENERATIONS - Every generation of the family is affected • Homozygotes – Genetically lethal

22. Autosomal dominant inheritance • NO SKIPS IN GENERATIONS • BOTH MALES AND FEMALES EQUALLY AFFECTED

23. Punnet square in AUTOSOMAL DOMINANT DISORDER • Affected heterozygous mother and normal homozygous father: • Affected heterozygous mother and affected heterozygous father • Affected homozygous mother and normal homozygous father

24. Special features of AD inheritance • Late onset – present very late in life • Variable expressivity – intensity of the disease varies from person to person or family members with the same disease. • Reduced Penetrance – absence of the disease even though the person is affected with the disease • New mutations – sudden development of disease in a family. • Pleiotropy - refers to a situation when a disorder has multiple effects on the body (multiple phenotypic presentations)

25. Autosomal dominant NEED TO REMEMBER THIS !!

26. Autosomal co-dominant inheritence • Two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein • Both alleles influence the genetic trait or determine the characteristics of the genetic condition. • E.g. ABO locus

27. Structure of blood group antigens

28. Autosomal Recessive Inheritance • Clinically expressed only in their homozygous states (egaa) • Disease generally seen only in one generation of a pedigree • Located on autosomes – males and females affected in roughly equal frequencies

29. Autosomal recessive inheritence • Both males and females are equally affected (homozygous) • Usually have Unaffected parents • Skipped generations • Increased incidence with consanguineous marriages • Enzyme deficiencies disorders are most common ( manifests very early in life).

30. Autosomal recessive pattern

31. Punnet square • Normal heterozygous mother and normal heterozygous father • Affected homozygous mother and normal homozygous father • Affected homozygous mother and normal heterozygous father

32. Autosomal recessive disease NEED TO REMEMBER THIS !!

33. X-linked dominant • Twice the number of females than males(F>M) • Father-to-son transmission does not occur • Males usually die ( genetic lethal). • Heterozygous females are mildly to overtly affected depending on the skew of the X chromosome inactivation. • Homozygous females (double dose) are overtly affected.

34. X chromosome inactivation • Males carry a X chromosome from mother and Y chromosome from father. Females get one X chr from each parent • Y CHR – 30 protein coding genes • X chr – hundreds of protein coding genes •   X INACTIVATION IS A PROCESS TO EQUALIZE • BLASTOCYST stage (100 cells ) • INACTIVATED X CHR FORMS A BARR BODY • RANDOM • INCOMPLETE • ALL X CHROMOSOMES ARE INACTIVATED EXCEPT ONE • Eg. If there are three X chromosomes in a cell = 2 Barr bodys

35. X-linked dominant inheritance

36. X-linked dominant inheritance

37. Examples of X- liked dominant inheritance • Fragile X syndrome • Hypophosphatemic rickets

38. X-linked recessive • The disorder is observed only in males. Females? • The characteristic family pedigree shows skipped generations • Father-to-son transmission does not occur • Males are usually sterile. • Heterozygous females are clinically normal but may be mildly affected depending on the skew of the X chromosome inactivation.

39. X-linked recessive Sons always affected

40. X-linked recessive

41. Y-linked inheritance • Only males affected • Transmission from father to all his sons • Hairy ears – hypertrichosis • Webbed toes. • Because the Y-chromosome is small and does not contain many genes, few traits are Y-linked, and Y-linked diseases are rare

42. Y-linked inheritance

43. Mitochondrial inheritance • Usually Mother to all the children • Sometimes sporadic • Affected males will not transmit the disease Affected Male doesn’t transmit the disease

44. Mitochondrial inheritance

45. Decision tree

46. PENETRANCE • The penetrance of a disease –causing mutation is the percentage of individuals who are known to have the disease-causing genotype who display the disease phenotype (or develop disease symptoms )

47. Incomplete Penetrance • Some individulals who have the disease genotype don’t display the phenotype • Fragile X syndrome :Males 100% penetrance Females 60% penetrance Calculation :- Recurrent risk = Calculated risk X penetrance

48. Variable expression • Effect of Environment • Allelic Heterogeneity • Modifier Loci • Incomplete Penetrance

49. Genetic heterogeneity • It is a phenomenon in which it includes a number of phenotypes that are similar but are actually determined by different genotypes.  • Allelic heterogeneity – different mutations in a single locus. • May cause less severe or more severe symptoms • Example – Missense mutation in factor VIII gene tend to produce less severe hemophilia than non-sense mutations which result in a truncated protein.

50. Locus heterogeneity – Same disease caused by mutations in different loci Example –Osteogenesisimperfecta Two members of the trimer are encoded by a gene on chromosome 17, and a third by a gene on Chr 7.Mutations of either of these faulty collagen.Often we cannot distinguish clinically b/w mutations in Chr 17 and Chr7. Modifier Loci – Disease expression may be affected by the action of other loci. Often these are not identified.